Estrogen-Like Disruptive Effects of Dietary Exposure to Bisphenol A or 17α-Ethinyl Estradiol in CD1 Mice

Abstract

Bisphenol A (BPA) is an endocrine disrupting chemical that is ubiquitous in wild and built environments. Due to variability in study design, the disruptive effects of BPA have proven difficult to experimentally replicate. This study was designed to assess the disruptive actions of dietary BPA exposure, while carefully controlling for known confounders. Parental CD1 mice were acclimated to defined diet containing BPA (0.03, 0.3, 3, 30, or 300 ppm) or 17α-ethinyl estradiol (EE; 0.0001, 0.001, and 0.01 ppm) and bred to produce progeny (F1) that were maintained through adulthood on the same diet as the parents. In F1 females, uterine weights were increased in all EE and the 30-ppm BPA-exposure groups, demonstrating model sensitivity and estrogen-like actions of BPA. In BPA-exposed females, no treatment-related differences were observed in parental reproductive function, or in the timing of puberty and metabolic function in female offspring. In F1 males, modest changes in body weight, adiposity and glucose tolerance, consistent with improved metabolic function, were observed. Associated with increased prolactin and increased circulating testosterone levels, balanopreputial separation was accelerated by 0.03 and 3.0 ppm BPA and anogenital distance at postnatal day 21 was increased in males by 0.03 ppm BPA. Sperm counts were also increased with 3.0 ppm BPA exposures. Overall, BPA was found to have modest, sex specific endocrine disruptive effects on a variety of end points below the established no observed adverse effect level. The dose response characteristics for many of the effects were nonmonotonic and not predictable from high-dose extrapolations.

Comparison of endpoints relevant to toxicity assessments in 3 generations of CD-1 mice fed irradiated natural and purified ingredient diets with varying soy protein and isoflavone contents

“…Similarly, others have used soy-free diets in multigenerational reproductive studies in rats and mice ( e.g. , Kendig et al, 2012; Sprando et al, 2000); however, some literature suggested that the specific soy- and alfalfa-free diet that we had used might be problematic in studies in the CD-1 mouse (Ruhlen et al, 2008). This diet, designated 5K96, was originally designed to be nutritionally equivalent to the open-formula NIH-31 diet.…”

Early programing of uterine tissue by bisphenol A: Critical evaluation of evidence from animal exposure studies

“…However, these results may not be reliable, as estrus cycling is not yet consistent in mice at this age, and given the small number of individual mice studied (n=5 per group). This study, and three others [69–71], examine effects of BPA on uterine weights. Unfortunately, none of these studies [61,67–71] reported measures to control for effects of the estrus cycle on uterine weights, i.e.…”

“…This study, and three others [69–71], examine effects of BPA on uterine weights. Unfortunately, none of these studies [61,67–71] reported measures to control for effects of the estrus cycle on uterine weights, i.e. by collecting uteri at a consistent stage of the estrus cycle.…”

“…The uterus also responds to estrogens by increasing cell division, which contributes to uterine growth [72,73]. These studies [61,67–71] were therefore excluded from further consideration.…”

“…Early BPA exposure was reported to have various effects on uterine weight later in life [68–71], however, none of these studies explicitly controlled for the estrus cycle stage when the uteri were collected. Indeed, no effect on uterine weight or effect of only very high dose [75] was seen in seven other studies where the estrus cycle stage when tissues were collected was properly controlled [62,74–79].…”