The prevalence of neuropsychiatric disorders has risen globally at an alarming rate. The ubiquitous presence of endocrine disrupting chemicals (EDCs), which are capable of mimicking hormones in the body and disrupting endocrine system functioning, is suspected to contribute to declining mental health. Fetal programming with these chemicals, specifically, can reorganize developing systems in the body and predispose the fetus to adverse health outcomes throughout life. Additionally, changes in estrogen are also linked with increased susceptibility to mood disorders in women. We hypothesized that fetal programming of Sprague-Dawley rats with various EDCs, especially EDC mixtures, would sex- and dose-dependently alter stress-related behaviors and neurobiological mechanisms. Chronic treatment with estradiol (E2) in female offspring would exacerbate these effects. Our results confirm that male and female offspring behaviors are differentially affected as a result of prenatal EDC exposure. In male offspring, exposure to multiple EDCs reduced their ability to defend themselves from an aversive stimulus in an active manner. Di-(2-ethylhexyl) phthalate (DEHP) treatment at a low dose induced a passive behavioral phenotype in male offspring, whereas high-dose (HD) DEHP treatment feminized anxiety-like behavior. Female offspring showed altered anxiety-like and defensive behaviors in response to prenatal EDCs at low doses, particularly to the bisphenol A (BPA) + DEHP mixture. Within the brain, EDC-exposed male offspring had marked deficits in dopamine levels in the paraventricular hypothalamic nucleus, which was correlated with their defensive behaviors. Female offspring with DEHP (HD) treatment alone or in combination with BPA showed a persistent hyperactivity of monoaminergic activity in the brain. In healthy control female offspring, E2 treatment in adulthood increased unconditioned anxiety and reduced active coping abilities. In EDC-exposed females, contrastingly, E2 treatment often reversed or abolished the effects on behavior and brain neurotransmitters observed in sham counterparts, implying that EDCs interact with E2 to alter neurobehavior. Finally, we also discovered that prenatal exposure to BPA analogues has deleterious effects on reproductive parameters in both dams and offspring, rendering them unsafe alternatives to BPA. These findings raise concerns about EDC mixtures and low-dose EDC exposures in male and female offspring, and call for increased regulation of these chemicals.
