Better explicating the strengths and shortcomings of these models will help refine projections and improve transparency in the years ahead.
Image credit: Witsawat.S.
Are you having little luck in the search for your soulmate? When you finally meet a woman does she seem disinterested? What could it be? Your breath? Your clothes? Findings from a new study (1) suggest it may be your mother's dietary exposure to bisphenol A (BPA). In the study published in PNAS, Jašarevic′ et al. (1) find that maternal BPA exposure impairs spatial ability, decreases exploratory behavior, and reduces attractiveness of male deer mice progeny. These traits are sexually dimorphic and are subjected to sexual selection because they are essential characteristics needed to find mates and reproduce in male deer mice (and other polygynous species) (2). Male deer mice, much like male meadow voles, traverse large territories during the breeding season to gain access to dispersed females (3). Female meadow voles prefer male meadow voles with better spatial ability, and male meadow voles with better spatial ability visit more female nest boxes (4, 5). Thus, home range size and spatial ability favor males in most polygynous species. Intriguingly, these sexually dimorphic traits also manifest in the hippocampus, an area important for spatial memory. Males have a larger hippocampus and greater levels of adult hippocampal neurogenesis than females during the breeding season (6, 7). The expression of sexually dimorphic spatial ability depends on both early (pre- or perinatal) and adult levels of sex hormones in rodents (3). The report by Jašarevic′ et al. (1) shows that these sexually dimorphic traits, spatial ability and exploratory behavior, in addition to attractiveness, are affected by maternal dietary exposure to the environmental endocrine disrupter BPA. Specifically, the authors show that maternal consumption of low levels of dietary BPA renders male offspring at a disadvantage for mating, not only because of poorer spatial navigation and greater anxiety-like behavior but also because they are less attractive to female conspecifics. These findings are significant as coupled with other studies, it seems that maternal dietary consumption of low levels of BPA may affect the fecundity of adult offspring through a number of mediating factors.
Bisphenol A
BPA is a synthetic xenoestrogen (8) that binds weakly to the classic estrogen receptors (ERα and ERβ) (8–10) and more potently to estrogen membrane receptors, including GPR30 and ERR-γ (8). BPA mimics as well as disrupts normal estrogen actions in a tissue-specific manner through various pathways. For example, BPA reduces levels of aromatase, binds to ERs, and acts as an androgen receptor
Maternal consumption of low levels of dietary BPA renders male offspring at a disadvantage for mating.
antagonist, and BPA's metabolites have estrogenic properties (8–10).
BPA is one of the most widely produced chemicals in the world, resulting in widespread exposure of humans to this chemical. BPA is used in the manufacturing of polycarbonate plastics, epoxy resins, and flame retardants (8–10). Exposure to BPA occurs through many sources, including reusable water bottles, baby bottles, metallic food cans, thermal paper, carbonless copy paper, and consumer electronics including computers, cell phones, and video game consoles. Indeed, a recent study found that BPA was transferred to the skin after handling receipts printed on thermal paper, although the authors were not able to assess the levels of BPA that actually penetrated into the systemic circulation (11). More research is needed before a proper evaluation of the ability of BPA to cause systemic effects after dermal exposure can be made.
The wide use of BPA in consumer products has lead to extensive human exposure: 91% of Canadians, 93% of Americans, and 99% of Germans have detectable levels of BPA (8–10). In 2008 Canada became the first country to ban the import and sale of polycarbonate baby bottles containing BPA and in 2010 added BPA to Canada's toxic substances list. In 2010 the US Food and Drug Administration announced that they had “some concern” about the potential negative effects that BPA may have on developing children.
The current acceptable limit of BPA exposure is 50 μg/kg per day for humans, but animal studies show that chronic exposure to lower levels has effects on biological processes in first- and second-generation offspring (8, 10), suggesting that a reevaluation of this acceptable limit is required (12). For example, daily exposure to this dose in adulthood for 1 month prevents the normal estradiol-induced increase in synapses in the hippocampus and prefrontal cortex of nonhuman primates (13), which could in turn impair cognition. Indeed, prenatal and postnatal BPA exposure in rodents impairs passive avoidance and spatial reference memory (8–10). Additionally, exposure to low doses of BPA (below the current acceptable dose) significantly altered estrus cyclicity and increased anogenital distance in female rodents (8). It is important to note that the maternal dose of BPA used in the study by Jašarevic′ et al. (1) is well below the acceptable dose in mice. That detrimental effects on biological processes are seen at much lower doses of BPA than are currently acceptable is certainly a concern for determining health risks in the greater population.
Maternal Hormonal State Matters
Maternal BPA may exert its effects on offspring through changes in maternal behavior or by direct exposure in the intrauterine environment. In the study by Jašarevic′ et al. (1), maternal behavior was not examined in the deer mice. However, maternal BPA exposure does influence rodent maternal behavior, as exposed dams spend less time licking their pups and on the nest. Levels of maternal behavior produce epigenetic modifications and affect spatial ability in the offspring (9). Furthermore, BPA can alter the epigenome of the fetus either directly in utero or indirectly in offspring by altering maternal behavior of the dam. Epigenetic modifications by BPA include hypo- or hypermethylating specific CpG sites in a tissue-specific manner (9). These alterations in epigenetic makeup of offspring exposed to BPA can have severe consequences for outcomes in adulthood, including disease susceptibility (9, 10). Furthermore, there may be transgenerational inheritance of adverse effects through epigenetic alterations (9).
BPA may also act as a glucocorticoid receptor agonist (8). Indeed, maternal BPA exposure influences the expression of glucocorticoid receptors in the hippocampus and corticosterone levels in adolescent females (14). There is ample evidence that maternal hormonal state during gestation or postpartum influences offspring development and vulnerability to neuropsychiatric diseases. For example, high levels of stress or exposure to glucocorticoids during gestation or postpartum influences hippocampal plasticity and spatial ability and increases vulnerability of the adult offspring to develop neuropsychiatric disorders (15). Maternal BPA exposure increases anxiety-like behavior in rodents and, consistent with the findings of the Jašarevic′ study (1), male offspring were more affected than female offspring (8–10). This is significant because postpartum corticosterone or stress exposure also increases anxiety-like behavior in adult offspring (15). Thus, the maternal hormone state, disrupted by stress or a xenoestrogen such as BPA during gestation and/or postpartum can influence the emotional and cognitive outcomes of offspring and may increase vulnerability to neuropsychiatric disorders.
BPA Exposure During Adolescence and Adulthood
There is no question that pre- and perinatal BPA exposure produces long-lasting effects in the offspring; however, adult exposure to BPA can also influence neurobiology. Exposure to BPA for 28 d eliminated the estradiol-induced increase in synapses in the hippocampus and prefrontal cortex of adult female primates (13). In addition, exposure to BPA during adolescence abolishes sex differences in anxiety-like behaviors and spatial reference memory (16). It is also possible that BPA exposure during gestation and postpartum will adversely affect the mother, beyond its effects on maternal behavior. Reproductive experience influences neuroplasticity and cognition later in life, and BPA exposure may alter these effects (17, 18). It remains to be determined whether adult exposure to BPA also produces epigenetic modifications, as occurs with pre- and perinatal exposure to BPA.
Sex Matters
One of the prominent effects of early BPA exposure is that it eliminates a number of sex differences in brain and behavior, as seen in the Jašarevic′ study (1). Elimination of these sex differences may not only disrupt reproductive behaviors but could change the physiology of females and males. These types of changes could have far-reaching repercussions for diseases that disproportionately affect the sexes.
The article in PNAS (1) also highlights another important fact: that research needs to focus on both sexes. Indeed, maternal exposure to BPA through diet reduced spatial ability, exploratory behavior, and attractiveness of the male, but not female, offspring (1). This is not to say that BPA exposure does not influence females: There have been a number of studies showing that BPA influences females as outlined above (8–10). Sex differences in the effects of sex hormones are important, but there are also significant sex differences in the efficacy of pharmacological treatments and disease manifestation (19) that are important considerations that are likely modulated by sex hormones and/or environmental endocrine disruptors.
Sex hormones play a vital role not only in reproductive behaviors but also in nonreproductive behaviors. Indeed, when a sex difference is observed this suggests that sex hormones play a role. For example, women are more likely to develop depression or Alzheimer's disease, and lower levels of sex hormones are associated with increased incidence of these diseases in men and women (19, 20). Studies demonstrate that developing male brains respond differently to maternal BPA than female brains. It is important to note that route of administration, timing of exposure, and sex likely all play a role in the manifestation of BPA's effects. It is of the utmost importance to investigate the effects on neuroplasticity and behavior in both males and females, particularly when modeling diseases that exhibit sex differences in incidence, etiology, or treatment. Moreover, it should not be surprising that a manufactured estrogenic compound that activates or inhibits normal endocrine function could disrupt a variety of sexually dimorphic functions beyond reproductive behaviors.
References
Maternal bisphenol A (BPA) decreases attractiveness of male offspring
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