Mechanisms of atrazine endocrine disruption

项目总结 内分泌干扰物(EDCs)是一类广泛的化学物质，会导致无数有害健康的物质。 效果。到目前为止，大多数研究都集中在下游目标系统和不利的健康后果上。 受到EDC暴露的影响，但现在有越来越多的证据表明神经内分泌是主要靶点。与 下丘脑作为多个内分泌轴的中枢调节器，具有多种不同的特异性 对于以神经内分泌系统为靶点的内分泌细胞，可能会观察到不良的健康后果。阿特拉津，一种 EDC，是美国第二种最常用的农业除草剂，也是最常见的 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 饮用水中的浓度为十亿分之三(ppb；微克/L)，但浓度超过这一规定 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 神经方面的不良影响。大多数发现集中在下丘脑-垂体-性腺轴上，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 斧头。总体而言，研究支持阿特拉津影响多个内分泌轴和一种 下丘脑毒性靶点，但其作用机制尚不清楚，有待进一步研究。在……里面 此外，在目前美国环保局附近，有关于阿特拉津内分泌干扰作用的相互矛盾的报道 最高污染物水平(MCL)为3 ppb。我们使用斑马鱼模型系统进行的研究表明， 胚胎阿特拉津的暴露浓度从1/10倍到10倍，是目前美国环保局MCL导致的 与神经和生殖系统发育相关的基因表达变化 功能、细胞周期与致癌；与神经元相关的microRNAs(MiRNAs)的去调控 分化和成熟与癌症；全球低甲基化；改变幼虫的头部长度。 此外，我们观察到胚胎阿特拉津暴露的成年鼠的产卵成功率下降。 这些成年女性的卵巢孕酮和卵泡闭锁也增加，而 5-羟色胺代谢产物和5-羟色胺在大脑中的周转。与不同分子相关的基因变化 在成年雌性和中枢神经系统的脑组织中观察到内分泌和中枢神经系统的通路。 男性。这些研究支持胚胎时期的阿特拉津暴露足以导致晚年的不良后果。 与多个内分泌轴相关的健康结果。这项研究的中心假设是 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 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 过去对多个内分泌轴的研究。我们将评估几个神经内分泌终结点 胚胎发生以确定下丘脑和/或垂体发育和神经元结构的障碍 下丘脑-垂体交界处的轴突生长改变。

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.