Impact of xenoestrogens on male fertility: a systematic review (2019)

Hum Reprod Update. 2019 Jul; 25(4): 397–421. This article has been cited by other articles in PMC.AbstractBACKGROUNDOverall, the incidence of male reproductive disorders has increased in recent decades. Testicular development during fetal life is crucial for subsequent male reproductive function. Non-genomic factors such as environmental chemicals, pharmaceuticals and lifestyle have been proposed to impact on human fetal testicular development resulting in subsequent effects on male reproductive health. Whilst experimental studies using animal models have provided support for this hypothesis, more recently a number of experimental studies using human tissues and cells have begun to translate these findings to determine direct human relevance.OBJECTIVE AND RATIONALEThe objective of this systematic review was to provide a comprehensive description of the evidence for effects of prenatal exposure(s) on human fetal testis development and function. We present the effects of environmental, pharmaceutical and lifestyle factors in experimental systems involving exposure of human fetal testis tissues and cells. Comparison is made with existing epidemiological data primarily derived from a recent meta-analysis.SEARCH METHODSFor identification of experimental studies, PubMed and EMBASE were searched for articles published in English between 01/01/1966 and 13/07/2018 using search terms including ‘endocrine disruptor’, ‘human’, ‘fetal’, ‘testis’, ‘germ cells’, ‘testosterone’ and related search terms. Abstracts were screened for selection of full-text articles for further interrogation. Epidemiological studies involving exposure to the same agents were extracted from a recent systematic review and meta-analysis. Additional studies were identified through screening of bibliographies of full-texts of articles identified through the initial searches.OUTCOMESA total of 25 experimental studies and 44 epidemiological studies were included. Consistent effects of analgesic and phthalate exposure on human fetal germ cell development are demonstrated in experimental models, correlating with evidence from epidemiological studies and animal models. Furthermore, analgesic-induced reduction in fetal testosterone production, which predisposes to the development of male reproductive disorders, has been reported in studies involving human tissues, which also supports data from animal and epidemiological studies. However, whilst reduced testosterone production has been demonstrated in animal studies following exposure(s) to a variety of environmental chemicals including phthalates and bisphenol A, these effects are not reproduced in experimental approaches using human fetal testis tissues.WIDER IMPLICATIONSDirect experimental evidence for effects of prenatal exposure(s) on human fetal testis development and function exists. However, for many exposures the data is limited. The increasing use of human-relevant models systems in which to determine the effects of environmental exposure(s) (including mixed exposures) on development and function of human tissues should form an important part of the process for assessment of such exposures by regulatory bodies to take account of animal–human differences in susceptibility.Keywords: human fetus, testis, endocrine disruptor, environmental chemical, pharmaceutical, testosterone, germ cell, Leydig cell, Sertoli cell, steroidogenesisIntroductionDevelopment of the male reproductive system and its subsequent function is impacted by events that occur in utero. Perturbations in testicular development or function during fetal life may result in male reproductive disorders that present postnatally (van den Driesche et al., 2017). This includes anatomical abnormalities identified at birth, such as cryptorchidism and hypospadias, or disorders presenting in adulthood, including testicular cancer or infertility (Sharpe and Skakkebaek, 2008). These associated disorders are collectively referred to as the testicular dysgenesis syndrome (TDS). The development of TDS has been shown in rats to be influenced by a reduction in androgen production or action during a key period of fetal life, known as the masculinization programming window (MPW) (Welsh et al., 2008; van den Driesche et al., 2017). The increasing incidence of TDS disorders over recent decades, highlights the potential importance of environmental impacts in their etiology (Skakkebaek et al., 2016). Environmental factors that have been proposed to affect fetal testis development and predispose to TDS disorders include environmental chemicals (e.g. plasticizers and pesticides), pharmaceuticals (e.g. analgesics, metformin and diethylstilboestrol) and lifestyle factors (e.g. diet, alcohol and smoking) (Habert et al., 2014; Kilcoyne and Mitchell, 2017).In order to understand how in-utero exposures might disrupt fetal development and result in postnatal testicular disorders, it is important to consider the normal development of the germ and somatic cell populations in the human fetal testis (Fig. ​1). During fetal life, germ cells migrate into the developing gonad (4–5 weeks in human) where they undergo differentiation from gonocytes to spermatogonia. This transition takes place during fetal and early postnatal life and involves the loss of expression of pluripotency factors (e.g. POU5F1) and gain of differentiated germ cell-specific protein expression (e.g. MAGEA4) (Mitchell et al., 2008). Failure of gonocyte differentiation can result in the development of pre-malignant germ cell neoplasia in-situ cells (GCNIS), which results in the development of testicular germ cell cancer (TGCC) in adulthood (Rajpert-De Meyts et al., 2016) whilst loss of germ cells as a result of in-utero events can also potentially impact future fertility.
Testicular development and function during fetal life and reproductive disorders associated with testicular dysgenesis syndrome. DHT, dihydrotestosterone.Germ cell development during fetal life is supported by somatic cells that form the germ-stem cell niche. Sertoli cells surround the gonocytes, forming seminiferous cords, at ~6–7 gestational weeks (GW) in the human (O’Shaughnessy and Fowler, 2011; Heeren et al., 2015). Sertoli cells are fundamental for germ cell development (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 present in the interstitium of the testis from six GWs in humans and are responsible for the production of hormones involved in testicular descent. Insl3 is involved in the transabdominal phase of testicular descent, whilst testosterone is required to enable the testis to traverse the inguinal canal (Hughes and Acerini, 2008). Leydig cell-derived testosterone is also converted to dihydrotestosterone (DHT) in peripheral tissues for masculinization of the fetus, which includes development of external genitalia. Therefore, perturbations to the function of fetal Leydig cells can predispose to the development of male reproductive disorders including TDS and some disorders of sex development (DSD) (van den Driesche et al., 2017).The majority of experimental studies investigating the effects of environmental exposures on fetal testis development and function involve rodents. These studies have provided a large amount of valuable information highlighting the potential for effects of in-utero exposure to a wide variety of environmental chemicals on male reproductive development. However, there are important differences in fetal testicular development between rodent and human in terms of germ cell development (McKinnell et al., 2013) and steroidogenesis (Scott et al., 2009). Furthermore, the exposures used for these studies may not reflect the levels of exposure that are directly relevant to humans. Assessment of experimental studies using experimental animal models must take account of the variations in model systems (in-vitro versus in-vivo), exposure regimen and drug metabolism, whilst also accounting for the impact of species differences for each of these parameters (Kilcoyne and Mitchell, 2017). As a result, animal studies often report findings based on relative exposures which exceed human-relevant exposures, often by several orders of magnitude.In order to gain information on the potential for in-utero environmental exposures to impact development of male reproductive disorders in humans, epidemiological studies can be employed. A recent systematic review has described the epidemiological evidence for associations between prenatal exposures and male reproductive disorders in humans (Bonde et al., 2016). A number of important considerations must be applied when assessing epidemiological evidence for such associations. These include, but are not limited to (i) the relevance and/or size of the population group, (ii) measurement of the exposure (direct/indirect) (iii) biological plausibility for the exposure alone causing the effect and elimination of potential confounders (reviewed in Foster et al., 2017) (Fig. ​2 and Table ​I).
Comparison of approaches to comparing the effects of environmental and pharmaceutical exposures on human fetal testis development and function. TGCC, testicular germ cell cancer.Table IKey considerations for the assessment of human studies using epidemiological, or experimental (xenograft or in-vitro) approaches.EpidemiologyXenograftIn vitro
Potential limitation—population/tissue used may be unrepresentative of target population/tissue
Is the population studied representative of the target population (e.g. pregnant women)?
Is the tissue representative of the target population (e.g. fetal tissue)?
Is the tissue representative of the target population (e.g. fetal tissue or cells)?
Potential limitation—agent under investigation may be not be representative of the exposure under investigation (e.g. metabolite) or there may be additional confounding agents
Is the relevant agent being measured in the population?Is there potential for confounding by other/similar exposures?
Is the investigated agent relevant to potential human exposure?Is it metabolized in the host animal to an active/inactive form (e.g. DBP–MBP)?
Is the investigated agent relevant to potential human exposure?Is the active agent or metabolite added to the medium?
Potential limitation—assessment of exposure in epidemiological studies or regimen used in experimental studies may not accurately reflect true human exposure
Is the exposure measured in the subjects (e.g. indirect measurement of fetal exposure through maternal serum/urine) or indirectly assessed (e.g. self-report) and does this accurately capture actual fetal exposure?
Is the dose, frequency, duration and route of exposure? representative of human exposure (e.g. pharmaceuticals)?
Is the concentration of agent placed in the media representative of human levels (e.g. maternal serum, amniotic fluid, fetal serum) and/or human dosing regimen?
Potential limitation—timing of assessment of exposure in epidemiological studies or developmental stage of tissue used in experimental studies may not accurately reflect the relevant stage
Is exposure measured at the appropriate developmental stage (e.g. trimester of fetal life or MPW)?Does timing and frequency of measurement accurately reflect internal exposure?
Is the transplanted tissue at the same developmental stage (e.g. trimester of fetal life or MPW)?Does the experimental system maintain tissue development and function?
Is the tissue cultured at the same developmental stage (e.g. trimester of fetal life or MPW)?Does the experimental system maintain tissue development and function?
Potential limitation—the effects of exposure may be measured directly or through association and direct effects of exposure may not result in clinical consequences
Is there a direct clinical association with fetal exposure (e.g. cryptorchidism) or is it a surrogate marker for clinical effects (e.g. AGD)?What is the magnitude of effect and is it statistically significant?Is there a plausible mechanism?
Is the effect clinically relevant (e.g. potential for reduced testosterone to induce cryptorchidism)?What is the magnitude of effect and is it statistically significant?Has the mechanism for the effect been defined?
Is the effect relevant to in-vivo situation?Is the effect clinically relevant (e.g. potential for reduced testosterone to induce cryptorchidism)?What is the magnitude of effect and is it statistically significant?Has the mechanism for the effect been defined?While human epidemiological and animal experimental studies are extremely informative, there remains a large gap in our understanding of how specific environmental exposures may directly affect the human fetal testis. Therefore, development of model systems using human fetal tissues and human-relevant doses can bridge the gap between direct evidence from animal experimental models and indirect evidence based on epidemiological data. A number of recent studies have utilized in-vitro or xenograft approaches using human fetal testis tissues to determine the effect of environmental and pharmaceutical exposures. As with epidemiological studies, there are a number of key considerations when interpreting the results of these studies relating to model system, exposure regimen and biological relevance of the measured outcome (Fig. ​2 and Table ​I).A comprehensive review of the experimental evidence for effects of environmental exposures on fetal testicular development and function using human cells or tissues has not previously been reported. This systematic review will detail the experimental evidence for impacts of environmental chemicals, pharmaceuticals and lifestyle factors on human fetal testis development and function. For each class of exposure for which human experimental evidence exists, we will first summarize the findings of animal studies and then provide a critical review of the epidemiological evidence. We will then describe in detail the evidence to support or refute these findings based on experimental models using human fetal testis tissues.MethodsThe study was designed as a systematic review of the published literature relating to the effects of in-utero exposures on human fetal testis development and function in experimental models. The study followed the principles of the PRISMA guidelines for reporting systematic reviews (Moher et al., 2009). The protocol for searching and assessing the literature was determined prior to the start of the literature search. It is not currently possible to register laboratory experimental studies with PROSPERO.Information sourcesWe performed an online search of PubMed and EMBASE (13/07/2018) to identify all experimental studies relating to testicular effects of fetal exposures to environmental, pharmaceutical and lifestyle factors, limited to studies utilizing human fetal tissues or cells. For identification of relevant epidemiological studies, we included the publications identified in a recent systematic review and meta-analysis of associations between prenatal exposures and male reproductive disorders (Bonde et al., 2016). Additional epidemiological studies were identified from the reference lists of the screened articles.Eligibility for inclusionWe performed a systematic search of original publications according to the following criteria for inclusion: English language articles published between 01/01/1966 and 13/07/2018; experimental studies on exposure of human fetal testis tissue or cells to a clearly defined environmental, pharmaceutical or lifestyle factor; and outcomes including effects on testicular hormone production (e.g. testosterone, Insl3, AMH), germ or somatic (Sertoli, Leydig) cell development.Exclusion criteriaWe excluded studies according to the following criteria: exposure of tissues or cells representative of a period other than fetal life; exposure of non-testicular tissues or cells; outcomes other than those described above; and review articles.Search and study selectionWe searched the databases using a combination of medical subject headings and generic terms relating to effects of exposures on human fetal testis development (Supplementary Table S1). We identified 3229 hits. Both authors screened the titles and/or abstracts independently to assess eligibility. Full texts were requested for studies that included in the abstract the use of human fetal testis tissue or cells and the effect of exposure to environmental, pharmaceutical or lifestyle factors. Full texts for 40 studies were obtained and a total of 25 publications were included in the review of experimental evidence (Supplementary Table S2; Fig. ​3). A total of 15 studies were excluded (Supplementary Table S3). A further 44 publications were included in the review of epidemiological evidence (Supplementary Table S4).
Prisma flow diagram for identification and selection of studies.
# Supplementary Table S2; * Supplementary Table S3.Summary measuresStudies included in-vitro and ex-vivo (xenograft) approaches and results were assessed primarily for effects on testosterone secretion and on germ cell number (both expressed as % change compared to vehicle control). Effects on additional testicular hormones, AMH (produced by SC) and Insl3 (produced by LC) are also reported.ResultsThe distribution of studies based on exposure type and year of publication is shown in Fig. ​4. The majority of the studies were published from 2007 to 2018. The earlier studies primarily investigated phthalates, pesticides and smoking, whilst more recent studies have mainly focused on bisphenols and analgesics.
Number of publications involving experimental exposures to environmental agents and pharmaceuticals using human fetal testis tissues or cells. DES, diethylstilboestrol. For (A) ‘All Publications’, a breakdown of the investigated agents into (B) environmental, (C) pharmaceutical and (D) lifestyle is included. NB: Some publications include exposure to several different agents.Environmental chemicalsPhthalatesPhthalates are a class of industrial chemicals used mainly to soften polyvinyl chloride-based products and are found in a wide array of general plastic products. Exposure to phthalates may occur via inhalation, ingestion or direct contact with items including packaging, oils, food storage and personal care products. Phthalates are not stored in the body but are instead rapidly metabolized into monoesters with a urinary excretion half-life of 4 weeks) (Jensen et al., 2010) or during the second trimester (Hurtado-Gonzalez and Mitchell, 2017), which would coincide with at least part of the postulated critical human MPW period (8–14 GW) (Welsh et al., 2008). A reduction in fetal testosterone production, as demonstrated in experimental studies described above, could provide a mechanistic explanation for paracetamol-induced cryptorchidism in male offspring, although proving this in humans is challenging. However, measurement of the AGD in offspring can provide an indirect read-out of fetal androgen production, linking the reported association with the proposed mechanism (Dean and Sharpe, 2013). A recent study has shown an association between paracetamol exposure (inclusive of the MPW) and reduced AGD in boys up to 24 months, independent of body size (Fisher et al., 2016). Nevertheless, for these epidemiological studies, extrapolation of results to direct clinical effects should be considered with caution, primarily due to the lack of direct analgesic measurements and the reliance on retrospective questionnaires for exposure classification which may involve a degree of recall bias.Experimental evidence from human studies Several recent studies have investigated the effect of analgesics on human fetal testis using experimental models (Table ​V).Table VSummary of experimental studies investigating effects of analgesic exposure in human fetal testis tissue.Paracetamol – Hormones
In-vitro studies using first trimester testis (8–12 GW) exposed to paracetamol (10−5 M) for 1–3 days did not alter testosterone production, compared with vehicle controls (Mazaud-Guittot et al., 2013). This was also the case for the paracetamol metabolite AM404 (10−5 M) (Mazaud-Guittot et al., 2013). A recent study using an organotypic in-vitro culture system of first trimester human fetal testes explants showed that exposure to paracetamol in a dose range of 10−8 to 10−6 M increased testosterone by 25%; however, higher doses of 10−5 M and 10−4 M did not have any effect on testosterone production (Gaudriault et al., 2017).The conflicting results between rodent and human in-vitro studies may relate to the stage of testis development (i.e. timing within the MPW) or differences in the experimental system (Mazaud-Guittot et al., 2013). Caution should be exercised when relating effects using in-vitro models to the in-vivo situation in humans, as the former cannot directly recapitulate normal pharmacokinetics, including in-vivo peak and trough concentrations. To circumvent some of the potential limitations of the in-vitro approaches for the human fetal testis, subsequent studies have utilized an ex-vivo approach involving 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-relevant regimen of paracetamol (20 mg/kg; three times daily) for 1 week significantly reduced (−45%) host serum testosterone and seminal vesicle (androgen dependent organ) weight (−18%), unlike a single daily exposure which had no effect on either parameter (van den Driesche et al., 2015a). Further confirmation of the human relevance of paracetamol exposure is evident from the finding that 1 h after the final dose in host mice, plasma paracetamol concentrations were significantly lower than post-therapeutic levels reported in pregnant women (Rayburn et al., 1986). However, it must be considered that circulating paracetamol levels in pregnant women may not be a direct indicator of intra-testicular levels in the developing fetus.Insl3 hormone production was significantly reduced in first trimester human fetal testis cultures exposed to paracetamol, in which a clear dose–response relationship with increasing paracetamol exposure (at 10−7 M to 10−4 M) was demonstrated (Mazaud-Guittot et al., 2013).Paracetamol – Germ cells An in-vitro study using first trimester human fetal testis (8–12 GW) exposed to paracetamol (10−5 M) for 1–3 days found no alteration in germ cell number (Mazaud-Guittot et al., 2013). However, a more recent in vitro study with a longer period (7 days) of exposure showed that similar paracetamol concentration (10−5 M) significantly reduced (−28%) gonocyte number (Hurtado-Gonzalez et al., 2018). The differing findings in these studies may reflect the longer period of exposure in the latter study or may be the result of differences in the culture systems. To further investigate the potential effect of paracetamol exposure on the human fetal testis, a xenograft approach was also used alongside the in-vitro model (Hurtado-Gonzalez et al., 2018). Xenografted second trimester tissue (14–20 GW) exposed to paracetamol using a human-relevant exposure regimen (20 mg/kg, three times daily) resulted in a reduction in gonocyte number after 7 days exposure (−32%). Interestingly, a reduction in gonocyte number (−17%) was also demonstrated after just 1 day of exposure to paracetamol (Hurtado-Gonzalez et al., 2018).Whilst most of circulating paracetamol in humans comes from use of paracetamol-containing medications, an alternative source has also been described. The industrial chemical aniline, which is found in a wide variety of manufactured products, such as rubber, pharmaceuticals, cosmetics and cigarette smoke, is rapidly metabolized to paracetamol inside the body (Modick et al., 2014, 2016). Furthermore, in-vivo studies in which male mice exposed in utero to aniline have shown similar fetal anti-androgenic effects to those described for exposure to paracetamol (Holm et al., 2015). Only one study has investigated the effect 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 effect on testosterone production across a range of doses (10−8 M to 10−5 M) apart from a small reduction (−20%) for an intermediate concentration (10−7 M) (Gaudriault et al., 2017).Ibuprofen – Hormones Exposure of first trimester human fetal testis explants to ibuprofen using an organotypic culture system did not affect testosterone production (Gaudriault et al., 2017). However, another in-vitro study reported a reduction in steroidogenic enzyme expression across a similar range of concentrations (10−4 M, 10−5 M). This effect was only evident for early first trimester testes (8–9 GW), as there was no effect at any other gestational time-point examined (10 GW) (Ben Maamar et al., 2017). Similarly, there was no effect of exposure to ibuprofen on testosterone production in host mice carrying xenografts of second trimester human fetal testis tissue (Ben Maamar et al., 2017).Ibuprofen exposure for 3 days in an in-vitro model 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); however, no significant difference in AMH was found after 7 days of exposure of host mice carrying second trimester human fetal testis xenografts (Ben Maamar et al., 2017).Insl3 production was not affected in early first trimester (8–10 GW) human fetal testis following in-vitro culture with ibuprofen, whilst for late first trimester (10–12 GW) testis, an overall dose response reduction was demonstrated (Ben Maamar et al., 2017). The fact that ibuprofen exposure affects testosterone and Insl3 production only during specific periods of human fetal testis development, has implications for the potential of this analgesic to impact testis descent, i.e. cryptorchidism (which is under the control of these two hormones).Ibuprofen – Germ cells
In-vitro culture and exposure of first trimester human fetal testis to ibuprofen for 7 days resulted in a reduction in gonocyte number (−22%). However, there were no significant changes to germ cell number following exposure of second trimester xenografted testis tissue (Hurtado-Gonzalez et al., 2018).Aspirin – Hormones Aspirin exposure of first trimester testis explants in an organotypic culture system, did not alter testosterone production across a range of concentrations (10−4 to 10−8 M) (Gaudriault et al., 2017). However, in a separate in-vitro culture study, a significant dose–response relationship was reported whereby aspirin exposure for 3 days significantly increased the production of testosterone by early first trimester (8–9 GW), but 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 not affect Insl3 production (Mazaud-Guittot et al., 2013), whereas AMH production was significantly increased.Aspirin – Germ cells
In-vitro exposure to aspirin did not affect germ cell number in first trimester (8–10 GW) human fetal testis tissue (Mazaud-Guittot et al., 2013).Indomethacin – Hormones Similar to rodent studies, there are conflicting results of experimental studies using in-vitro culture of human fetal testis. Exposure 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 effect (Gaudriault et al., 2017). In contrast, a previous study found that indomethacin exposure (10−5 M) increased testosterone production (+20%), when first trimester (8–12 GW) testes were exposed in-vitro for a similar 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 not affect Insl3 production (Mazaud-Guittot et al., 2013).Indomethacin – Germ cells
In-vitro exposure to indomethacin (10−5 M) for 2 days did not affect germ cell number in first trimester (8–12 GW) human fetal testis cultures (Mazaud-Guittot et al., 2013).Summary—analgesics Exposure to analgesics has been linked to abnormalities in testicular function and development of male reproductive disorders across a range of studies. This includes epidemiological and experimental studies using animal and human tissues. Results regarding testosterone production are not consistent and this may reflect differences between species, model systems or dose, timing and duration of exposure (Table ​I and Fig. ​2). However, there is increasing evidence from human studies that paracetamol and ibuprofen can affect germ cell number in the fetal testis and evidence exists for similar effects on germ cells in the fetal ovary (Hurtado-Gonzalez et al., 2018). These studies involve exposure to human-relevant concentrations of these drugs and for xenograft studies they include comparable dosing regimens to those used therapeutically in humans. Whilst the evidence for effects of paracetamol and ibuprofen on germ cells appears robust, the potential for such exposures to impact subsequent male reproductive function and fertility are unexplored. Indeed, it is possible that there may be compensation later in gestation or during childhood that would rescue the effects of any fetal germ cell loss. Large-scale prospective epidemiological studies and longer-term experimental (e.g. xenograft) studies can help to address this particular question.DiethylstilboestrolDiethylstilboestrol (DES) is a synthetic estrogen that was used clinically to prevent spontaneous miscarriage and pre-term labor from the 1940 s until the early 1970 s (Marselos and Tomatis, 1992). DES was withdrawn from clinical use after the demonstration of a causal role in the development of vaginal carcinoma in girls born to exposed mothers (Herbst et al., 1971). In addition to the effects on female offspring, an association with structural abnormalities of the male reproductive tract was also described including epididymal cysts, microphallus and testicular hypoplasia (Toppari et al., 1996).Animal studies Animal studies involving in-vitro culture of rat and mouse fetal testis, have reported a reduction in testosterone production following exposure to DES (N’Tumba-Byn et al., 2012), similar to the results of previous in-vitro studies involving fetal mice (Delbes et al., 2005) and in-vivo studies in rats (Haavisto et al., 2001).Epidemiology For TDS disorders, which are linked to a reduction in androgen action during fetal life, there is conflicting evidence regarding their association with maternal DES exposure. Three studies have reviewed the literature relating to exogenous estrogen exposure and male reproductive disorders (Toppari et al., 1996; Storgaard et al., 2006; Martin et al., 2008). Whilst early studies reported that hypospadias was significantly associated with DES exposure (Henderson et al., 1976), it has subsequently been pointed out that this related to urethral abnormalities resulting from exposure to exogenous estrogens (including DES), which may have resulted from abnormalities in penile development rather than an effect on urethral formation as a result of reduced androgen exposure (Joffe, 2002). The meta-analysis of all available evidence revealed a significant association between DES exposure and hypospadias; however, it was concluded that any effect of DES on hypospadias is likely to be small (Martin et al., 2008). For cryptorchidism, an increased risk in association with DES exposure is reported; however, this was dependent on the statistical model used and was indicative of heterogeneity (Martin et al., 2008). A subsequent cohort study has reported an association between in-utero exposure to DES and an increased risk of cryptorchidism, however, only for those in whom the initial exposure occurred prior to the 11th week of gestation with no significant association following exposure after 11 GWs (Palmer et al., 2009). Studies have demonstrated no effect of prenatal DES exposure on sperm counts (Leary et al., 1984) or fertility (Wilcox et al., 1995); however, this is in contrast to a previous study demonstrating an association between prenatal exposure to DES and semen parameters in adult men (Gill et al., 1979). Importantly, this study included analysis of men born to a large cohort of mothers who participated in an RCT involving DES exposure during pregnancy.Experimental evidence from human studies To date, only two studies have investigated the effect of DES exposure on the human fetal testis (Table ​VI). In-vitro organ culture of first trimester human fetal testis exposed to DES (10−5 to 10−6 M) for 3 days did not alter testosterone production (N’Tumba-Byn et al., 2012). Interestingly, this study compared effects of DES exposure in rodent and human fetal testis demonstrating contrasting results between species using an identical experimental system (N’Tumba-Byn et al., 2012).In a separate study using the xenograft model, exposure to DES (100μg/kg, three times weekly) for 35 days resulted in no significant difference in testosterone production by second trimester (15–19 GW) testis tissue. Interestingly, host mouse seminal vesicles were significantly increased in weight, which was indicative of increased testosterone production from the xenografted tissue over the entire grafting period (Mitchell et al., 2013). The reason for this unexpected increase in testosterone is unclear.Summary—diethylstilboestrol Whilst rodent studies have indicated a profoundly negative effect 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 studies utilizing human fetal testis tissues have failed to identify similar effects (N’Tumba-Byn et al., 2012; Mitchell et al., 2013), which may relate 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 potential effect of DES exposure on male reproductive development is likely to be of small magnitude. Taken together the results suggest an important species difference in terms of DES effects on fetal testosterone production which may explain why this frequently results in the development of male reproductive disorders in rodents, whilst associations between DES and subsequent male reproductive disorders in humans are rather modest. Whilst DES is unlikely to be used in pregnant women in the future, the findings of this study offer some reassurance regarding the potential of low-level exposure to environmental estrogens to affect human male reproductive development, given their extremely low potency compared with DES and the high exposures that resulted from therapeutic use of DES.MetforminMetformin is a biguanide used as an insulin sensitizer in the treatment of Type 2 Diabetes and obesity. Metformin may also be prescribed during pregnancy in individuals with pre-existing diabetes or those that have developed gestational diabetes during their pregnancy (https://bnf.nice.org.uk/drug/metformin-hydrochloride.html#pregnancy).Animal studies Exposure to metformin has been shown to reduce testosterone production in mouse fetal testis following in-vitro or in-vivo exposure. Exposure of pregnant mice to metformin (300 mg/gk/d) from embryonic day (e) 0.5 resulted in a significant reduction in testosterone at e16.5 (Tartarin et al., 2012).Epidemiology To date, there has been no epidemiological data relating in-utero exposure to metformin to TDS disorders at birth, although one study found no association between prepubertal testicular volumes in offspring born to mothers who had received metformin, compared with insulin, for gestational diabetes (Tertti et al., 2016).Experimental evidence from human studies A recent study has investigated the effect of metformin exposure on the human fetal testis using an in-vitro culture system (Tartarin et al., 2012) (Table ​VI). Exposure to a range of metformin concentrations (5×10−5M to 5×10−3M) resulted in a significant decrease in testosterone production from the testis. Importantly, the lowest concentration (5×10−5M) reflects the serum levels measured in humans following a therapeutic dose of metformin (Robert et al., 2003).Table VISummary of experimental studies investigating effects of pharmaceutical exposure in human fetal testis tissue.Azole antifungals and abirateroneAzole antifungals (e.g. ketoconazole, fluconazole) and abiraterone are drugs known to inhibit key enzymes of the steroidogenic pathway including P450scc (CYP17A1; ketoconazole) and CYP17A1 & 3βHSD (abiraterone). As a result, exposure of the fetal testis to these agents could be predicted to affect testosterone production and potentially to result in the development of male reproductive disorders.Epidemiology Exposure to ‘azole’ antifungals that interfere with steroidogenesis may be relevant to pregnancy, given that they are frequently prescribed for the treatment of vaginal candidiasis. No association between maternal use of antifungals and hypospadias has been reported in two studies (Carter et al., 2008) (Norgaard et al., 2008), or for AGD after exposure to antifungals administered as vaginal tablets or as topical cream (Mogensen et al., 2017). However, the latter study demonstrated a significant association between oral fluconazole and reduced AGD in the male offspring (Mogensen et al., 2017). Importantly, for each of these three studies, the numbers of cases was small and larger prospective studies would be required to provide definitive evidence of associations between antifungals and indicators of fetal testosterone production.Experimental evidence from human studies Exposure to ketoconazole results in a significant reduction (50–90%) in testosterone following in-vitro exposure of first trimester human fetal testis for 96 h (Gaudriault et al., 2017) (Table ​VI). Similar results have been described for ketoconazole with a progressive reduction in testosterone production after 24 h (−20%), 48 h (−90%) and 72 h (−95%), compared to vehicle-exposed tissue (Mazaud-Guittot et al., 2013). This study also reported a ketoconazole-induced reduction in INSL3 (−100%) and AMH (−50%) after 72 h of culture.Abiraterone (an anti-androgen used in prostate cancer) has also been shown to result in a reduction in testosterone production (−80%) in second trimester human fetal testis xenografts (grafted for 14 days), whilst no effect on germ cell number was demonstrated (Spade et al., 2014) (Table ​VI). Indeed, these agents may be considered as positive controls for studies investigating the effects of exposures on testosterone production in human fetal testes (Mazaud-Guittot et al., 2013; Spade et al., 2014).Other pharmaceuticalsA recent study has described the effect of exposure to 27 different chemicals, including several additional pharmaceuticals, on the human fetal testis using an in-vitro system (Gaudriault et al., 2017) (Table ​VI). A dose dependent reduction in testosterone production was determined for clomiphene (an anti-estrogenic substance used to stimulate ovulation), theophylline (a methylxanthine drug which acts as a non-selective phosphodiesterase inhibitor used in asthma) and valproate (an anti-epileptic) following in-vitro culture of human fetal testis tissue for 96 h (Gaudriault et al., 2017). Interestingly, valproate has been associated with hypospadias in male offspring of exposed mothers (Veroniki et al., 2017).LifestyleExposures that relate to lifestyle may also impact on the development of male reproductive disorders. However, to date only a limited number of studies using human fetal tissues have been conducted in this area (Table VII).Table VIISummary of experimental studies investigating effects of lifestyle exposures in human fetal testis tissue.XanthinesXanthines are a class of compounds that share a common structure and have stimulant properties, including caffeine, one of the most commonly used recreational drugs worldwide. Effects of several of these compounds have been investigated in vitro (Gaudriault et al., 2017).Experimental evidence from human studies No negative effects on testosterone production from cultured human fetal testis tissue were demonstrated following exposure to caffeine, paraxanthine, theobromine or 1,3,7 trimethyluric acid (TMUA), albeit there appeared to be a modest decrease in testosterone production for caffeine only at the lowest concentration (Table VII).AlcoholAlcohol exposure during pregnancy is known to impact on fetal development, and its mechanism of action could occur centrally or in the placenta. Fetal alcohol syndrome is well described and can include neurodevelopmental disorders, facial dysmorphism and growth abnormality (Nash and Davies, 2017).Epidemiology An epidemiological study involving a Danish–Finnish cohort (~2500 boys), demonstrated an association between maternal alcohol consumption and increased risk of cryptorchidism in sons (Damgaard et al., 2007).Experimental evidence from human studies The effect of exposure to alcohol on human fetal testis has only been investigated in one study (Table VII). Interestingly, exposure of first trimester human fetal testis to ethanol (10−8 M to 10−5 M for 72 h) using in-vitro culture resulted in a significant increase in testosterone production across a wide dose range (Gaudriault et al., 2017).SmokingMaternal smoking is known to have many potentially harmful effects on the developing fetus including intra-uterine growth retardation and low birth weight (Abraham et al., 2017).Epidemiology Epidemiological studies have measured sperm counts in men exposed in-utero to maternal cigarette smoke, which demonstrated a reduction in sperm concentration (38–48%) in exposed- compared to unexposed-men (Storgaard et al., 2003; Ramlau-Hansen et al., 2007). Use of nicotine substitutes during pregnancy significantly increased the risk of cryptorchidism in male offspring (Damgaard et al., 2008) and an association between maternal smoking during pregnancy and cryptorchidism in male offspring has also been demonstrated (Jensen et al., 2007).Experimental evidence from human studies Hormones One study compared testosterone levels in plasma of human fetuses exposed to maternal cigarette smoke with those of non-smoking mothers and found no difference in testosterone between the groups despite a significant reduction in hCG (Fowler et al., 2009).Germ cells The effects of maternal smoking on human fetal testis has been investigated in two experimental studies, both of which used exposure to components of cigarette smoke (Coutts et al., 2007; Angenard et al., 2010). In-vitro exposure of human fetal testis to DMBA-DHD, the active metabolite of polyaromatic hydrocarbons found in cigarette smoke, resulted in a significant increase in apoptosis in germ cells, which could be rescued by antagonism of the aryl hydrocarbon receptor (AHR), indicating that activation of the AHR is the likely mechanism for the effects of DMBA-DHD on germ cells (Coutts et al., 2007). Cadmium (another component of cigarette smoke)-exposure of first trimester human fetal testis resulted in increased apoptosis in germ cells, without any effect on testosterone production (Angenard et al., 2010).MixturesOver recent years, it has been increasingly recognized that the impact of environmental exposures depends not only on the individual agents, but also on the combination of agents. A number of animal studies have investigated the effects of ‘mixtures’; however, to date such approaches using human fetal testis tissues is limited. A key aspect of this is whether the effects can be considered as additive or synergistic. The effect of four separate mixtures (all including BPA) has been investigated in a recent study involving in-vitro exposure of first trimester human fetal testis for 96 h (Gaudriault et al., 2017). This included two mixtures (four agents each) of BPA + pharmaceuticals and two mixtures (eight agents each) which included additional environmental (pesticides and bisphenols) chemicals.As expected, each mixture resulted in a reduction in testosterone production. Importantly, the authors compared the individual dose–response results to those predicted by the additive effect of the individual agents. There was a high correlation between predicted and actual response for each of the four mixtures indicating that these agents acted in an additive manner (Gaudriault et al., 2017). This allows such experimental systems to use the results of exposure to individual agents for approximation of the combined anti-androgenic effect of multiple exposures, based on an assumption of dose-addition. This has important implications for informing regulation of environmental chemicals and pharmaceutical exposures.DiscussionWhilst a relatively large body of animal data exists for determining the impacts of in-utero exposures on fetal testicular development and male reproductive disorders, a limited number of experimental studies involving human tissues have been conducted. Animal models offer the potential to conduct more expansive studies involving exposures across multiple developmental periods and generation of dose response data. An additional advantage of animal studies is the possibility of conducting in-vivo fetal exposure studies in animals which is not possible for human studies which currently rely on in-vitro or ex-vivo (xenograft) approaches. However, this review has described several exposures for which the studies utilizing human tissues have demonstrated important differences to those found in animals. This may relate to differences in study design, dose administered or exposure regimen; however, it has also been shown that many of these differences appear to result from fundamental species differences in the effect of specific agents at human-relevant levels of exposure. Whilst epidemiological studies can to some extent bridge the gap between effects demonstrated in animal studies and human-relevance, such studies cannot demonstrate direct causation or elicit underlying mechanisms for effects; such studies are also prone to confounding. This highlights the importance of experimental models using human fetal tissues in determining the potential impact of in-utero environmental and pharmaceutical exposures in humans.Future perspectivesIt is clear that understanding effects of in-utero exposures on male reproductive development will continue to rely on interpretation of a combination of animal studies, epidemiology and experimental studies utilizing human tissues. Conducting co-ordinated studies that combine these methods represents an important approach. This may include combining experimental studies using in-vitro and in-vivo approaches (Kristensen et al., 2011; Hurtado-Gonzalez et al., 2018), studies comparing results in both rodent and human tissues (Ben Maamar et al., 2015; Hurtado-Gonzalez et al., 2018), or combined studies of epidemiological and experimental evidence (Kristensen et al., 2011).Epidemiological studies may be enhanced by developing large-scale prospective cohort studies. This is of particular importance to ensure that the timing of measurement of exposure coincides with the expected mechanism of effect (e.g. in-utero exposure and cryptorchidism/hypospadias identified in the neonatal period). Furthermore, for pharmaceuticals with relatively short half-lives, which are taken intermittently and do not accumulate in the body, obtaining accurate and detailed records of exposure during pregnancy is essential. This information is extremely difficult to obtain retrospectively and is prone to recall bias making prospective studies crucial for such exposures.The future for determining effects of in-utero exposure(s) on male testicular development and reproduction is also likely to involve refinement of existing experimental approaches. Whilst recent development of in-vitro and xenograft approaches has allowed direct testing of environmental chemicals and pharmaceuticals on the human fetal testis, these models may be limited by tissue supply and heterogeneity between individuals. The recent development of organoids for a variety of organs and tissues may prove critical for future studies to test the effects of exposures in organoids generated from human testicular tissues (Alves-Lopes and Stukenborg, 2017). Computational and mathematical modeling may also be used to predict the effects of exposure(s) in-silico (Krysiak-Baltyn et al., 2012), although this will be dependent on the robustness of the imputation of biological data.The scientific and public interest in the effects of chemical exposures in humans is likely to continue to increase. Regulation of these agents will increasingly rely on models that can provide direct human-relevant data. Therefore, we propose that assessment of the experimental evidence from studies using human fetal tissues should be an integral part of informing regulatory policies in relation to the effects of environmental and pharmaceutical exposures on male reproductive development.Supplementary MaterialHRU-18-0051-R1-SuppTables_dmz004Authors’ rolesR.T.M. developed the concept for the article. R.T.M. and K.K. performed the systematic search of the literature, assessment of eligibility, data extraction and tabulation of data. R.T.M. and K.K. wrote, revised and approved the final version of the article.FundingR.T.M. was in receipt of a Wellcome Intermediate Clinical Fellowship (Grant no. 098522). The Medical Research Council (MRC) Centre for Reproductive Health is supported by an MRC Centre Grant (MR/N022556/1). The funding bodies have had no input into the conduct of the research or the production of this article.Conflict of interestThe authors declare that they have no conflict of interest.References
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