Endocrine active metals, prenatal stress and enhanced neurobehavioral disruption

Abstract

Metals, including lead (Pb), methylmercury (MeHg) and arsenic (As), are long-known developmental neurotoxicants. More recently, environmental context has been recognized to modulate metals toxicity, including nutritional state and stress exposure. Modulation of metal toxicity by stress exposure can occur through shared targeting of endocrine systems, such as the hypothalamic-pituitary-adrenal axis (HPA). Our previous rodent research has identified that prenatal stress (PS) modulates neurotoxicity of two endocrine active metals (EAMs), Pb and MeHg, by altering HPA and CNS systems disrupting behavior. Here, we review this research and further test the hypothesis that prenatal stress modulates metals neurotoxicity by expanding to test the effect of developmental As ± PS exposure. Serum corticosterone and behavior was assessed in offspring of dams exposed to As ± PS. PS increased female offspring serum corticosterone at birth, while developmental As exposure decreased adult serum corticosterone in both sexes. As + PS induced reductions in locomotor activity in females and reduced response rates on a Fixed Interval schedule of reinforcement in males, with the latter suggesting unique learning deficits only in the combined exposure. As-exposed males showed increased time in the open arms of an elevated plus maze and decreased novel object recognition whereas females did not. These data further confirm the hypothesis that combined exposure to chemical (EAMs) and non-chemical (PS) stressors results in enhanced neurobehavioral toxicity. Given that humans are exposed to multiple environmental risk factors that alter endocrine function in development, such models are critical for risk assessment and public health protection, particularly for children.