Hum Reprod Update. 2019 Jul; 25(4): 397–421.
Total, the incidence of male reproductive disorders has elevated in most trendy a long time. Testicular constructing accurate through fetal life is essential for subsequent male reproductive characteristic. Non-genomic components such as environmental chemical substances, pharmaceuticals and standard of living had been proposed to impact on human fetal testicular constructing ensuing in subsequent outcomes on male reproductive correctly being. Even as experimental analysis using animal fashions occupy equipped enhance for this hypothesis, extra now not too prolonged within the past quite loads of experimental analysis using human tissues and cells occupy begun to translate these findings to resolve assert human relevance.
OBJECTIVE AND RATIONALE
The aim of this systematic overview became to give a comprehensive description of the evidence for outcomes of prenatal exposure(s) on human fetal testis constructing and characteristic. We most trendy the implications of environmental, pharmaceutical and standard of living components in experimental systems interesting exposure of human fetal testis tissues and cells. Comparability is made with reward epidemiological data basically derived from a most trendy meta-prognosis.
For identification of experimental analysis, PubMed and EMBASE had been looked for articles revealed in English between 01/01/1966 and 13/07/2018 using search phrases including ‘endocrine disruptor’, ‘human’, ‘fetal’, ‘testis’, ‘germ cells’, ‘testosterone’ and linked search phrases. Abstracts had been screened for quantity of elephantine-text articles for added interrogation. Epidemiological analysis interesting exposure to the identical brokers had been extracted from a most trendy systematic overview and meta-prognosis. Extra analysis had been known through screening of bibliographies of elephantine-texts of articles known throughout the preliminary searches.
A total of 25 experimental analysis and 44 epidemiological analysis had been included. Fixed outcomes of analgesic and phthalate exposure on human fetal germ cell constructing are demonstrated in experimental fashions, correlating with evidence from epidemiological analysis and animal fashions. Moreover, analgesic-introduced about good purchase in fetal testosterone production, which predisposes to the enchancment of male reproductive disorders, has been reported in analysis interesting human tissues, which additionally supports data from animal and epidemiological analysis. On the opposite hand, whereas reduced testosterone production has been demonstrated in animal analysis following exposure(s) to a fluctuate of environmental chemical substances including phthalates and bisphenol A, these outcomes aren’t reproduced in experimental approaches using human fetal testis tissues.
Affirm experimental evidence for outcomes of prenatal exposure(s) on human fetal testis constructing and characteristic exists. On the opposite hand, for many exposures the details is proscribed. The increasing employ of human-linked fashions systems in which to resolve the implications of environmental exposure(s) (including blended exposures) on constructing and characteristic of human tissues ought to beget a actually powerful half of the intention for analysis of such exposures by regulatory our bodies to lift account of animal–human variations in susceptibility.
Keywords: human fetus, testis, endocrine disruptor, environmental chemical, pharmaceutical, testosterone, germ cell, Leydig cell, Sertoli cell, steroidogenesis
Pattern of the male reproductive system and its subsequent characteristic is impacted by events that occur in utero. Perturbations in testicular constructing or characteristic accurate through fetal life might perhaps perhaps also result in male reproductive disorders that most trendy postnatally (van den Driesche et al., 2017). This entails anatomical abnormalities known at initiating, such as cryptorchidism and hypospadias, or disorders presenting in adulthood, including testicular cancer or infertility (Sharpe and Skakkebaek, 2008). These associated disorders are collectively generally known as the testicular dysgenesis syndrome (TDS). The intention of TDS has been shown in rats to be influenced by a good purchase in androgen production or action accurate through a key duration of fetal life, generally known as the masculinization programming window (MPW) (Welsh et al., 2008; van den Driesche et al., 2017). The increasing incidence of TDS disorders over most trendy a long time, highlights the possible significance of environmental impacts in their etiology (Skakkebaek et al., 2016). Environmental components which had been proposed to impress fetal testis constructing and predispose to TDS disorders consist of environmental chemical substances (e.g. plasticizers and pesticides), pharmaceuticals (e.g. analgesics, metformin and diethylstilboestrol) and standard of living components (e.g. weight-reduction blueprint, alcohol and smoking) (Habert et al., 2014; Kilcoyne and Mitchell, 2017).
In describe to snatch how in-utero exposures might perhaps perhaps also disrupt fetal constructing and result in postnatal testicular disorders, it is serious to think in regards to the same earlier constructing of the germ and somatic cell populations within the human fetal testis (Fig. 1). During fetal life, germ cells migrate into the establishing gonad (4–5 weeks in human) where they endure differentiation from gonocytes to spermatogonia. This transition takes location accurate through fetal and early postnatal life and entails the loss of expression of pluripotency components (e.g. POU5F1) and secure of differentiated germ cell-explicit protein expression (e.g. MAGEA4) (Mitchell et al., 2008). Failure of gonocyte differentiation can result within the enchancment of pre-malignant germ cell neoplasia in-situ cells (GCNIS), which outcomes within the enchancment of testicular germ cell cancer (TGCC) in adulthood (Rajpert-De Meyts et al., 2016) whereas loss of germ cells as a outcomes of in-utero events can additionally presumably impact future fertility.
Testicular constructing and characteristic accurate through fetal life and reproductive disorders associated with testicular dysgenesis syndrome. DHT, dihydrotestosterone.
Germ cell constructing accurate through fetal life is supported by somatic cells that beget the germ-stem cell area of interest. Sertoli cells surround the gonocytes, forming seminiferous cords, at ~6–7 gestational weeks (GW) within the human (O’Shaughnessy and Fowler, 2011; Heeren et al., 2015). Sertoli cells are traditional for germ cell constructing (Bitgood et al., 1996), regression of the Müllerian ducts (AMH, anti-Müllerian hormone) and initiation of fetal Leydig cell differentiation (Pierucci-Alves et al., 2001; Yao et al., 2002; Griswold and Behringer, 2009).
Fetal Leydig cells are most trendy within the interstitium of the testis from six GWs in other folks and are guilty for the production of hormones occupied with testicular descent. Insl3 is occupied with the transabdominal segment of testicular descent, whereas testosterone is required to enable the testis to traverse the inguinal canal (Hughes and Acerini, 2008). Leydig cell-derived testosterone is additionally converted to dihydrotestosterone (DHT) in peripheral tissues for masculinization of the fetus, which includes constructing of external genitalia. Therefore, perturbations to the characteristic of fetal Leydig cells can predispose to the enchancment of male reproductive disorders including TDS and some disorders of sex constructing (DSD) (van den Driesche et al., 2017).
The bulk of experimental analysis investigating the implications of environmental exposures on fetal testis constructing and characteristic involve rodents. These analysis occupy equipped an amazing amount of precious data highlighting the possible of outcomes of in-utero exposure to a extensive form of environmental chemical substances on male reproductive constructing. On the opposite hand, there are indispensable variations in fetal testicular constructing between rodent and human in phrases of germ cell constructing (McKinnell et al., 2013) and steroidogenesis (Scott et al., 2009). Moreover, the exposures extinct for these analysis might perhaps perhaps also now not replicate the stages of exposure which would be accurate away linked to other folks. Review of experimental analysis using experimental animal fashions must lift account of the diversifications in mannequin systems (in-vitro versus in-vivo), exposure regimen and drug metabolism, whereas additionally accounting for the impact of species variations for each of these parameters (Kilcoyne and Mitchell, 2017). Which potential, animal analysis in most cases inform findings basically basically based on relative exposures which exceed human-linked exposures, in most cases by several orders of magnitude.
In describe to secure data on the possible of in-utero environmental exposures to impact constructing of male reproductive disorders in other folks, epidemiological analysis might perhaps perhaps also additionally be employed. A most trendy systematic overview has described the epidemiological evidence for associations between prenatal exposures and male reproductive disorders in other folks (Bonde et al., 2016). deal of indispensable concerns desires to be utilized when assessing epidemiological evidence for such associations. These consist of, nonetheless aren’t restricted to (i) the relevance and/or size of the inhabitants neighborhood, (ii) measurement of the exposure (assert/oblique) (iii) biological plausibility for the exposure on my own causing the attain and elimination of possible confounders (reviewed in Foster et al., 2017) (Fig. 2 and Table I).
Comparability of approaches to evaluating the implications of environmental and pharmaceutical exposures on human fetal testis constructing and characteristic. TGCC, testicular germ cell cancer.
Key concerns for the analysis of human analysis using epidemiological, or experimental (xenograft or in-vitro) approaches.
|Inhabitants||Skill limitation—inhabitants/tissue extinct might perhaps perhaps even be unrepresentative of target inhabitants/tissue|
|Agent||Skill limitation—agent below investigation might perhaps perhaps even be now not be representative of the exposure below investigation (e.g. metabolite) or there might perhaps perhaps even be extra confounding brokers|
|Publicity||Skill limitation—analysis of exposure in epidemiological analysis or regimen extinct in experimental analysis might perhaps perhaps also now not accurately replicate appropriate human exposure|
|Timing||Skill limitation—timing of analysis of exposure in epidemiological analysis or developmental stage of tissue extinct in experimental analysis might perhaps perhaps also now not accurately replicate the linked stage|
|Live||Skill limitation—the implications of exposure might perhaps perhaps even be measured accurate away or through affiliation and assert outcomes of exposure might perhaps perhaps also now not result in scientific penalties|
While human epidemiological and animal experimental analysis are extraordinarily informative, there stays an amazing hole in our figuring out of how explicit environmental exposures might perhaps perhaps also accurate away impact the human fetal testis. Therefore, constructing of mannequin systems using human fetal tissues and human-linked doses can bridge the outlet between assert evidence from animal experimental fashions and oblique evidence basically basically based on epidemiological data. deal of most trendy analysis occupy utilized in-vitro or xenograft approaches using human fetal testis tissues to resolve the attain of environmental and pharmaceutical exposures. As with epidemiological analysis, there are quite loads of key concerns when decoding the implications of these analysis in terms of mannequin system, exposure regimen and biological relevance of the measured final result (Fig. 2 and Table I).
A comprehensive overview of the experimental evidence for outcomes of environmental exposures on fetal testicular constructing and characteristic using human cells or tissues has now not previously been reported. This systematic overview will component the experimental evidence for impacts of environmental chemical substances, pharmaceuticals and standard of living components on human fetal testis constructing and characteristic. For each class of exposure for which human experimental evidence exists, we are able to first summarize the findings of animal analysis after which provide a critical overview of the epidemiological evidence. We can then list in component the evidence to enhance or refute these findings basically basically based on experimental fashions using human fetal testis tissues.
The analysis became designed as a scientific overview of the revealed literature in terms of the implications of in-utero exposures on human fetal testis constructing and characteristic in experimental fashions. The analysis adopted the principles of the PRISMA guidelines for reporting systematic opinions (Moher et al., 2009). The protocol for looking and assessing the literature became resolute earlier than the launch of the literature search. It is now not currently imaginable to register laboratory experimental analysis with PROSPERO.
We performed an on-line search of PubMed and EMBASE (13/07/2018) to title all experimental analysis in terms of testicular outcomes of fetal exposures to environmental, pharmaceutical and standard of living components, restricted to appear at utilizing human fetal tissues or cells. For identification of linked epidemiological analysis, we included the publications known in a most trendy systematic overview and meta-prognosis of associations between prenatal exposures and male reproductive disorders (Bonde et al., 2016). Extra epidemiological analysis had been known from the reference lists of the screened articles.
Eligibility for inclusion
We performed a scientific search of customary publications basically basically based on the following standards for inclusion: English language articles revealed between 01/01/1966 and 13/07/2018; experimental analysis on exposure of human fetal testis tissue or cells to a clearly defined environmental, pharmaceutical or standard of living component; and outcomes including outcomes on testicular hormone production (e.g. testosterone, Insl3, AMH), germ or somatic (Sertoli, Leydig) cell constructing.
We excluded analysis basically basically based on the following standards: exposure of tissues or cells representative of a duration diversified than fetal life; exposure of non-testicular tissues or cells; outcomes diversified than these described above; and overview articles.
Search and analysis decision
We searched the databases using a mixture of medical self-discipline headings and generic phrases in terms of outcomes of exposures on human fetal testis constructing (Supplementary Table S1). We known 3229 hits. Each and each authors screened the titles and/or abstracts independently to evaluate eligibility. Stout texts had been requested for analysis that included within the abstract using human fetal testis tissue or cells and the attain of exposure to environmental, pharmaceutical or standard of living components. Stout texts for 40 analysis had been obtained and a total of 25 publications had been included within the overview of experimental evidence (Supplementary Table S2; Fig. 3). A total of 15 analysis had been excluded (Supplementary Table S3). A extra 44 publications had been included within the overview of epidemiological evidence (Supplementary Table S4).
Reviews included in-vitro and ex-vivo (xenograft) approaches and outcomes had been assessed basically for outcomes on testosterone secretion and on germ cell quantity (both expressed as % swap when put next with car preserve watch over). Outcomes on extra testicular hormones, AMH (produced by SC) and Insl3 (produced by LC) are additionally reported.
The distribution of analysis basically basically based on exposure form and yr of e-newsletter is shown in Fig. 4. The bulk of the analysis had been revealed from 2007 to 2018. The earlier analysis basically investigated phthalates, pesticides and smoking, whereas extra most trendy analysis occupy mainly centered on bisphenols and analgesics.
Different of publications interesting experimental exposures to environmental brokers and pharmaceuticals using human fetal testis tissues or cells. DES, diethylstilboestrol. For (A) ‘All Publications’, a breakdown of the investigated brokers into (B) environmental, (C) pharmaceutical and (D) standard of living is included. NB: Some publications consist of exposure to several diversified brokers.
Environmental chemical substances
Phthalates are a class of commercial chemical substances extinct mainly to soften polyvinyl chloride-basically basically based products and are tag in a huge fluctuate of traditional plastic products. Publicity to phthalates might perhaps perhaps also occur through inhalation, ingestion or assert contact with objects including packaging, oils, food storage and deepest care products. Phthalates aren’t kept within the body nonetheless are as a change like a flash metabolized into monoesters with a urinary excretion half of-life of <24 h (Koch et al., 2012). Commonly used plasticisers over recent decades include di-(2-ethylhexyl) phthalate (DEHP) which is converted to its monoester metabolite, mono-2-ethylhexyl phthalate (MEHP) and di-n-butyl phthalate (DBP), which is metabolized to mono-n-butyl phthalate MBP. In 2015, DEHP was banned from general use under EU law under the REACH restriction (Registration, Evaluation, Authorization and Restriction of Chemical Substances) and has been replaced by di-isononyl phthalate (DiNP), and more recently di-isononyl cyclohexane-1,2-dicarboxylate (DINCH), both of which are deemed less biologically active (Gray et al., 2000). Recent biomonitoring data has shown that DiNP metabolites measured in human urinary samples are increasing in both America (Silva et al., 2013) and Europe (Goen et al., 2011).
The majority of published experimental studies investigating the effects of in-utero exposure to certain phthalates (primarily DEHP or DBP) have used rodent models and have demonstrated a disruption of normal fetal testis development and subsequent development of male reproductive disorders, resulting from decreased fetal testosterone production in male offspring (Parks et al., 2000; Mylchreest et al., 2002; Habert et al., 2014; Kilcoyne et al., 2014; Fisher et al., 2016). Moreover, effects primarily result from exposure during the MPW (Welsh et al., 2008; Kilcoyne et al., 2014; van den Driesche et al., 2017) which is believed to equate to ~8–14 weeks gestation in humans (Scott et al., 2009; Fowler et al., 2011).
Epidemiology – DBP/MBP
In humans, DBP is rapidly metabolized (primarily to MBP) and excreted (Koch et al., 2012). Therefore measuring the effects of phthalate exposure on fetuses in pregnant women is challenging. Despite this, urinary concentrations of several phthalate metabolites (including MBP) have been shown to be positively correlated with the incidence of male developmental abnormalities in the newborn, such as cryptorchidism and shortened anogenital distance (AGD; a biological readout of fetal testosterone exposure) (Marsee et al., 2006). Further indirect evidence for effects of maternal MBP/DBP exposure on steroidogenesis in the human fetal testis has also been reported in retrospective association studies (Marsee et al., 2006; Swan, 2008). These studies demonstrate a negative correlation between maternal urinary MBP concentration and AGD in males, although the changes are minor. However, a separate small prospective study failed to find any correlation (Huang et al., 2009). Furthermore, whilst an association between urinary MBP during second and third trimester and AGD has been demonstrated (Swan et al., 2005), a similar study has shown no such association when urinary MBP is measured during the first trimester (Swan et al., 2015).
Several phthalate monoesters have been detected in maternal breast milk over a large concentration range (1.5–1 410 μg/L) and these have been correlated with infant hormone levels (Main et al., 2006). Despite the reported association between phthalates (including MBP) in maternal breast milk and altered testosterone levels of infant males (Main et al., 2006), a recent study did not detect significant associations between MBP concentrations in breast milk and either testosterone or INSL3 in newborns (Chevalier et al., 2015). Importantly, this study found no association between MBP in breast milk and the presence of cryptorchidism, consistent with maternal MBP concentrations postnatally not being associated with human fetal testosterone production.
Phthalates, including DBP, have also been used in the enteric coating of several commonly used medications including proton pump inhibitors (e.g. omeprazole) and anti-epileptics (e.g. valproate, carbemazepine) (Kelley et al., 2012; Jamieson and McCully, 2015). This can result in an increase in urinary phthalate levels in the region of 50–100 times, compared with the general population (Hernandez-Diaz et al., 2009; Seckin et al., 2009; Hait et al., 2014). As a result, it may be expected that the regular use of these medications during pregnancy may be associated with an increased risk of male reproductive disorders in the offspring of exposed mothers. DBP has been used in the coating of mesalazine (a 5-aminosalicylic acid drug), an anti-inflammatory agent used to treat inflammatory bowel disease (IBD). Several studies have reported the pregnancy outcomes for women taking 5-ASA drugs during pregnancy and a meta-analysis of 2200 pregnant women with IBD has reported no increased incidence of congenital abnormalities as a result of exposure to mesalazine during pregnancy (n = 642), in comparison to non-exposed mothers with IBD (n = 1158) (Rahimi et al., 2008). It is important to point out that a limitation of the studies included in the meta-analysis is that they were not specifically designed to identify associations with male reproductive disorders; however, it is reassuring to note that none of the studies to date have reported an increase in the development of these disorders. Prospective studies designed to answer this specific question would be desirable, although conducting such studies will be challenging due to the widespread removal of DBP from these medications.
Epidemiology – DEHP/MEHP
DEHP has been detected in fetal cord blood samples (of 1.1 × 10−8 M) and cord blood of newborns (Latini et al., 2003; Lin et al., 2011), demonstrating that fetal exposure to DEHP can begin from an early stage. MEHP, measured in the urine of pregnant women (n = 111; 9–40 weeks gestation) has been associated with a significant reduction in AGD in male offspring (Suzuki et al., 2012). DEHP metabolites in pregnant women during the first trimester have been shown to be significantly and inversely related with AGD in male newborns (n = 366) (Swan et al., 2015), whereas no such association was identified for maternal urinary MEHP in second or third trimesters (Swan et al., 2005). A similar inverse relationship between the anoscrotal distance (AGDas) in newborn males (n = 168) and maternal DEHP metabolite, concentrations specifically during the first trimester, has also been described (Martino-Andrade et al., 2016). These findings are in contrast to a Swedish study which found no significant association between first trimester concentrations of DEHP metabolites in mothers and AGDas in 196 males aged 21 months (Bornehag et al., 2015). Interestingly, this is despite the authors reporting a significant association between AGDas (4% reduction) and some DiNP metabolites (Bornehag et al., 2015).
The timing of measurement of exposure may be important given that whilst an association between first trimester maternal urine concentrations of DEHP and AGDas have been described, no association was found for second or third trimester DEHP concentrations (Martino-Andrade et al., 2016). Another recent study measured urinary phthalates (including DEHP metabolites) concentration in pregnant women during late second and third trimester and reported no association between prenatal phthalate exposure and AGD in male offspring (n = 273) at 3 months of age (Jensen et al., 2016). Furthermore, a study involving measurement of 5cx-MEPP (a DEHP metabolite) in amniotic fluid during the second trimester found no association with cryptorchidism or hypospadias (Jensen et al., 2015).
Experimental evidence from human studies
Investigating phthalate exposure directly using human fetal testis is challenging; however, several studies have utilized in-vitro cell or tissue culture and/or in-vivo xenograft models to explore potential human effects (Table II).
Summary of experimental studies investigating effects of phthalate exposure in human fetal testis tissue.
DBP/MBP – Hormones
Effects of exposure to DBP/MBP have been investigated in human fetal testis tissues using in-vitro or xenograft approaches. In-vitro exposure of second trimester human fetal testis explants to MBP had no effect on (basal or hCG stimulated) testosterone production after 48 h (Hallmark et al., 2007), whilst the same study demonstrated a reduction in testosterone production in fetal rat testis explants after hCG stimulation (Hallmark et al., 2007). Use of an ex-vivo xenograft system may represent a more physiological approach to investigating potential effects of phthalates on the human fetal testis. Despite several studies xenografting first and/or second trimester human fetal testes into different host species, and at different locations (rat; renal subcapsular space) (Heger et al., 2012; Spade et al., 2014) (mouse; subcutaneous tissue) (Mitchell et al., 2012), no effects on steroidogenic gene expression, seminal vesicle weight or circulating testosterone levels were identified at levels of exposure equivalent to those used in rat pregnancy studies, which are far in excess of human exposure. This included varying duration of DBP exposure for 4 or 21 days (Mitchell et al., 2012) or for 14 days (Heger et al., 2012; Spade et al., 2014). Furthermore, substituting MBP instead of DBP for 21 days also had no effect on testosterone production from xenografts (Mitchell et al., 2012). Exposure of human fetal testis xenografts to DBP at varying doses (100, 250, 500 mg/kg) over a more limited time-window (24, 48, 72 h) did not alter mRNA expression of Leydig cell genes including several steroidogenic genes and the hormone Insl3 (produced by Leydig cells and involved in testicular descent) (Heger et al., 2012).
Further support for the lack of effect of exposure to DBP/MBP on testosterone production and development of male reproductive disorders in primates is evident following in-utero exposure of marmoset monkeys to MBP (McKinnell et al., 2009). Pregnant marmosets (n = 5–6) were dosed with 500 mg/kg MBP from ~7 to 15 weeks gestation and testicular and male reproductive effects were assessed in the neonate or adult. No effects on testicular morphology or germ cell number were identified at birth or adulthood following in-utero MBP exposure and testosterone levels at birth were unaffected. Importantly, there were no cases of hypospadias, cryptorchidism, impaired spermatogenesis or focal testicular dysgenesis in any of the exposed animals (McKinnell et al., 2009).
DBP/MBP – Germ cells
Despite the lack of effect of DBP exposure on testosterone production or steroidogenic gene expression in the human fetal testis, abnormal morphology of germ cells within the seminiferous cords has been described following DBP exposure in the xenograft model, including an increase in the number of multi-nucleated gonocytes (MNGs) (Heger et al., 2012). Furthermore, DBP-exposure (500 mg/kg) for 21 days in a similar xenograft model reduced the number of gonocytes and induced a higher proportion of MNGs in human fetal testes (van den Driesche et al., 2015b). These effects of DBP exposure, namely reduced gonocyte number and increased MNGs, is in keeping with findings from rodent studies using comparable DBP exposure (Ferrara et al., 2006; Jobling et al., 2011; van den Driesche et al., 2015b).
DEHP/MEHP – Hormones
In-vitro exposure of human first trimester testis to a range of doses of MEHP (10−4, 10−5, 10−6 M) using an organotypic culture system resulted in unchanged testosterone (basal or LH-stimulated) production compared to control after 72 h of culture (Lambrot et al., 2009). In keeping with a lack of effect on Leydig cell function, there was also no change in gene expression of steroidogenic enzymes or Insl3 (Lambrot et al., 2009). These results are in keeping with similar in-vitro (Hallmark et al., 2007) and xenograft (Heger et al., 2012; Mitchell et al., 2012; Spade et al., 2014) studies involving DBP/MBP exposure of human fetal testis tissue.
In addition to assessing effects of MEHP exposure on testosterone production in the human fetal testis, exposure of first trimester testis (7–12 weeks gestation) to 10−4 M MEHP for 72 h resulted in a reduction in AMH mRNA, although Sertoli cell-derived AMH protein expression was not affected (Lambrot et al., 2009).
DEHP/MEHP – Germ cells
Exposure of human first trimester testis tissue to MEHP (10−5 M) in-vitro via an organotypic culture system resulted in an approximately 40-50% increase in apoptotic gonocytes compared to control testis tissue (Muczynski and Cravedi et al., 2012). In-vitro studies using mouse fetal testis tissue conducted in parallel, demonstrated similar effects with a 30% reduction in gonocyte number and a 4-fold increase in the rate of apoptotic gonocytes (Muczynski and Lecureuil et al., 2012). These results support the findings of a previous study in first trimester human fetal testes exposed to a range of doses of MEHP (10−4, 10−5, 10−6 M) for 72 h. Using a similar in-vitro system, MEHP-exposure resulted in a 40% reduction in germ cell number via increased apoptosis (without altering GC proliferation) at both 10−4 and 10−5 M MEHP under basal conditions, whilst 10−5 M MEHP resulted in a reduction in gonocyte number under basal and LH-stimulated conditions (Lambrot et al., 2009). As described for DBP/MBP, the germ cell effects were similar between MEHP-exposed human and mouse fetal testes, as gonocyte number was also significantly reduced in mouse fetal testes after MEHP exposure, via an increase in apoptotic gonocytes (Chauvigne et al., 2009; Lehraiki et al., 2009). However, in-vitro organ culture of fetal rat testes (at embryonic Day 13 or 18) with MEHP showed no effect on the mitotically quiescent germ cells (Li and Kim, 2003).
Exposure to DBP/DEHP has consistently been shown to reduce fetal testosterone production resulting in a high frequency of TDS disorders in rats, whereas epidemiological studies have reported inconsistent associations between maternal phthalate exposures and indirect measures of fetal testosterone production, namely AGD, and no studies have reported an association between phthalate exposure and either cryoptorchidism or hypospadias. In addition, no effects of phthalates on testosterone production have been described in experimental models using in-vitro culture or xenografting of human fetal testis tissues and a single in-vivo study in a non-human primate. This is despite administration of phthalate doses that far exceed environmental/human exposure levels and includes exposure during the proposed MPW. Furthermore, the in-vivo study involving in-utero exposure of marmoset monkeys failed to demonstrate the development of male TDS disorders that result from a reduction in testosterone. Taken together the results indicate that exposure to environmental levels of DBP/DEHP are unlikely to result in effects on fetal testosterone production in humans. Interestingly, whilst no effects of phthalate exposure have been demonstrated in human fetal testes, anti-androgenic effects have been shown to occur in adult human testis following in-vitro culture, suggesting that the effect of exposure is dependent on the developmental stage of the testis (Albert and Jegou, 2014).
However, for germ cells effects, the results of experimental studies in rodents and human fetal tissues are more consistent, with a reduction in gonocyte number and an increase in multi-nucleated gonocytes being reported in several studies following phthalate exposure. The implications of these findings in terms of future fertility are uncertain.
Bisphenols are synthetic chemicals, widely used in the manufacture of hard plastic products. Bisphenol A (BPA) is also a component of epoxy-resins, used as the inner coating of metallic food and beverage cans. BPA has weak estrogenic properties, albeit several orders of magnitude less potent than endogenous 17β-oestradiol (Leffers et al., 2001).
In-vivo rodent studies have reported conflicting results regarding the effect of in-utero BPA exposure on testosterone production by the fetal testis. Exposure of pregnant rats to high concentrations of BPA throughout pregnancy was associated with a reduction in testosterone production in male fetuses around birth (Tanaka et al., 2006), whilst other studies have reported no effect of in-utero exposure to BPA on AGD in male offspring (Kobayashi et al., 2002; Howdeshell et al., 2008). In-vitro studies have demonstrated a reduction in testosterone production in mouse and rat fetal testis following exposure to high concentrations of BPA (N’Tumba-Byn et al., 2012). Given the conflicting results of animal studies involving BPA, a large collaborative study (CLARITY-BPA) is currently being undertaken in rodents to determine the effects of BPA on a range of body systems including reproductive organs (Schug et al., 2013). A recent publication from the consortium reported no effects of combined in-utero and postnatal exposure on several testicular morphometric and histological endpoints, including adult testis weight, except at very high doses that far exceed environmental exposure (Dere et al., 2018).
A limited number of epidemiological studies have investigated the relationship between human pregnancy exposure to BPA and male reproductive disorders. In a study involving measurement of cord blood in 52 newborn boys with cryptorchidism and 126 controls, no association was found between BPA exposure and testosterone; however, a significant negative correlation between BPA and Insl3 was identified (Chevalier et al., 2015). Given that Insl3 and testosterone are both involved in testicular descent, it is interesting to note that there was no association between BPA levels in cord blood and cryptorchidism (Fenichel et al., 2012; Chevalier et al., 2015). Similarly, in another case-control study, no association was identified between BPA exposure, as measured in maternal urine, and cryptorchidism in the male offspring (Chevrier et al., 2012). The relationship between BPA and cryptorchidism has also been investigated in 98 boys with unilateral cryptorchidism aged 1–4 years. Serum BPA was measured prior to surgery and a significant association was found between total BPA and cryptorchidism in boys compared to 57 healthy controls (Komarowska et al., 2015). However, no association was found between free (unconjugated) BPA and cryptorchidism and it is of interest to note the wide variation and high degree of overlap between the BPA levels of the two groups. An association between urogenital abnormality (cryptorchidism or hypospadias) and free BPA levels in term placenta was also described in a study involving 79 boys (Fernandez et al., 2016). In this study, placental BPA was significantly higher in the cases compared to controls; however, an association between BPA and cryptorchidism/hypospadias was only apparent for the upper tertile of BPA exposure which included just 26 (12 cases and 14 controls) boys (Fernandez et al., 2016). In addition, this study was not able to assess BPA exposure during fetal life which temporally separates the measurement of the exposure from the development of the disorder. An association has been described between maternal occupational exposure to BPA and AGD in 56 exposed male offspring when compared to 97 unexposed controls (Miao et al., 2011). Care must be taken when interpreting this data as the exposure to BPA was determined by personal air sampling with extrapolation to estimate past exposure for the index pregnancy.
Experimental evidence from human studies
Several experimental studies have investigated the effect of BPA exposure using human fetal testis tissue and cells (Table III). A key consideration when assessing the results of experimental studies involving effects of exposure(s) on the human fetal testis is the concentration/doses to which the tissue is exposed. For BPA, human internal exposure to unconjugated BPA has been reported to be in the range 10−2 M to 10−3 M, including in pregnant women (Vandenberg et al., 2010) and mean cord blood levels have been reported closer to 10−3 M (Fenichel et al., 2012). However, a recent study involving 48 samples from 30 healthy pregnant women, which accounted for potential post-sampling contamination, reported serum BPA concentrations below the LOD apart from 12 (25%) samples which ranged from 10−9 to 10−12 M, demonstrating that exposures may be substantially lower than previously reported (Teeguarden et al., 2016).
Summary of experimental studies investigating effects of bisphenol exposure in human fetal testis tissue.
A number of studies have investigated the effect of exposure to BPA on testosterone production by human fetal testis tissue using an in-vitro system (N’Tumba-Byn et al., 2012; Ben Maamar et al., 2015; Eladak et al., 2015). Exposure of human fetal testis explants (6–11 GW) to BPA did not affect testosterone production at a concentration of 10−12 M; however, exposure to higher concentrations (10−8 to 10−5 M) resulted in a reduction of 20–50% (N’Tumba-Byn et al., 2012). Further studies have compared the effect of BPA exposure under basal and gonadotrophin supplemented conditions (Ben Maamar et al., 2015; Eladak et al., 2015). Exposure of human fetal testis explants (7–12 GW) to 10−5 M BPA for 72 h resulted in a significant reduction in testosterone production under basal (70%), hLH- (30%) and hCG-stimulated (60%) conditions (Ben Maamar et al., 2015; Gaudriault et al., 2017). However, exposure to lower concentrations did not result in significant differences except for 10−8 M under basal conditions in which a 30% reduction was reported (Ben Maamar et al., 2015). Similar results were obtained in another study in which exposure to BPA for 72 h under basal conditions resulted in a significant reduction in testosterone production by human fetal testis tissue (6–11 GW) across a range of concentrations (10−8 to 10−5 M), whereas reduction in testosterone only occurred at the highest concentration (10−5 M) under hLH supplemented conditions (Eladak et al., 2015). Two separate studies using the xenograft system have also investigated the effect of BPA on testosterone production using first and second trimester human fetal testis tissue (Eladak et al., 2015; Eladak et al., 2018). Exposure of host mice to 10−5 M BPA in drinking water for 5 weeks did not affect testosterone production from xenografted tissue, as measured by host mouse seminal vesicle weight or serum testosterone. Importantly, the authors were able to demonstrate that the plasma levels of unconjugated and total BPA were significantly higher in the BPA exposed host mice compared to the vehicle controls. Similarly, for second trimester xenografts, daily oral gavage of host mice with 0.5 or 50 μg/kg BPA for 5 weeks did not impact on testosterone production (Eladak et al., 2018). In both xenograft studies, hCG was administered to the host mice to mimic the hormonal environment of pregnancy as previously described (Mitchell et al., 2010).
The use of gonadotrophin supplementation in the in-vitro and ex-vivo systems is a key consideration. Supplementation of media with hCG was able to maintain testosterone levels across the culture period, as opposed to hLH or basal conditions in which testosterone levels declined during culture under control (no BPA) conditions (Ben Maamar et al., 2015). The demonstration that BPA effects are largely eliminated in the human fetal testis by addition of hLH in the media, indicates that under physiological conditions of pregnancy, in which gonadotrophin (hCG and/or LH) levels are extremely high, environmental exposure to BPA is unlikely to affect testosterone production in the human fetal testis (Eladak et al., 2015). Moreover, a recent study has investigated the effects of alternative bisphenols that have been proposed as replacements for BPA (Eladak et al., 2015). For unstimulated conditions, similar effects to those of BPA occurred following exposure to high concentrations of BPS, BPE and BPF, although the effects tended to be of lower magnitude and towards the higher concentrations compared to BPA (Eladak et al., 2015; Gaudriault et al., 2017).
AMH production from Sertoli cells appears to be unchanged as a result of BPA exposure in the human fetal testis (Ben Maamar et al., 2015).
Insl3 is reduced following in-vitro exposure of human fetal testis to BPA (Ben Maamar et al., 2015). This occurred only at the highest (10−5 M) and lowest (10−8 M) concentrations of BPA tested and also only under basal conditions. However, levels of Insl3 were generally much lower in these basal conditions than in media supplemented with hLH or hCG. For gonadotrophin supplemented cultures, BPA did not affect Insl3 production at any of the concentrations tested, similar to the results already described for testosterone (Ben Maamar et al., 2015).
A recent study has investigated the effects of BPA exposure on germ cells in the human fetal testis. For first trimester testis (6–12 GW) using the in-vitro approach, exposure to 10−5 M BPA resulted in a significant increase in the number of apoptotic gonocytes after 72 h, although there was no effect on apoptosis at lower concentrations (Eladak et al., 2018). In xenografts, long-term (5 weeks) exposure to high concentrations of BPA (10−5 M) in drinking water resulted in a modest (−19%) reduction in germ cells/mm2, indicating that a sustained increase in apoptosis of germ cells could reduce their number. Analysis of the individual germ cell populations demonstrated that there was a significant reduction in the proportion of germ cells expressing the gonocyte marker (AP2γ) with a reciprocal increase in pre-spermatogonial (MAGEA4) population. These findings are consistent with a reduction in gonocytes or alternatively an acceleration in the normal germ cell differentiation from gonocyte to pre-spermatogonium following BPA exposure (Eladak et al., 2018).
Animal studies investigating effects of BPA exposure on fetal testis development have reported inconsistent results for indicators of testosterone production and germ cell development. Similarly, results of epidemiological studies investigating association between BPA and clinical indicators of reduced fetal testosterone (cryptorchidism and hypospadias) are inconsistent. For experimental studies involving human testis tissue, whilst the results of in-vitro experiments indicate the potential for BPA to reduce testosterone production from the fetal testis, this has been under basal conditions and xenograft studies have failed to demonstrate similar effects in either first or second trimester human fetal testis under gonadotrophin stimulation, as occurs in normal pregnancy. Furthermore, typical human exposure is likely to be well below the concentrations used for experimental studies involving animal(s) or human tissues based on meta-analysis and latest data on human BPA exposure using LC/MS/MS (Teeguarden et al., 2016). Whilst germ cell effects have been described in one small study involving human fetal testis xenografts and relatively high BPA exposure (Eladak et al., 2018), future studies should focus on exposures within the human-relevant range and on potential effects during different periods of gestation in order to determine the potential for effects on germ cells and future fertility in humans.
Pesticides and fungicides
Pesticides and fungicides represent a heterogeneous group of chemicals widely used in agriculture. Many of these agents (e.g. Vinclozolin, Procymidone and prochloraz) are known to have anti-androgenic properties (Albert and Jegou, 2014). Whilst reproductive effects of many of these agents have been investigated in animal models (Taxvig et al., 2013) and epidemiological studies (Bonde et al., 2016), relatively few have been studied in experimental models involving the use of human tissues.
Several pesticides and fungicides have been proposed to be anti-androgenic with potential to impact testicular development and function in animal studies (Taxvig et al., 2013). This includes in-vivo studies demonstrating effects of in-utero exposure to the fungicides Procymidone (Ostby et al., 1999) or Prochloraz (Vinggaard et al., 2005) on fetal testosterone production in experimental animals. Given that these agents are known to act as anti-androgens via interfering directly with the androgen receptor (Robitaille et al., 2015), it can be hypothesized that effects occurring in rodent models might be more likely to be translated into human effects, as opposed to other agents (e.g. phthalates) in which the mechanism of action is less clear.
Whilst a number of epidemiological studies have reported associations between in-utero exposure to selected pesticides and the development of male reproductive disorders (Bonde et al., 2016), the majority of these studies involve different pesticides or exposure periods (e.g. outside the fetal period) to those investigated in experimental studies using human tissues. For studies in which human experimental data is available, epidemiological data exists only for Dieldrin (Damgaard et al., 2006; Shen et al., 2008). Higher concentrations of Dieldrin have been reported in the placentae of Danish compared to Finnish women. This correlates at the population level with the higher prevalence of cryptorchidism in Denmark than in Finland (Shen et al., 2008); however, a study of Danish subjects from the same cohort did not identify a significant association between Dieldrin in breast milk and the development of cryptorchidism, when compared to controls (Damgaard et al., 2006).
Experimental evidence from human studies
Experimental studies investigating the effects of exposure to pesticides on human fetal testicular development and function are limited. To date, only two studies have reported the effects of pesticide exposure on human fetal testis tissue/cells (Table IV). This includes a study investigating the effects of Dieldrin, an insecticide, on second trimester (14–16 GW) human fetal testis in an in-vitro system.
Summary of experimental studies investigating effects of pesticide exposure in human fetal testis tissue.
Exposure to concentrations of Dieldrin relevant to environmental and maternal serum levels in pregnancy (10−12 M to 10−9 M) did not affect testosterone production under basal conditions; however, testosterone (−30%) and gene expression of the steroidogenic enzyme ‘steroidogenic acute regulatory protein’ (StAR) were significantly reduced under LH-induced conditions (Fowler et al., 2007). No effect of Dieldrin exposure was found on AMH production from Sertoli cells. A more recent study investigated the effect of a wide variety of chemicals, including pesticides, on testosterone production in human fetal testis using an in-vitro culture system (Gaudriault et al., 2017). This study identified dose-dependent reductions in testosterone as a result of exposure to a range of pesticides including imazalil, propiconazole, bitertanol, prochloraz, chlordecone, and for the majority of these chemicals, exposure to ~10−5 M resulted in a 50% reduction in testosterone production compared to basal. For glyphosate and atrazine, there was no clear reduction in testosterone across the entire dose range and for ortho-phenylphenol, a reduction in testosterone was only demonstrated at the highest concentration (10−4 M).
Potential effects of exposure to pesticides and antifungals on germ cell development in the human fetal testis have been investigated in one study (Bendsen et al., 2001). The effects of 4-octylphenol, a surfactant used as a component of several pesticides, were investigated in prolonged (3 weeks) culture of first trimester (6–12 GW) human fetal testis tissue. Exposure resulted in a significant decrease in the mitotic index and in the number of spermatogonia per unit area compared to vehicle-exposed controls (Bendsen et al., 2001).
Summary—pesticides and fungicides
Evidence for effects of several pesticides have been described in a limited number of experimental studies using human fetal testis tissues. The majority of the agents investigated thus far have demonstrated a reduction in testosterone production following short term in-vitro culture. However, the relationship between the concentrations used for each individual agent and measures of human exposure remain to be elucidated. Furthermore, the possibility of correlating the results of epidemiological and experimental studies is hindered by the variation in agents investigated by each approach.
Over recent years, there has been increasing interest in the potential effects of pharmaceutical exposure during pregnancy on reproductive development and subsequent reproductive function in the offspring. The use of pharmaceuticals during pregnancy results in direct exposure to mother and the developing fetus. Therefore exposure to relatively high concentrations of the circulating drug may result, which contrasts with the very low level exposure to environmental chemicals such as those described above. In addition, for some pharmaceuticals (e.g. analgesics) the frequency of use during pregnancy may be high resulting in sustained exposures.
Analgesics are the most commonly used medications worldwide. Several of these are available without prescription and it has been reported in many countries that 50–90% of women will use an analgesic at some stage during pregnancy (Kristensen et al., 2016). Paracetamol (acetaminophen) is the most commonly used analgesic, whilst non-steroidal anti-inflammatory drugs (NSAIDs) including ibuprofen are also used by up to 15% of pregnant women (Kristensen et al., 2016).
Paracetamol exposure reduced fetal androgen production in rodents in studies using both in-vivo and in-vitro approaches (Kristensen et al., 2011, 2012; Axelstad et al., 2014; Holm et al., 2015; van den Driesche et al., 2015a), similar to findings for aspirin exposure following in-vivo (20% reduction in AGD) (Gupta and Goldman, 1986) or in-vitro (70% reduction in testosterone) (Kristensen et al., 2012) exposure. For indomethacin exposure in mice, results are conflicting in terms of fetal testosterone production, with one in-vivo study describing a 20% reduction in AGD (Gupta and Goldman, 1986), whilst rat studies described either no effect in vivo (Dean, Mungall et al., 2013), or a 30% reduction in fetal testosterone production in vitro (Kristensen et al., 2012).
The majority of studies that investigated associations between maternal analgesic exposure and cryptorchidism in male offspring have reported a significant positive association (Berkowitz and Lapinski, 1996; Jensen et al., 2010; Kristensen et al., 2011; Snijder et al., 2012), although this is not a consistent finding (Philippat et al., 2011). The timing of maternal exposure may be a key factor as most associations are reported to occur following prolonged exposure (>4 weeks) (Jensen et al., 2010) or accurate throughout the 2d trimester (Hurtado-Gonzalez and Mitchell, 2017), which would coincide with as a minimum half of the postulated serious human MPW duration (8–14 GW) (Welsh et al., 2008). purchase in fetal testosterone production, as demonstrated in experimental analysis described above, might perhaps perhaps also provide a mechanistic explanation for paracetamol-introduced about cryptorchidism in male offspring, despite the true fact that proving this in other folks is stressful. On the opposite hand, measurement of the AGD in offspring can provide an oblique be taught-out of fetal androgen production, linking the reported affiliation with the proposed mechanism (Dean and Sharpe, 2013). A most trendy analysis has shown an affiliation between paracetamol exposure (inclusive of the MPW) and reduced AGD in boys up to 24 months, self sustaining of body size (Fisher et al., 2016). On the opposite hand, for these epidemiological analysis, extrapolation of outcomes to assert scientific outcomes ought to be regarded as with caution, basically due to the inability of assert analgesic measurements and the reliance on retrospective questionnaires for exposure classification that will perhaps also involve a diploma of rob bias.
Experimental evidence from human analysis
Several most trendy analysis occupy investigated the attain of analgesics on human fetal testis using experimental fashions (Table V).
Summary of experimental analysis investigating outcomes of analgesic exposure in human fetal testis tissue.
Paracetamol – Hormones
In-vitro analysis using first trimester testis (8–12 GW) uncovered to paracetamol (10−5 M) for 1–3 days did now not alter testosterone production, when compared with car controls (Mazaud-Guittot et al., 2013). This became additionally the case for the paracetamol metabolite AM404 (10−5 M) (Mazaud-Guittot et al., 2013). A most trendy analysis using an organotypic in-vitro tradition system of first trimester human fetal testes explants confirmed that exposure to paracetamol in a dose fluctuate of 10−8 to 10−6 M elevated testosterone by 25%; on the opposite hand, elevated doses of 10−5 M and 10−4 M did now not occupy any attain on testosterone production (Gaudriault et al., 2017).
The conflicting outcomes between rodent and human in-vitro analysis might perhaps perhaps also portray to the stage of testis constructing (i.e. timing at some level of the MPW) or variations within the experimental system (Mazaud-Guittot et al., 2013). Caution ought to be exercised when relating outcomes using in-vitro fashions to the in-vivo space in other folks, because the faded can now not accurate away recapitulate same earlier pharmacokinetics, including in-vivo height and trough concentrations. To avoid some of the essential possible barriers of the in-vitro approaches for the human fetal testis, subsequent analysis occupy utilized an ex-vivo methodology interesting subcutaneous xenografting of human fetal testis tissues (n = 5; 14–20 GW) into host castrate nude mice. Oral exposure of these mice to a human-linked regimen of paracetamol (20 mg/kg; three times day-to-day) for 1 week a great deal reduced (−45%) host serum testosterone and seminal vesicle (androgen dependent organ) weight (−18%), unlike a single day-to-day exposure which had no attain on both parameter (van den Driesche et al., 2015a). Additional confirmation of the human relevance of paracetamol exposure is evident from the finding that 1 h after the the leisure dose in host mice, plasma paracetamol concentrations had been a great deal lower than put up-therapeutic stages reported in pregnant ladies (Rayburn et al., 1986). On the opposite hand, it desires to be regarded as that circulating paracetamol stages in pregnant ladies might perhaps perhaps also now not be a appropriate away indicator of intra-testicular stages within the establishing fetus.
Insl3 hormone production became a great deal reduced in first trimester human fetal testis cultures uncovered to paracetamol, in which a clear dose–response relationship with increasing paracetamol exposure (at 10−7 M to 10−4 M) became demonstrated (Mazaud-Guittot et al., 2013).
Paracetamol – Germ cells
An in-vitro analysis using first trimester human fetal testis (8–12 GW) uncovered to paracetamol (10−5 M) for 1–3 days found no alteration in germ cell quantity (Mazaud-Guittot et al., 2013). On the opposite hand, a extra most trendy in vitro analysis with a protracted duration (7 days) of exposure confirmed that identical paracetamol concentration (10−5 M) a great deal reduced (−28%) gonocyte quantity (Hurtado-Gonzalez et al., 2018). The differing findings in these analysis might perhaps perhaps also replicate the longer duration of exposure within the latter analysis or might perhaps perhaps even be the implications of variations within the tradition systems. To extra investigate the possible attain of paracetamol exposure on the human fetal testis, a xenograft methodology became additionally extinct alongside the in-vitro mannequin (Hurtado-Gonzalez et al., 2018). Xenografted 2d trimester tissue (14–20 GW) uncovered to paracetamol using a human-linked exposure regimen (20 mg/kg, three times day-to-day) resulted in a good purchase in gonocyte quantity after 7 days exposure (−32%). Curiously, a good purchase in gonocyte quantity (−17%) became additionally demonstrated after correct 1 day of exposure to paracetamol (Hurtado-Gonzalez et al., 2018).
Even as most of circulating paracetamol in other folks comes from employ of paracetamol-containing medications, an different provide has additionally been described. The industrial chemical aniline, which is tag in a extensive form of manufactured products, such as rubber, pharmaceuticals, cosmetics and cigarette smoke, is like a flash metabolized to paracetamol at some level of the body (Modick et al., 2014, 2016). Moreover, in-vivo analysis in which male mice uncovered in utero to aniline occupy shown identical fetal anti-androgenic outcomes to those described for exposure to paracetamol (Holm et al., 2015). Handiest one analysis has investigated the attain of aniline on the human fetal testis (Gaudriault et al., 2017). In-vitro exposure of first trimester (10–12 GW) human fetal testis to aniline for 96 h had no attain on testosterone production across a fluctuate of doses (10−8 M to 10−5 M) as antagonistic to a minute good purchase (−20%) for an intermediate concentration (10−7 M) (Gaudriault et al., 2017).
Ibuprofen – Hormones
Publicity of first trimester human fetal testis explants to ibuprofen using an organotypic tradition system did now not impact testosterone production (Gaudriault et al., 2017). On the opposite hand, one other in-vitro analysis reported a good purchase in steroidogenic enzyme expression across a identical fluctuate of concentrations (10−4 M, 10−5 M). This attain became finest evident for early first trimester testes (8–9 GW), as there became no attain at any diversified gestational time-level examined (<8 GW or >10 GW) (Ben Maamar et al., 2017). In a similar vogue, there became no attain of exposure to ibuprofen on testosterone production in host mice carrying xenografts of 2d trimester human fetal testis tissue (Ben Maamar et al., 2017).
Ibuprofen exposure for 3 days in an in-vitro mannequin reduced AMH in first trimester human fetal testes at 7–8 GW (10−5 M), and at 8–10 GW (10−4 M to 10−5 M); on the opposite hand, no critical disagreement in AMH became found after 7 days of exposure of host mice carrying 2d trimester human fetal testis xenografts (Ben Maamar et al., 2017).
Insl3 production became now not affected in early first trimester (8–10 GW) human fetal testis following in-vitro tradition with ibuprofen, whereas for late first trimester (10–12 GW) testis, an general dose response good purchase became demonstrated (Ben Maamar et al., 2017). The true fact that ibuprofen exposure affects testosterone and Insl3 production finest accurate through explicit periods of human fetal testis constructing, has implications for the possibility of this analgesic to impact testis descent, i.e. cryptorchidism (which is below the preserve watch over of these two hormones).
Ibuprofen – Germ cells
In-vitro tradition and exposure of first trimester human fetal testis to ibuprofen for 7 days resulted in a good purchase in gonocyte quantity (−22%). On the opposite hand, there had been no critical changes to germ cell quantity following exposure of 2d trimester xenografted testis tissue (Hurtado-Gonzalez et al., 2018).
Aspirin – Hormones
Aspirin exposure of first trimester testis explants in an organotypic tradition system, did now not alter testosterone production across a fluctuate of concentrations (10−4 to 10−8 M) (Gaudriault et al., 2017). On the opposite hand, in a separate in-vitro tradition analysis, a predominant dose–response relationship became reported whereby aspirin exposure for 3 days a great deal elevated the production of testosterone by early first trimester (8–9 GW), nonetheless now not in late first trimester (10–12 GW) testes (Mazaud-Guittot et al., 2013). In-vitro exposure of human fetal testis (10–12 GW) to aspirin for 3 days did now not impact Insl3 production (Mazaud-Guittot et al., 2013), whereas AMH production became a great deal elevated.
Aspirin – Germ cells
In-vitro exposure to aspirin did now not impact germ cell quantity in first trimester (8–10 GW) human fetal testis tissue (Mazaud-Guittot et al., 2013).
Indomethacin – Hormones
Comparable to rodent analysis, there are conflicting outcomes of experimental analysis using in-vitro tradition of human fetal testis. Publicity of first trimester human fetal testis explants (10–12 GW) to indomethacin (10−4 M) for 72 h, reduced testosterone (−20%), whereas exposure at lower concentrations (10−5 M to 10−8 M) had no attain (Gaudriault et al., 2017). In inequity, a earlier analysis found that indomethacin exposure (10−5 M) elevated testosterone production (+20%), when first trimester (8–12 GW) testes had been uncovered in-vitro for a identical duration (Mazaud-Guittot et al., 2013). In-vitro exposure of human fetal testis (10–12 GW) to indomethacin (10−5 M) for 2 days did now not impact Insl3 production (Mazaud-Guittot et al., 2013).
Indomethacin – Germ cells
In-vitro exposure to indomethacin (10−5 M) for 2 days did now not impact germ cell quantity in first trimester (8–12 GW) human fetal testis cultures (Mazaud-Guittot et al., 2013).
Publicity to analgesics has been linked to abnormalities in testicular characteristic and constructing of male reproductive disorders across a fluctuate of analysis. This entails epidemiological and experimental analysis using animal and human tissues. Outcomes in terms of testosterone production aren’t constant and this might perhaps perhaps perhaps also replicate variations between species, mannequin systems or dose, timing and duration of exposure (Table I and Fig. 2). On the opposite hand, there might perhaps be increasing evidence from human analysis that paracetamol and ibuprofen can impact germ cell quantity within the fetal testis and evidence exists for identical outcomes on germ cells within the fetal ovary (Hurtado-Gonzalez et al., 2018). These analysis involve exposure to human-linked concentrations of these capsules and for xenograft analysis they consist of linked dosing regimens to those extinct therapeutically in other folks. Even as the evidence for outcomes of paracetamol and ibuprofen on germ cells seems tough, the possible of such exposures to impact subsequent male reproductive characteristic and fertility are unexplored. Certainly, it is imaginable that there might perhaps perhaps even be compensation later in gestation or accurate through childhood that will rescue the implications of any fetal germ cell loss. Tremendous-scale prospective epidemiological analysis and longer-timeframe experimental (e.g. xenograft) analysis can relieve to tackle this explicit ask.
Diethylstilboestrol (DES) is a synthetic estrogen that became extinct clinically to discontinuance spontaneous miscarriage and pre-timeframe labor from the 1940 s till the early 1970 s (Marselos and Tomatis, 1992). DES became withdrawn from scientific employ after the demonstration of a causal characteristic within the enchancment of vaginal carcinoma in girls born to uncovered mothers (Herbst et al., 1971). To boot to the implications on baby girl, an affiliation with structural abnormalities of the male reproductive tract became additionally described including epididymal cysts, microphallus and testicular hypoplasia (Toppari et al., 1996).
Animal analysis interesting in-vitro tradition of rat and mouse fetal testis, occupy reported a good purchase in testosterone production following exposure to DES (N’Tumba-Byn et al., 2012), corresponding to the implications of earlier in-vitro analysis interesting fetal mice (Delbes et al., 2005) and in-vivo analysis in rats (Haavisto et al., 2001).
For TDS disorders, which would be linked to a good purchase in androgen action accurate through fetal life, there might perhaps be conflicting evidence in terms of their affiliation with maternal DES exposure. Three analysis occupy reviewed the literature in terms of exogenous estrogen exposure and male reproductive disorders (Toppari et al., 1996; Storgaard et al., 2006; Martin et al., 2008). Even as early analysis reported that hypospadias became a great deal associated with DES exposure (Henderson et al., 1976), it has subsequently been identified that this linked to urethral abnormalities ensuing from exposure to exogenous estrogens (including DES), that will perhaps also occupy resulted from abnormalities in penile constructing somewhat than an attain on urethral formation as a outcomes of reduced androgen exposure (Joffe, 2002). The meta-prognosis of all obtainable evidence revealed a predominant affiliation between DES exposure and hypospadias; on the opposite hand, it became concluded that any attain of DES on hypospadias is possible to be minute (Martin et al., 2008). For cryptorchidism, an elevated chance in affiliation with DES exposure is reported; on the opposite hand, this became reckoning on the statistical mannequin extinct and became indicative of heterogeneity (Martin et al., 2008). A subsequent cohort analysis has reported an affiliation between in-utero exposure to DES and an elevated chance of cryptorchidism, on the opposite hand, finest for these in whom the preliminary exposure took place earlier than the 11th week of gestation and not using a critical affiliation following exposure after 11 GWs (Palmer et al., 2009). Reviews occupy demonstrated no attain of prenatal DES exposure on sperm counts (Leary et al., 1984) or fertility (Wilcox et al., 1995); on the opposite hand, right here’s unlike a earlier analysis demonstrating an affiliation between prenatal exposure to DES and semen parameters in grownup men (Gill et al., 1979). Importantly, this analysis included prognosis of men born to an amazing cohort of mothers who participated in an RCT interesting DES exposure accurate through pregnancy.
Experimental evidence from human analysis
Up to now, finest two analysis occupy investigated the attain of DES exposure on the human fetal testis (Table VI). In-vitro organ tradition of first trimester human fetal testis uncovered to DES (10−5 to 10−6 M) for 3 days did now not alter testosterone production (N’Tumba-Byn et al., 2012). Curiously, this analysis when compared outcomes of DES exposure in rodent and human fetal testis demonstrating contrasting outcomes between species using the same experimental system (N’Tumba-Byn et al., 2012).
In a separate analysis using the xenograft mannequin, exposure to DES (100μg/kg, three times weekly) for 35 days resulted in no critical disagreement in testosterone production by 2d trimester (15–19 GW) testis tissue. Curiously, host mouse seminal vesicles had been a great deal elevated in weight, which became indicative of elevated testosterone production from the xenografted tissue over the final grafting duration (Mitchell et al., 2013). The explanation for this sudden amplify in testosterone is unclear.
Even as rodent analysis occupy indicated a profoundly negative attain of DES exposure on testosterone production by the fetal testis (Haavisto et al., 2001; Delbes et al., 2005; N’Tumba-Byn et al., 2012), experimental analysis utilizing human fetal testis tissues occupy did now not title identical outcomes (N’Tumba-Byn et al., 2012; Mitchell et al., 2013), that will perhaps also portray to the presence of ESR1 in rodent Leydig cells, and the absence of this estrogen receptor in human fetal testis (Mitchell et al., 2013). Epidemiological data suggests that any possible attain of DES exposure on male reproductive constructing is possible to be of minute magnitude. Taken together the implications counsel a actually powerful species disagreement in phrases of DES outcomes on fetal testosterone production that will perhaps also reward why this recurrently outcomes within the enchancment of male reproductive disorders in rodents, whereas associations between DES and subsequent male reproductive disorders in other folks are somewhat modest. Even as DES is unlikely to be extinct in pregnant ladies ultimately, the findings of this analysis offer some reassurance in terms of the possibility of low-level exposure to environmental estrogens to impress human male reproductive constructing, given their extraordinarily low efficiency when compared with DES and the excessive exposures that resulted from therapeutic employ of DES.
Metformin is a biguanide extinct as an insulin sensitizer within the treatment of Style 2 Diabetes and weight problems. Metformin might perhaps perhaps also additionally be prescribed accurate through pregnancy in other folks with pre-reward diabetes or of us who occupy developed gestational diabetes accurate through their pregnancy (https://bnf.advantageous.org.uk/drug/metformin-hydrochloride.html#pregnancy).
Publicity to metformin has been shown to within the good purchase of testosterone production in mouse fetal testis following in-vitro or in-vivo exposure. Publicity of pregnant mice to metformin (300 mg/gk/d) from embryonic day (e) 0.5 resulted in a predominant good purchase in testosterone at e16.5 (Tartarin et al., 2012).
Up to now, there has been no epidemiological data relating in-utero exposure to metformin to TDS disorders at initiating, despite the true fact that one analysis found no affiliation between prepubertal testicular volumes in offspring born to mothers who had got metformin, when compared with insulin, for gestational diabetes (Tertti et al., 2016).
Experimental evidence from human analysis
A most trendy analysis has investigated the attain of metformin exposure on the human fetal testis using an in-vitro tradition system (Tartarin et al., 2012) (Table VI). Publicity to a fluctuate of metformin concentrations (5×10−5M to 5×10−3M) resulted in a predominant decrease in testosterone production from the testis. Importantly, the lowest concentration (5×10−5M) reflects the serum stages measured in other folks following a therapeutic dose of metformin (Robert et al., 2003).
Summary of experimental analysis investigating outcomes of pharmaceutical exposure in human fetal testis tissue.
Azole antifungals and abiraterone
Azole antifungals (e.g. ketoconazole, fluconazole) and abiraterone are capsules known to inhibit key enzymes of the steroidogenic pathway including P450scc (CYP17A1; ketoconazole) and CYP17A1 & 3βHSD (abiraterone). Which potential, exposure of the fetal testis to those brokers would be predicted to impress testosterone production and presumably to result within the enchancment of male reproductive disorders.
Publicity to ‘azole’ antifungals that interfere with steroidogenesis might perhaps perhaps even be linked to pregnancy, on condition that they are recurrently prescribed for the treatment of vaginal candidiasis. No affiliation between maternal employ of antifungals and hypospadias has been reported in two analysis (Carter et al., 2008) (Norgaard et al., 2008), or for AGD after exposure to antifungals administered as vaginal capsules or as topical cream (Mogensen et al., 2017). On the opposite hand, the latter analysis demonstrated a predominant affiliation between oral fluconazole and reduced AGD within the male offspring (Mogensen et al., 2017). Importantly, for each of these three analysis, the numbers of cases became minute and elevated prospective analysis might perhaps perhaps be required to give definitive evidence of associations between antifungals and indicators of fetal testosterone production.
Experimental evidence from human analysis
Publicity to ketoconazole outcomes in a predominant good purchase (50–90%) in testosterone following in-vitro exposure of first trimester human fetal testis for 96 h (Gaudriault et al., 2017) (Table VI). The same outcomes had been described for ketoconazole with a modern good purchase in testosterone production after 24 h (−20%), 48 h (−90%) and 72 h (−95%), when put next with car-uncovered tissue (Mazaud-Guittot et al., 2013). This analysis additionally reported a ketoconazole-introduced about good purchase in INSL3 (−100%) and AMH (−50%) after 72 h of tradition.
Abiraterone (an anti-androgen extinct in prostate cancer) has additionally been shown to result in a good purchase in testosterone production (−80%) in 2d trimester human fetal testis xenografts (grafted for 14 days), whereas no attain on germ cell quantity became demonstrated (Spade et al., 2014) (Table VI). Certainly, these brokers might perhaps perhaps even be regarded as as distinct controls for analysis investigating the implications of exposures on testosterone production in human fetal testes (Mazaud-Guittot et al., 2013; Spade et al., 2014).
A most trendy analysis has described the attain of exposure to 27 diversified chemical substances, including several extra pharmaceuticals, on the human fetal testis using an in-vitro system (Gaudriault et al., 2017) (Table VI). A dose dependent good purchase in testosterone production became resolute for clomiphene (an anti-estrogenic substance extinct to stimulate ovulation), theophylline (a methylxanthine drug which acts as a non-selective phosphodiesterase inhibitor extinct in bronchial asthma) and valproate (an anti-epileptic) following in-vitro tradition of human fetal testis tissue for 96 h (Gaudriault et al., 2017). Curiously, valproate has been associated with hypospadias in male offspring of uncovered mothers (Veroniki et al., 2017).
Standard of living
Exposures that portray to traditional of living might perhaps perhaps also additionally impact on the enchancment of male reproductive disorders. On the opposite hand, to this level finest a restricted quantity of analysis using human fetal tissues had been performed in this condominium (Table VII).
Summary of experimental analysis investigating outcomes of standard of living exposures in human fetal testis tissue.
Xanthines are a class of compounds that share a same earlier structure and occupy stimulant properties, including caffeine, one among the most recurrently extinct recreational capsules worldwide. Outcomes of several of these compounds had been investigated in vitro (Gaudriault et al., 2017).
Experimental evidence from human analysis
No negative outcomes on testosterone production from cultured human fetal testis tissue had been demonstrated following exposure to caffeine, paraxanthine, theobromine or 1,3,7 trimethyluric acid (TMUA), albeit there appeared as if it might perhaps perhaps perhaps be a modest decrease in testosterone production for caffeine finest at the lowest concentration (Table VII).
Alcohol exposure accurate through pregnancy is principal to impact on fetal constructing, and its mechanism of action might perhaps perhaps also occur centrally or within the placenta. Fetal alcohol syndrome is correctly described and might perhaps consist of neurodevelopmental disorders, facial dysmorphism and development abnormality (Nash and Davies, 2017).
An epidemiological analysis interesting a Danish–Finnish cohort (~2500 boys), demonstrated an affiliation between maternal alcohol consumption and elevated chance of cryptorchidism in sons (Damgaard et al., 2007).
Experimental evidence from human analysis
The attain of exposure to alcohol on human fetal testis has finest been investigated in a single analysis (Table VII). Curiously, exposure of first trimester human fetal testis to ethanol (10−8 M to 10−5 M for 72 h) using in-vitro tradition resulted in a predominant amplify in testosterone production across a extensive dose fluctuate (Gaudriault et al., 2017).
Maternal smoking is principal to occupy many presumably grisly outcomes on the establishing fetus including intra-uterine development retardation and low initiating weight (Abraham et al., 2017).
Epidemiological analysis occupy measured sperm counts in men uncovered in-utero to maternal cigarette smoke, which demonstrated a good purchase in sperm concentration (38–48%) in uncovered- when put next with unexposed-men (Storgaard et al., 2003; Ramlau-Hansen et al., 2007). Exercise of nicotine substitutes accurate through pregnancy a great deal elevated the chance of cryptorchidism in male offspring (Damgaard et al., 2008) and an affiliation between maternal smoking accurate through pregnancy and cryptorchidism in male offspring has additionally been demonstrated (Jensen et al., 2007).
Experimental evidence from human analysis
One analysis when compared testosterone stages in plasma of human fetuses uncovered to maternal cigarette smoke with these of non-smoking mothers and found no disagreement in testosterone between the groups no matter a predominant good purchase in hCG (Fowler et al., 2009).
The outcomes of maternal smoking on human fetal testis has been investigated in two experimental analysis, both of which extinct exposure to parts of cigarette smoke (Coutts et al., 2007; Angenard et al., 2010). In-vitro exposure of human fetal testis to DMBA-DHD, the energetic metabolite of polyaromatic hydrocarbons tag in cigarette smoke, resulted in a predominant amplify in apoptosis in germ cells, which would be rescued by antagonism of the aryl hydrocarbon receptor (AHR), indicating that activation of the AHR is the possible mechanism for the implications of DMBA-DHD on germ cells (Coutts et al., 2007). Cadmium (one other ingredient of cigarette smoke)-exposure of first trimester human fetal testis resulted in elevated apoptosis in germ cells, without any attain on testosterone production (Angenard et al., 2010).
Over most trendy years, it has been an increasing number of known that the impact of environmental exposures is dependent now not finest on the person brokers, nonetheless additionally on the mix of brokers. deal of animal analysis occupy investigated the implications of ‘combos’; on the opposite hand, to this level such approaches using human fetal testis tissues is proscribed. A key facet of right here’s whether the implications might perhaps perhaps also additionally be regarded as as additive or synergistic. The attain of four separate combos (all including BPA) has been investigated in a most trendy analysis interesting in-vitro exposure of first trimester human fetal testis for 96 h (Gaudriault et al., 2017). This included two combos (four brokers each) of BPA + pharmaceuticals and two combos (eight brokers each) which included extra environmental (pesticides and bisphenols) chemical substances.
As anticipated, each mixture resulted in a good purchase in testosterone production. Importantly, the authors when compared the person dose–response outcomes to those predicted by the additive attain of the person brokers. There became a excessive correlation between predicted and proper response for each of the four combos indicating that these brokers acted in an additive intention (Gaudriault et al., 2017). This permits such experimental systems to make employ of the implications of exposure to person brokers for approximation of the blended anti-androgenic attain of additional than one exposures, basically basically based on an assumption of dose-addition. This has indispensable implications for informing regulation of environmental chemical substances and pharmaceutical exposures.
Even as a somewhat tremendous body of animal data exists for figuring out the impacts of in-utero exposures on fetal testicular constructing and male reproductive disorders, a restricted quantity of experimental analysis interesting human tissues had been performed. Animal fashions offer the possible to behavior extra mountainous analysis interesting exposures across extra than one developmental periods and expertise of dose response data. A further relieve of animal analysis is the possibility of conducting in-vivo fetal exposure analysis in animals which is now not imaginable for human analysis which currently rely on in-vitro or ex-vivo (xenograft) approaches. On the opposite hand, this overview has described several exposures for which the analysis utilizing human tissues occupy demonstrated indispensable variations to those tag in animals. This would perhaps also portray to variations in analysis get, dose administered or exposure regimen; on the opposite hand, it has additionally been shown that a broad selection of these variations seem to result from traditional species variations within the attain of explicit brokers at human-linked stages of exposure. Even as epidemiological analysis can to a level bridge the outlet between outcomes demonstrated in animal analysis and human-relevance, such analysis can now not tag assert causation or elicit underlying mechanisms for outcomes; such analysis are additionally inclined to confounding. This highlights the importance of experimental fashions using human fetal tissues in figuring out the possible impact of in-utero environmental and pharmaceutical exposures in other folks.
It is obvious that figuring out outcomes of in-utero exposures on male reproductive constructing will proceed to rely on interpretation of a mixture of animal analysis, epidemiology and experimental analysis utilizing human tissues. Conducting co-ordinated analysis that combine these systems represents a actually powerful methodology. This would perhaps also consist of combining experimental analysis using in-vitro and in-vivo approaches (Kristensen et al., 2011; Hurtado-Gonzalez et al., 2018), analysis evaluating outcomes in both rodent and human tissues (Ben Maamar et al., 2015; Hurtado-Gonzalez et al., 2018), or blended analysis of epidemiological and experimental evidence (Kristensen et al., 2011).
Epidemiological analysis might perhaps perhaps even be enhanced by establishing tremendous-scale prospective cohort analysis. Here is of explicit significance to be sure that that the timing of measurement of exposure coincides with the anticipated mechanism of attain (e.g. in-utero exposure and cryptorchidism/hypospadias known within the neonatal duration). Moreover, for pharmaceuticals with somewhat short half of-lives, which would be taken intermittently and beget now not rep within the body, obtaining horny and detailed data of exposure accurate through pregnancy is essential. This data is amazingly complex to manufacture retrospectively and is inclined to rob bias making prospective analysis essential for such exposures.
The prolonged speed for figuring out outcomes of in-utero exposure(s) on male testicular constructing and reproduction is additionally possible to involve refinement of reward experimental approaches. Even as most trendy constructing of in-vitro and xenograft approaches has allowed assert finding out of environmental chemical substances and pharmaceuticals on the human fetal testis, these fashions might perhaps perhaps even be restricted by tissue provide and heterogeneity between other folks. Essentially the most trendy constructing of organoids for a fluctuate of organs and tissues might perhaps perhaps also tag serious for future analysis to confirm the implications of exposures in organoids generated from human testicular tissues (Alves-Lopes and Stukenborg, 2017). Computational and mathematical modeling might perhaps perhaps also additionally be extinct to foretell the implications of exposure(s) in-silico (Krysiak-Baltyn et al., 2012), despite the true fact that this might perhaps perhaps perhaps be reckoning on the robustness of the imputation of biological data.
The scientific and public pastime within the implications of chemical exposures in other folks is possible to proceed to amplify. Laws of these brokers will an increasing number of rely on fashions that can provide assert human-linked data. Therefore, we propose that analysis of the experimental evidence from analysis using human fetal tissues ought to be an integral half of informing regulatory policies in relation to the implications of environmental and pharmaceutical exposures on male reproductive constructing.
Supplementary Self-discipline matter
R.T.M. developed the thought that for the article. R.T.M. and Okay.Okay. performed the systematic search of the literature, analysis of eligibility, data extraction and tabulation of information. R.T.M. and Okay.Okay. wrote, revised and accredited the the leisure model of the article.
R.T.M. became in receipt of a Wellcome Intermediate Scientific Fellowship (Grant no. 098522). The Clinical Analysis Council (MRC) Centre for Reproductive Successfully being is supported by an MRC Centre Grant (MR/N022556/1). The funding our bodies occupy had no enter into the behavior of the analysis or the production of this text.
Battle of pastime
The authors negate that they don’t desire any war of pastime.
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