Sex and dose-dependent effects of developmental exposure to bisphenol A on anxiety and spatial learning in deer mice (Peromyscus maniculatus bairdii) offspring

Abstract

Bisphenol A (BPA) is a widely produced, endocrine disrupting compound that is pervasive in the environment. Data suggest that developmental exposure to BPA during sexual differentiation of the brain leads to later behavioral consequences in offspring. Outbred deer mice (Peromyscus maniculatus bairdii) are an excellent animal model for such studies as they exhibit well-defined sex- and steroid-dependent behaviors. Here, dams during gestation and lactation were fed a phytoestrogen-free control diet, the same diet supplemented with either ethinyl estradiol (0.1 parts per billion), or one of three doses of BPA (50 mg, 5 mg, 50 μg/kg feed weight). After weaning, pups were maintained on control diet until they reached sexually maturity and then assessed for both spatial learning capabilities and anxiety-like and exploratory behaviors. Relative to controls, males exposed to the two upper but not the lowest dose of BPA demonstrated similar impairments in spatial learning, increased anxiety and reduced exploratory behaviors as ethinyl estradiol-exposed males, while females exposed to ethinyl estradiol, but not to BPA, exhibited masculinized spatial abilities. We also determined whether dams maintained chronically on the upper dose of BPA contained environmentally relevant concentrations of BPA in their blood. While serum concentrations of unconjugated BPA in controls were below the minimum level of detection, those from dams on the BPA diet were comparable (5.48 ± 2.07ng/ml) to concentrations observed that have been observed in humans. Together, these studies demonstrate that developmental exposure to environmentally relevant concentrations of BPA can disrupt adult behaviors in a dose- and sex-dependent manner.

Environmental Health Factors and Sexually Dimorphic Differences in Behavioral Disruptions

“…Across animal models, male sexually selected traits that affect intrasexual competition and intersexual choice appear to be especially vulnerable to the EDCs that have been tested to date. EDCs also seem to exert sex-specific effects on anxiety/depressive-like behaviors in animal models and human epidemiological studies [24••, 39, 49, 58–60, 63–65]. While only a handful of studies have directly assessed linkages between BPA exposure and sex-specific behavioral differences in humans, a somewhat consistent finding is that prenatal BPA exposure is linked to increased externalizing behavioral problems, particularly in older boys [63–65].…”

“…Consequently, this behavior might be considered a sexually selected cognitive trait, which requires prenatal exposure to testosterone and photoperiod-dependent increases in this same hormone [47, 48]. Developmental exposure to environmentally relevant concentrations of BPA or ethinyl estradiol (EE) through the maternal diet compromises this behavior in males, as determined when both sexes are tested at adulthood in a dry-land spatial navigation maze (a Barnes maze) [24••, 49]. Under the notion that BPA may act through its weak binding of ESR1/ESR2 [43], the US Food and Drug Administration (FDA) has mandated that any study that is to be considered in influencing policy decisions must include EE as a positive control.…”

“…However, females that are developmentally exposed to a low dose of BPA or EE at doses comparable to human exposure exhibit masculinized or increased spatial abilities and exploratory behaviors [24••, 49]. …”

Loss of Hippocampal Oligodendrocytes Contributes to the Deficit of Contextual Fear Learning in Adult Rats Experiencing Early Bisphenol A Exposure

“…Continuous BPA exposure during this period has been shown to have profound effects on the brain and behavior [8], leading to altered learning and memory [9][10][11], hyperactivity [12], increased expression of anxiety, and aggression [11]. As such, early BPA exposure (EBE) has been linked to the development of some neuropsychiatric disorders such as autism, schizophrenia in the later life [12][13][14].…”

Bisphenol A Exposure During Early Development Induces Sex-Specific Changes in Adult Zebrafish Social Interactions

“…Even in non-social behaviors, e.g., learning, emotion and exploration, males and females displayed differential outcomes due to developmental BPA exposures (human: Perera et al 2012; Braun et al 2011, 2009; fish: Saili et al 2012; mice: Jaṧareviḉ et al 2013; Kundakovic et al 2013; Palanza et al 2008 rats: Jones et al 2011). These behavioral disruptions are strongly correlated with a range of molecular, physiological, and organ-level mechanisms involved in sex-dependent behaviors, e.g., brain ER gene expression (rat: Cao et al 2013), fetal ovarian and gonadal development (fish: Chung et al 2011; mice: Kundakovic et al 2013; Tainaka et al 2012; Xi et al 2011a, 2011b; rat: Cao et al 2013; sheep: Veifa-Lopez et al 2013), pituitary and gonadotrophin development (mice: Brannick et al 2012), brain and gonadal enzyme activity (rat: Nanjappa et al 2012), altered hypothalamic-pituitary-gonadal (HPG) axis activity (mice: Xi et al 2011a; rats: Ramos et al 2003), and circulating testosterone levels (mice: Tanaka et al 2006).…”