ENVIRONMENTAL EFFECTS ON SPERMATOGENESIS

Abstract

Compelling evidence from human populations worldwide suggest that sperm counts have declined by ~50% over the last 40 years. It is thought perinatal exposure to endocrine disrupting chemicals (EDCs), such as bisphenol A (BPA), impact the developing germline, impairing spermatogenesis. Our laboratory previously demonstrated that brief, postnatal exposure to a low-dose of BPA elicits subtle changes in the developing spermatogonial stem cell (SSC) pool, thereby affecting all descendant spermatocytes. Specifically, exposures caused permanent reductions in the frequency of meiotic recombination (scored using foci of the crossover-associated protein, MLH1, in pachytene spermatocytes). The reduction in recombination levels yielded unpartnered chromosomes at metaphase I and, consequently, spermatocyte loss. Because changes to the SSC may be transmitted to future generations, we analyzed the transgenerational effects of estrogenic exposure. However, as human exposures span generations, we further asked: What are the effects of successive generations of exposure? We utilized recombination frequency in outbred CD-1 males as a means of quantitatively tracing exposure effects of 0.25 ng/g ethinyl estradiol across generations. A complex three generation exposure protocol allowed us to compare the effects of individual, paternal, and grandpaternal (ancestral) exposure. Our data indicate that multiple generations of exposure not only exacerbate germ cell exposure effects, but also increase the incidence and severity of reproductive tract abnormalities. Environmental contaminants are increasing in both number and diversity, and several recent inadvertent exposures in our laboratory have provided strong evidence of both the ubiquity of contaminants and the sensitivity of the neonatal male germline. Although BPA use has declined, it has been replaced with a plethora of “safe” substitutes. Our data demonstrate that the effects of neonatal exposure to a low-dose (20 ng/g) of four BPA analogs – diphenyl sulfone, BPS, BPF, and BPAF – are just as hazardous as BPA. As with BPA, neonatal exposure elicited fatal meiotic errors in the adult. Moreover, effects of inadvertent environmental exposure to BPS via damaged caging materials persisted for several generations. Taken together, our findings provide sobering evidence that, particularly during early postnatal life, the male germline is vulnerable to a variety of environmental contaminants that can adversely affect long-term reproductive health.