Replacement Bisphenols Adversely Affect Mouse Gametogenesis with Consequences for Subsequent Generations

Abstract

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.

Environmentally-relevant exposure to diethylhexyl phthalate (DEHP) alters regulation of double-strand break formation and crossover designation leading to germline dysfunction in Caenorhabditis elegans

“…The observation that only a subset of worms exhibits alterations in meiotic progression, and therefore that not all worms in a population are equally impacted by exposure to EDCs, is supported by our previous analysis showing that only 20-30% of worms exhibited defects in germline chromosome morphogenesis following dibutyl phthalate (DBP) exposure [33]. This variability is also evident in rodent studies in which control animals accidentally exposed to BPA via cage contamination showed striking variation in meiotic recombination among litters, as determined by quantifying the number of MLH1 foci [45]. Taken together, these data indicate that environmentally-relevant levels of DEHP can result in X chromosome nondisjunction and alter meiotic progression.…”

Toxicity and multigenerational effects of bisphenol S exposure to Caenorhabditis elegans on developmental, biochemical, reproductive and oxidative stress

“…66 BPS may disrupt the balance of sex hormones and adversely affect sexual development or reproduction. 29,67 Low levels of BPS may influence the feedback regulation loop of the hypothalamic-pituitary-gonadal (HPG) axis and impair the development of offspring. 32 Mammal studies have shown that BPS could induce testicular oxidative stress and exhibit antiandrogenic properties.…”

WOMEN IN REPRODUCTIVE SCIENCE: Errors and insight: intentional and accidental studies of human chromosome abnormalities

“…In a bizarre twist, nearly exactly 20 years after the inadvertent BPA exposure of our mice launched us into the world of EDCs, we again fell victim to an environmental exposure -this time to replacement bisphenols. Details of this latest misadventure -exposure to replacement bisphenols -and the insight provided by our studies to identify and eliminate the contaminants recently have been published (Horan et al 2018, Gorence et al 2019. These data demonstrate that, like BPA, several common replacement bisphenols induce meiotic effects in both males and females.…”

“…These findings confirm the need to obtain information not only on BPA but all bisphenols to which humans are now being exposed. They also provide a ray of hope in the dismal world of BPA and replacement bisphenols, suggesting that if we could eliminate these pervasive environmental contaminants, meiotic effects resulting from exposure would persist for several generations, but ultimately return to baseline levels (Horan et al 2018).…”