Arsenic Induces Differential Neurotoxicity in Male, Female, and E2-Deficient Females: Comparative Effects on Hippocampal Neurons and Cognition in Adult Rats.

We earlier reported that arsenic induced hippocampal neuronal loss, causing cognitive dysfunctions in male rats. This neuronal damage mechanism involved an altered bone morphogenetic protein (BMP2)/Smad and brain-derived neurotrophic factor (BDNF)/TrkB signaling. Susceptibility to toxicants is often sex-dependent, and hence we studied the comparative effects of arsenic in adult male and female rats. We observed that a lower dose of arsenic reduced learning-memory ability, examined through passive avoidance and Y-maze tests, in male but not female rats. Again, male rats exhibited greater learning-memory loss at a higher dose of arsenic. Supporting this, arsenic-treated male rats demonstrated larger reduction in the hippocampal NeuN and %-surviving neurons, together with increased apoptosis and altered BMP2/Smad and BDNF/TrkB pathways compared to their female counterparts. Since the primary female hormone, estrogen (E2), regulates normal brain functions, we next probed whether endogenous E2 levels in females offered resistance against arsenic-induced neurotoxicity. We used ovariectomized (OVX) rat as the model for E2 deficiency. We primarily identified that OVX itself induced hippocampal neuronal damage and cognitive decline, involving an increased BMP2/Smad and reduced BDNF/TrkB. Further, these effects appeared greater in arsenic + OVX compared to arsenic + sham (ovary intact) or OVX rats alone. The OVX-induced adverse effects were significantly reduced by E2 treatment. Overall, our study suggests that adult males could be more susceptible than females to arsenic-induced neurotoxicity. It also indicates that endogenous E2 regulates hippocampal BMP and BDNF signaling and restrains arsenic-induced neuronal dysfunctions in females, which may be inhibited in E2-deficient conditions, such as menopause or ovarian failure.