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Accidental exposure of our mice to bisphenol A (BPA) from damaged polycarbonate cages 20 y ago provided some of the first evidence of the harmful effects of exposure to this common chemical. Recently we found that housing mice in damaged polysulfone cages resulted in similar harmful effects due to exposure to bisphenol S (BPS). This problem was unexpected for 2 reasons. First, polysulfone is a far more chemically resistant polymer than polycarbonate. Second, BPS is not a component in the manufacture of polysulfone. We report here our efforts to verify the source of the BPS and eliminate the exposure. Our analysis of new polysulfone caging materials confirmed that BPS is a breakdown product of damaged polysulfone plastic. Furthermore, we found that BPS can cross-contaminate new or undamaged cages in facilities that process damaged caging materials. Neither the use of disposable cages nor replacement of caging materials used solely for our colony was sufficient to eliminate exposure effects. Only the replacement of all cages and water bottles in the facility corrected the problem and allowed us to resume our studies. Taken together, our previous and current findings underscore the concern that chemicals from plastics are harmful environmental contaminants for both humans and animals. Furthermore, our results provide strong evidence that the presence of damaged plastic in a facility may be sufficient to affect research results and, by extension, animal health.

The hypothesis that developmental estrogenic exposure induces a constellation of male reproductive tract abnormalities is supported by experimental and human evidence. Experimental data also suggest that some induced effects persist in descendants of exposed males. These multi- and transgenerational effects are assumed to result from epigenetic changes to the germline, but few studies have directly analyzed germ cells. Typically, studies of transgenerational effects have involved exposing one generation and monitoring effects in subsequent unexposed generations. This approach, however, has limited human relevance, since both the number and volume of estrogenic contaminants has increased steadily over time, intensifying rather than reducing or eliminating exposure. Using an outbred CD-1 mouse model, and a sensitive and quantitative marker of germline development, meiotic recombination, we tested the effect of successive generations of exposure on the testis. We targeted the germline during a narrow, perinatal window using oral exposure to the synthetic estrogen, ethinyl estradiol. 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. Taken together, our data suggest that male sensitivity to environmental estrogens is increased by successive generations of exposure., Author summary Developmental exposure to manmade chemicals that interfere with endogenous hormones (endocrine disrupting chemicals) has been reported to adversely affect male reproductive health, increasing the incidence of reproductive tract abnormalities and reducing sperm production. Experimental evidence suggests that some exposure effects can persist in unexposed descendant males. To date, however, studies of these transgenerational effects have failed to accurately model human exposure, which spans multiple generations and involves an increasing number and diversity of endocrine disrupting chemicals. Using a quantitative measure of exposure effects on the germline, we assessed the effects of successive generations of estrogenic exposure in mice. We found that multiple generations of exposure not only exacerbated previously reported effects on the male germline, but elicited reproductive tract defects that increased in frequency and severity. These results have important implications for human reproductive health, suggesting that multiple generations of exposure to common endocrine disrupting chemicals may increase male sensitivity to exposure.

In the span of a single generation, we have witnessed a revolution in the treatment of human infertility. The first baby conceived through in vitro fertilization (IVF) was born in 1978, and the nearly four decades since have produced an ever-increasing variety of treatment options available to men and women with impaired fertility. The development of treatments for patients with complete gametogenic failure represents the next frontier in the treatment of infertility, and recent technical advances in induced pluripotent stem (iPS) cell technology and in vitro culture suggest that this is within our grasp. Our understanding, however, of the environmental cues that shape the development of normal gametes and embryos remains woefully inadequate. In developing treatments for male infertility, an understanding of the normal testicular environment and how perturbations to it affect the programming of the spermatogonial stem cell (SSC) and its descendants is essential. This knowledge will drive the development of in vitro systems both for the culture of SSCs and the support of spermatogenesis ex vivo, and is essential in assessing the risk to male reproductive health posed by exposure to common environmental pollutants. In this chapter, we review current knowledge of naturally occurring environmental influences, focusing on the stages of male germ cell development they affect. Using this context, we summarize the best-characterized effects of exogenous exposures to endocrine disrupting chemicals (EDCs) on the male germline and questions currently driving the field.

Summary 20 years ago, accidental bisphenol A (BPA) exposure caused a sudden increase in chromosomally abnormal eggs from our control mice [1]. Subsequent rodent studies demonstrated developmental effects of exposure with repercussions on adult health and fertility (e.g., [2–9]; reviewed in [10–17]). Studies in monkeys, humans, fish, and worms suggest BPA effects extend across species (e.g., [18–30]; reviewed in [31–33]). Widespread use has resulted in ubiquitous environmental contamination and human BPA exposure. Consumer concern resulted in "BPA-free" products produced using structurally similar bisphenols that are now detectable environmental and human contaminants (e.g., [34–41]). We report here studies initiated by meiotic changes mirroring our previous BPA experience and implicating exposure to BPS (a common BPA replacement) from damaged polysulfone cages. Like with BPA [1, 2, 5], our data show that exposure to common replacement bisphenols induces germline effects in both sexes that may affect multiple generations. These findings add to growing evidence of the biological risks posed by this class of chemicals. Rapid production of structural variants of BPA and other EDCs circumvents efforts to eliminate dangerous chemicals, exacerbates the regulatory burden of safety assessment, and increases environmental contamination. Our experience suggests that these environmental contaminants pose a risk not only to reproductive health but also to the integrity of the research environment. EDCs, like endogenous hormones, can affect diverse processes. The sensitivity of the germline allows us to detect effects that, although not immediately apparent in other systems, may induce variability that undermines experimental reproducibility and impedes scientific advancement.