Zhou Rong, Chen Fang, Feng Xuejiao, Zhou Libin, Li Yingchun, Chen Ling
State Key Lab of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, China.
Department of Physiology, Nanjing Medical University, Nanjing 210029, China.
J Psychiatr Res. 2015 May;64:121-9. doi: 10.1016/j.jpsychires.2015.02.018. Epub 2015 Mar 11.
The present study focuses on detecting anxiety-like behavior and associated neurochemical alterations in adolescent rats exposed perinatally to bisphenol A (BPA), an estrogen-mimicking endocrine disrupter and investigating the possible involvement of metabotropic glutamate 2/3 receptors (mGlu2/3 receptors) in BPA-induced anxiogenic effects.
When female breeders were administered orally with BPA (40 μg/kg/d) during pregnancy and lactation, their pups (here named 'BPA-exposed offspring') developed an anxiety-like phenotype, characterized by the hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis, impaired glucocorticoid receptor (GR)-mediated negative feedback regulation of the HPA axis, altered hippocampal synaptic plasticity and increased anxiety-like behaviors. BPA-exposed offspring also showed a reduced expression of mGlu2/3 receptors in the hippocampus. BPA-exposed offspring further subjected to systemic administration of mGlu2/3 receptor agonist (LY379268, 0.5 mg/kg, i.p.) or antagonist (LY341495, 1.5 mg/kg, i.p.) twice per day for 6 days. The results indicated that chronic LY379268 treatment corrected the anxiety-like behaviors and associated neurochemical and endocrinological alterations in BPA-exposed offspring.
Our data demonstrate for the first time that the perinatal BPA exposure induces an anxiety-like phenotype in behaviors and -related neuroendocrinology, and suggest that the changes in mGlu2/3 receptor might lie at the core of the pathological reprogramming triggered by early-life adversity. mGlu2/3 receptor may serve as a novel biomarker and potential therapeutic target for anxiety disorders associated with adverse early-life agents including perinatal BPA exposure.
本研究聚焦于检测围产期暴露于双酚A（BPA，一种雌激素模拟内分泌干扰物）的青春期大鼠的焦虑样行为及相关神经化学改变，并探究代谢型谷氨酸2/3受体（mGlu2/3受体）在BPA诱导的致焦虑效应中的可能作用。
当雌性繁殖大鼠在怀孕和哺乳期经口给予BPA（40μg/kg/d）时，它们的幼崽（此处称为“BPA暴露后代”）出现焦虑样表型，其特征为下丘脑-垂体-肾上腺（HPA）轴功能亢进、糖皮质激素受体（GR）介导的HPA轴负反馈调节受损、海马突触可塑性改变以及焦虑样行为增加。BPA暴露后代海马中的mGlu2/3受体表达也降低。对BPA暴露后代进一步每天两次全身给予mGlu2/3受体激动剂（LY379268，0.5mg/kg，腹腔注射）或拮抗剂（LY341495，1.5mg/kg，腹腔注射），持续6天。结果表明，慢性LY379268治疗纠正了BPA暴露后代的焦虑样行为及相关神经化学和内分泌改变。
我们的数据首次证明，围产期BPA暴露会在行为和相关神经内分泌方面诱导出焦虑样表型，并表明mGlu2/3受体的变化可能是早期生活逆境引发的病理重编程的核心。mGlu2/3受体可能作为一种新型生物标志物以及与包括围产期BPA暴露在内的不良早期生活因素相关的焦虑症的潜在治疗靶点。
