Dept. of Environmental Medicine, University of Rochester School of Medicine, Rochester, NY, United States. Electronic address: marissa:
Dept. of Environmental Medicine, University of Rochester School of Medicine, Rochester, NY, United States.
Horm Behav. 2018 May;101:36-49. doi: 10.1016/j.yhbeh.2018.01.004. Epub 2018 Feb 1.
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.
金属，包括铅（Pb）、甲基汞（MeHg）和砷（As），是长期以来已知的发育神经毒物。最近，人们认识到环境背景会调节金属的毒性，包括营养状态和应激暴露。应激暴露通过内分泌系统的共同靶向（如下丘脑-垂体-肾上腺轴（HPA））来调节金属毒性。我们之前的啮齿动物研究已经确定，产前应激（PS）通过改变 HPA 和中枢神经系统系统扰乱行为，调节两种内分泌活性金属（EAMs）Pb 和 MeHg 的神经毒性。在这里，我们回顾了这项研究，并进一步测试了产前应激通过扩展到测试发育砷（As）±PS 暴露对金属神经毒性的影响来调节金属神经毒性的假设。评估了暴露于 As±PS 的母鼠后代的血清皮质酮和行为。PS 增加了雌性后代出生时的血清皮质酮，而发育性 As 暴露降低了两性的成年血清皮质酮。As+PS 诱导雌性的运动活性降低，并降低雄性的固定间隔强化程序的反应率，后者表明仅在联合暴露中存在独特的学习缺陷。暴露于 As 的雄性表现出在高架十字迷宫的开放臂中停留时间增加和新颖物体识别减少，而雌性则没有。这些数据进一步证实了以下假设，即同时暴露于化学（EAMs）和非化学（PS）应激源会导致增强的神经行为毒性。鉴于人类暴露于多种改变发育内分泌功能的环境风险因素，这种模型对于风险评估和公共卫生保护至关重要，尤其是对儿童而言。
