Academic journal article Environmental Health Perspectives

Systems Toxicology of Male Reproductive Development: Profiling 774 Chemicals for Molecular Targets and Adverse Outcomes

Academic journal article Environmental Health Perspectives

Systems Toxicology of Male Reproductive Development: Profiling 774 Chemicals for Molecular Targets and Adverse Outcomes

Article excerpt

Introduction

Exposure to chemicals during prenatal development may increase the risk of adverse outcomes, and biomonitoring studies suggest pregnant women are exposed to multiple environmental chemicals (Woodruff et al. 2011). Adverse trends in male developmental reproductive health have been reported for rates of testicular germ cell tumors (TGCT), low semen quality, and relatively common human developmental defects such as undescended testes (cryptorchidism) and malformations of the genital tubercle (e.g., hypospadias) (Sharpe and Skakkebaek 2008; Virtanen et al. 2005).

The testicular dysgenesis syndrome (TDS) hypothesis posits an interrelationship among these adverse outcomes, as manifestations of altered prenatal testicular development in humans (Aschim et al. 2004; Bay et al. 2006; Biggs et al. 2002; Kaleva and Toppari 2005; Scott et al. 2007; Sharpe and Skakkebaek 2008; Skakkebaek et al. 2001). Epidemiological studies, however, provide scant support for a shared mechanistic origin of the four elements contributing to the TDS hypothesis (decreased sperm counts/infertility/subfertility, and common developmental defects such as cryptorchidism and hypospadias, and increasing incidences of TGCT) (Akre and Richiardi 2009). On the other hand, human studies have reported associations between at least some adverse outcomes of male reproductive tract development: shortened anogenital distance (AGD) in boys with undescended testis (Jain and Singal 2013); reduced AGD/ penile length in patients with hypospadias or cryptorchidism (Thankamony et al. 2014); and TGCT with cryptorchidism/hypospadias/ genital malformations (Trabert et al. 2013). The TDS hypothesis is difficult to test experimentally because of the inaccessibility of the fetal testis during formation and organization (8-12 weeks gestation), the lengthy period between induction and manifestation of some adult outcomes (20-45 years), the lack of definitive etiology for prenatal studies underlying hypospadias/cryptorchidism, and the lack of animal models for TGCT (Sharpe and Skakkebaek 2008).

Evidence for reduced androgenicity in the human TDS hypothesis comes from linkage studies correlating TDS elements to familial mutations in the androgen receptor (AR) (Lottrup et al. 2013). Studies using animal models of prenatal endocrine dysfunction have shown increased incidence rates for cryptorchidism, hypospadias, and low sperm quality following exposure to environmental compounds that may be acting through an anti-androgenic mode of action (Gray et al. 2006; Hu et al. 2014; Mylchreest et al. 1998, 2000, 2002; Sharpe and Skakkebaek 2008; Virtanen et al. 2005; Wilson et al. 2008). For example, exposure of pregnant rats to dibutyl phthalate (DBP) during the critical period of male reproductive development resulted in reduced AGD, increased cryptorchidism and hypospadias, testicular atrophy with germ cell loss, and weight reductions in the epididymis, seminal vesicles, and prostate (Mylchreest et al. 1998, 2000). Exposure of pregnant rats to di(2-ethylhexyl) phthalate (DEHP) resulted in abnormal testes development with large aggregates or clusters of Leydig cells in the interstitial spaces, multinucleated germ cells in the seminiferous cords, and significant reductions in testosterone levels in the fetal rat testis (Parks et al. 2000). Phthalates may increase testicular testosterone production (low-dose effect) in fetal rats, but higher dosages decrease testosterone production in the fetal testis, thereby leading to reduced AGD and increased rates of cryptorchidism (Ge et al. 2007). The effect on fetal testosterone production has been linked to reduced expression of steriodogenic enzymes (CYP17, CYP11a, StAR) and insulin-like 3 (INSL3) (Wilson et al. 2008). INSL3, a Leydig cell hormone that drives development of the gubernaculum, may underlie phthalate-induced cryptorchidism (Johnson et al. 2010). These findings support the connectivity to prenatal disruption of androgen signaling (AR mutations in the human TDS hypothesis) or androgen homeostasis (phthalate syndrome in rats) during the critical period of sexual differentiation. …

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