Perinatal exposure to 50 ppb sodium arsenate induces hypothalamic-pituitary-adrenal axis dysregulation in male C57BL/6 mice.
Perinatal exposure to 50 ppb sodium arsenate induces hypothalamic-pituitary-adrenal axis dysregulation in male C57BL/6 mice.
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DOI：
10.1016/j.neuro.2012.08.010
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发表时间：
2012-10
期刊：
影响因子：
3.4
通讯作者：
Allan AM
中科院分区：
文献类型：
--
作者：
Goggin SL;Labrecque MT;Allan AM
在过去的二十年中，在理解不仅在高水平砷暴露（> 1 ppm）之后发生的复杂病理学方面取得了关键进展，而且在以前被认为是低水平（<100 ppb）之后也发生了这种病理学。过去的研究表明，砷对心血管、肺、免疫、呼吸、内分泌和神经系统的各种功能产生有害影响。其他研究表明，即使在非常低的砷暴露水平下，多种癌症的风险也会增加，精神病理学的发病率也会增加。下丘脑-垂体-肾上腺（HPA）轴代表了一个多位点整合中心，调节广泛的生物和生理过程：该系统内的故障可以产生一系列深远的影响，使其成为砷介导的损伤的一个有趣的候选人。我们使用小鼠模型，通过评估促肾上腺皮质激素释放因子（CRF）、阿黑皮素原（Pomc）mRNA、促肾上腺皮质激素（ACTH）、皮质酮（CORT）、11β-羟类固醇脱氢酶1（11β-HSD 1）和糖皮质激素受体（GR）蛋白和mRNA，检测围产期暴露于50 ppb砷酸钠对HPA轴功能的影响。与对照组相比，我们观察到围产期砷暴露的后代表现出下丘脑CRF的增加，在基线和应激反应中CORT分泌的改变，海马11β-HSD 1的减少和下丘脑亚细胞GR分布的改变。这些数据表明，显着HPA轴损伤，在出生后35天造成围产期暴露于50 ppb的砷酸钠。我们的研究结果表明，这一关键的调节轴的失调可能是暴露于砷后观察到的重要分子和认知病理学的基础。
Over the past two decades, key advancements have been made in understanding the complex pathology that occurs following not only high levels of arsenic exposure (>1ppm) but also levels previously considered to be low (<100 ppb). Past studies have characterized the deleterious effects of arsenic on the various functions of cardiovascular, pulmonary, immunological, respiratory, endocrine and neurological systems. Other research has demonstrated an elevated risk of a multitude of cancers and increased rates of psychopathology, even at very low levels of arsenic exposure. The hypothalamic-pituitary-adrenal (HPA) axis represents a multisite integration center that regulates a wide scope of biological and physiological processes: breakdown within this system can generate an array of far-reaching effects, making it an intriguing candidate for arsenic-mediated damage. Using a mouse model, we examined the effects of perinatal exposure to 50 ppb sodium arsenate on the functioning of the HPA axis through the assessment of corticotrophin-releasing factor (CRF), proopiomelanocortin (Pomc) mRNA, adrenocorticotrophin hormone (ACTH), corticosterone (CORT), 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD 1), and glucocorticoid receptor (GR) protein and mRNA. Compared to controls, we observed that the perinatal arsenic-exposed offspring exhibit an increase in hypothalamic CRF, altered CORT secretion both at baseline and in response to a stressor, decreased hippocampal 11β-HSD 1 and altered subcellular GR distribution in the hypothalamus. These data indicate significant HPA axis impairment at post-natal day 35 resulting from perinatal exposure to 50 ppb sodium arsenate. Our findings suggest that the dysregulation of this critical regulatory axis could underlie important molecular and cognitive pathology observed following exposure to arsenic.
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