Perinatal exposure to bisphenol A or S: Effects on anxiety-related behaviors and serotonergic system.

Bisphenols, synthetic organic compounds used in the production of plastics, are an extremely abundant class of Endocrine Disrupting Chemicals, i.e., exogenous chemicals or mixtures of chemicals that can interfere with any aspect of hormone action. Exposure to BPs can lead to a wide range of effects, and it is especially dangerous if it occurs during specific critical periods of life. Focusing on the perinatal exposure to BPA or its largely used substitute BPS, we investigated the effects on anxiety-related behaviors and the serotonergic system, which is highly involved in controlling these behaviors, in adult mice. We treated C57BL/6J dams orally with a dose of 4 µg/kg body weight/day (i.e., EFSA TDI) of BPA or BPS dissolved in corn oil or with vehicle alone, at the onset of mating and continued treatment until the offspring were weaned. Adult offspring of both sexes performed the elevated plus maze and the open field tests. Then, we analyzed the serotonergic system in dorsal (DR) and median (MnR) raphe nuclei by immunohistochemical techniques. Behavioral tests highlighted alterations in BPA- and BPS-treated mice, suggesting different effects of the bisphenols exposure on anxiety-related behavior in males (anxiolytic) and females (anxiogenic). The analysis of the serotonergic system highlighted a sex dimorphism in the DR only, with control females showing higher values of serotonin immunoreactivity (5-HT-ir) than control males. BPA-treated males displayed a significant increase of 5-HT-ir in all analyzed nuclei, whereas BPS-treated males showed an increase in ventral DR only. In females, both bisphenols-treated groups showed a significant increase of 5-HT-ir in dorsal DR compared to the controls, and BPA-treated females also showed a significant increase in MnR.These results provide evidence that exposure during the early phases of life to BPA or BPS alters anxiety and the raphe serotonergic neurons in a sex-dependent manner.

Effects of perinatal exposure to bisphenol A or S in EAE model of multiple sclerosis.

Epidemiological studies support the idea that multiple sclerosis (MS) is a multifactorial disease, overlapping genetic, epigenetic, and environmental factors. A better definition of environmental risks is critical to understand both etiology and the sex-related differences of MS. Exposure to endocrine-disrupting compounds (EDCs) fully represents one of these risks. EDCs are natural or synthetic exogenous substances (or mixtures) that alter the functions of the endocrine system. Among synthetic EDCs, exposure to bisphenol A (BPA) has been implicated in the etiology of MS, but to date, controversial data has emerged. Furthermore, nothing is known about bisphenol S (BPS), one of the most widely used substitutes for BPA. As exposure to bisphenols will not disappear soon, it is necessary to clarify their role also in this pathological condition defining their role in disease onset and course in both sexes. In this study, we examined, in both sexes, the effects of perinatal exposure to BPA and BPS in one of the most widely used mouse models of MS, experimental autoimmune encephalomyelitis (EAE). Exposure to bisphenols seemed to be particularly deleterious in males. In fact, both BPA- and BPS-treated males showed anticipation of the disease onset and an increased motoneuron loss in the spinal cord. Overall, BPA-treated males also displayed an exacerbation of EAE course and an increase in inflammation markers in the spinal cord. Analyzing the consequences of bisphenol exposure on EAE will help to better understand the role of both xenoestrogens and endogenous estrogens on the sexually dimorphic characteristics of MS.

Effects of chronic exposure to bisphenol A in adult female mice on social behavior, vasopressin system, and estrogen membrane receptor (GPER1).

Bisphenol A (BPA), an organic synthetic compound found in some plastics and epoxy resins, is classified as an endocrine disrupting chemical. Exposure to BPA is especially dangerous if it occurs during specific "critical periods" of life, when organisms are more sensitive to hormonal changes (i.e., intrauterine, perinatal, juvenile or puberty periods). In this study, we focused on the effects of chronic exposure to BPA in adult female mice starting during pregnancy. Three months old C57BL/6J females were orally exposed to BPA or to vehicle (corn oil). The treatment (4 µg/kg body weight/day) started the day 0 of pregnancy and continued throughout pregnancy, lactation, and lasted for a total of 20 weeks. BPA-treated dams did not show differences in body weight or food intake, but they showed an altered estrous cycle compared to the controls. In order to evidence alterations in social and sociosexual behaviors, we performed the Three-Chamber test for sociability, and analyzed two hypothalamic circuits (well-known targets of endocrine disruption) particularly involved in the control of social behavior: the vasopressin and the oxytocin systems. The test revealed some alterations in the displaying of social behavior: BPA-treated dams have higher locomotor activity compared to the control dams, probably a signal of high level of anxiety. In addition, BPA-treated dams spent more time interacting with no-tester females than with no-tester males. In brain sections, we observed a decrease of vasopressin immunoreactivity (only in the paraventricular and suprachiasmatic nuclei) of BPA-treated females, while we did not find any alteration of the oxytocin system. In parallel, we have also observed, in the same hypothalamic nuclei, a significant reduction of the membrane estrogen receptor GPER1 expression.