Mechanisms of atrazine endocrine disruption

项目摘要 内分泌干扰物（EDCs）是一组广泛的化学物质，可导致无数的不良健康 方面的影响.迄今为止，大多数研究都集中在下游目标系统和不良健康结果上 受EDC暴露的影响，但现在有越来越多的证据表明神经内分泌的主要目标。与 下丘脑作为多个内分泌轴的中央调节器，许多不同的特异性 对于靶向神经内分泌系统的EDCs，可以观察到不利的健康结果。阿特拉津 EDC是美国第二大最常用的农业除草剂， 饮用水供应中的污染物。阿特拉津受美国环境保护署（EPA）监管 在饮用水中的浓度为十亿分之三（ppb; µg/L），但浓度高于这一规定 限制经常被报道。实验室和流行病学研究报告了各种内分泌干扰和 神经系统的不良影响。大多数发现集中在沿着下丘脑-垂体-性腺轴，但 研究还观察到对下丘脑-垂体-甲状腺和下丘脑-垂体-肾上腺的干扰 轴。总体而言，研究支持阿特拉津影响多个内分泌轴， 下丘脑毒性靶点，但机制尚未明确阐明，需要进一步研究。在 此外，目前美国环保局关于阿特拉津的内分泌干扰作用的报告相互矛盾 最大污染物水平（MCL）为3 ppb。我们使用斑马鱼模型系统的研究表明， 胚胎暴露于浓度范围为1/10 X至10 X的阿特拉津， 与神经和生殖系统发育相关的基因表达改变， 功能、细胞周期和致癌作用;参与神经元细胞凋亡的microRNAs（miRNAs）的失调 分化和成熟与癌症;全球低甲基化;以及幼虫头部长度的改变。 此外，我们观察到胚胎阿特拉津暴露的成年人产卵成功率下降。 这些成年女性也有卵巢孕酮和卵泡闭锁的增加， 5-羟色胺代谢物和大脑中5-羟色胺的周转。与不同分子相关的基因改变 在成年雌性的脑组织中观察到内分泌和中枢神经系统的通路， 男性。这些研究支持胚胎阿特拉津暴露足以导致以后的生活不良 与多个内分泌轴相关的健康结果。本研究的中心假设是， 神经内分泌系统是阿特拉津内分泌干扰的靶点。我们试图定义的机制， 胚胎阿特拉津暴露的毒性，可以解释观察到的分子和功能结果 过去关于多个内分泌轴的研究。我们将评估几个神经内分泌终点， 胚胎发生，以确定下丘脑和/或垂体发育和神经元结构的破坏 和下丘脑-垂体界面的轴突生长改变。

PROJECT SUMMARY Endocrine disrupting chemicals (EDCs) are a broad group of chemicals resulting in a myriad of adverse health effects. Most research to date has focused on the downstream target systems and adverse health outcomes affected by EDC exposure, but there is now increasing evidence for neuroendocrine primary targets. With the hypothalamus serving as the central regulator of multiple endocrine axes, a multitude of different specific adverse health outcomes may be observed for EDCs that target the neuroendocrine system. Atrazine, an EDC, is the second most commonly used agricultural herbicide in the United States and is the most common contaminant in potable water supplies. Atrazine is regulated by the US Environmental Protection Agency (EPA) at a concentration of 3 parts per billion (ppb; µg/L) in drinking water, but concentrations above this regulatory limit are often reported. Laboratory and epidemiology studies report various endocrine disrupting and neurological adverse impacts. Most findings are focused along the hypothalamus-pituitary-gonadal axis, but studies also observe interference with the hypothalamus-pituitary-thyroid and hypothalamus-pituitary-adrenal axes. Overall, studies support that atrazine influences multiple endocrine axes and the hypothesis of a hypothalamic toxicity target, but the mechanisms are not yet clearly elucidated and warrant further research. In addition, there are conflicting reports of the endocrine disrupting effects of atrazine near the current US EPA maximum contaminant level (MCL) of 3 ppb. Our studies using the zebrafish model system show that an embryonic atrazine exposure at concentrations ranging from 1/10X to 10X the current US EPA MCL resulted in expression alterations in genes associated with neurological and reproductive system development and function, cell cycle, and carcinogenesis; deregulation of microRNAs (miRNAs) involved with neuronal differentiation and maturation and cancer; global hypomethylation; and altered head length in larvae. Furthermore, we observed a decrease in spawning success in adults with an embryonic atrazine exposure. These adult females also had an increase in ovarian progesterone and follicular atresia and a decrease in a serotonin metabolite and serotonin turnover in the brain. Alterations in genes associated with distinct molecular pathways of the endocrine and central nervous systems were observed in brain tissue of the adult females and males. These studies support an embryonic atrazine exposure is sufficient to result in later in life adverse health outcomes associated with multiple endocrine axes. The CENTRAL HYPOTHESIS of this study is that the neuroendocrine system is the target of atrazine endocrine disruption. We seek to define the mechanisms of toxicity of an embryonic atrazine exposure that would explain the observed molecular and functional outcomes of past studies on multiple endocrine axes. We will evaluate several neuroendocrine endpoints during embryogenesis to identify disruption of the hypothalamus and/or pituitary development and neuronal structure and axonal growth alterations at the hypothalamus-pituitary interface.