That prenatal BPA exposure impairs offspring’s brain and behavior in experimental animals through different mechanisms is a fact difficult to neglect based on dozens of independent academic peer-reviewed studies [4]. Surprisingly, most of these studies have not been usually considered by risk assessors, based on issues related to study design, animal strains, animal number per dose group, and/or the endpoints investigated (i.e. molecular and functional changes vs. gross endpoints such as organ weights) [7]. To reconcile these divergent views, the Consortium Linking Academic and Regulatory Insights on BPA Toxicity (CLARITY-BPA), was developed by three US agencies (National Institute of Environmental Health Sciences – NIEHS; National Toxicology Program – NTP; and US Food and Drug Administration – FDA). Briefly, CLARITY-BPA conducted a traditional regulatory-style toxicology study in an FDA facility, known as the “core” study, in conjunction with academic laboratories to test previous hypothesis following the same protocol, and sharing the same animals and/or tissues [7]. CLARITY-BPA evaluated a wide range of BPA doses (2.5, 25, 250, 2500, or 25,000 μg/kg per day). Although this dose range is several orders of magnitude higher than the human exposure range, the two lowest BPA doses tested are considered of relevance to humans.
In the CLARITY-BPA program, the developing brain has again emerged as probably the most sensitive organ disrupted by BPA, as reviewed in detail by Patisaul [7]. The most consistent finding between previous experimental studies and CLARITY-BPA data is that prenatal exposure to the lowest BPA dose tested (2.5 μg/kg per day) was able to alter the gene expression of estrogen receptors (ERs) in multiple brain regions [7], in line with alterations in the volume of the anteroventral periventricular (AVPV) nucleus of the hypothalamus, implicated in sexually dimorphic physiology and behaviors [7]. Untargeted transcriptomics additionally identified the highest number of differentially expressed genes in the male hypothalamus and female amygdala [7]. However, in contrast to previous findings showing effects of developmental BPA exposure on anxiety and exploratory behaviors, CLARITY-BPA found subtle and sporadic behavioral modifications [7]. Importantly, expected normal behavioral differences between male and female animals in the unexposed controls were not detected, suggesting some specificities of the Sprague-Dawley (SD) rat strain used, which appeared to be quite insensitive to test BPA-related sex-specific behavioral outcomes previously observed in other SD strains [7].
Overall, CLARITY-BPA supports that in utero BPA exposure could predispose later responses in sexually dimorphic brain areas to estradiol and other hormones throughout development, providing a mode of action for BPA effects on brain and behavior. Results from this consortium also highlights that the expected endpoints are subtle modifications in neuroendocrine function and behavior, rather than gross alterations in brain weight among other overt damages [7, 8]. However, these subtle modifications are not usually evaluated in regulatory studies, and therefore should be systematically collected from the available peer-reviewed academic studies.
Some of the lessons derived from the CLARITY-BPA program include: i) The existence of low-dose BPA effects that were not predicted by higher doses; ii) Unequivocal alterations of ER expression across the rat brain; and iii) Multiple low-dose adverse effects, including the mammary gland, prostate, kidney and body weight among others [7, 8].
Among the concerns raised by CLARITY-BPA are the animal strain used, and probably the particular lineage of that strain, which seems to influence the specific effects observed in response to BPA. Apart from the abovementioned lack of normal sexually-dimorphic behaviors in the experimental animals, the strain used in CLARITY-BPA was also quite insensitive to low doses of known estrogens such as ethynyl estradiol (EE) [8]. These limitations could be counteracted by adopting an integrative and systematic approach to gather available animal data from several strains, considering the whole academic literature between BPA exposure and neurotoxicity.
Although animal research provides invaluable information on modes of action and potential adverse effects, there are inherent limitations when extrapolating results from experimental animal models to humans. The difference is maximized in the case of brain structure and function. For example, testosterone is aromatized to estradiol, masculinizing the rodent brain acting through ERs [7, 9]. On the contrary, the sexual differentiation of the primate and human brain appears to be primarily driven by testosterone acting without an estrogen intermediary [10, 11]. Consequently, the sexually dimorphic brain and behavioral effects frequently reported for BPA in both rodents [4] and humans [2] could be compared to some extent, but perhaps not in the same direction nor occurring through the same mechanisms of action. Based on the previous limitations, the translatability of CLARITY-BPA and animal models to humans has been questioned [12]. Thus, Hagobian (2019) argues that to truly understand its health risks, BPA should be administered to humans under controlled conditions [12]. Although a preliminary intervention trial dosing adult human volunteers with BPA has shown short-term alterations in glucose and insulin parameters [12], this approach appears unacceptable in pregnant women due to the potential risk of teratogenic and long-lasting effects on the offspring. Therefore, the valuable information available for BPA from mother-child birth cohort studies should be carefully considered in decision-making.