Mechanisms of atrazine endocrine disruption
阿特拉津内分泌干扰机制
基本信息
- 批准号:9895294
- 负责人:
- 金额:$ 7.18万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-01-15 至 2021-12-31
- 项目状态:已结题
- 来源:
- 关键词:Adrenal GlandsAdultAffectAgricultureAnimal ModelAnterior Pituitary GlandAtrazineBehaviorBiological ModelsBrainCYP17A1 geneCell CycleCell Cycle RegulationChemical ExposureConflict (Psychology)CoupledCouplingCyclic AMPDataDevelopmentDiseaseEmbryoEmbryonic DevelopmentEndocrineEndocrine DisruptorsEndocrine disruptionFemaleFollicular AtresiaGene TargetingGenesGenetic TranscriptionHeadHealthHerbicidesHormonalHumanHypothalamic structureImageKnowledgeLaboratory StudyLarvaLengthLifeLiteratureMalignant NeoplasmsMicroRNAsMidwestern United StatesMolecularMolecular AnalysisNeuraxisNeurologicNeuronal DifferentiationNeuronsNeurosecretory SystemsOutcomeOvarianOvaryPathway interactionsPituitary GlandPosterior Pituitary GlandProgesteroneProtein AnalysisReportingReproductive systemResearchRiskSerotonergic SystemSerotoninSourceSteroid biosynthesisStructureSystemSystems DevelopmentTestingTestisThyroid GlandToxic effectTranscriptTranscription AlterationTranslatingTransport ProcessUnited StatesUnited States Environmental Protection AgencyUp-RegulationVertebratesWaterWater SupplyZebrafishagricultural regionaxon growthbrain tissuecarcinogenesischemical groupdrinking waterepidemiology studyfunctional outcomesmaleneurodevelopmentneuron developmentneurotoxicitynovelpituitary gland developmentpituitary gonadal axisprotein expressionreproductive functionsteroid hormonesuccesstranscriptomics
项目摘要
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.
项目概要
内分泌干扰化学物质 (EDC) 是一类广泛的化学物质,会对健康造成多种不利影响
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。
下丘脑作为多个内分泌轴的中央调节器,具有多种不同的特异性
针对神经内分泌系统的 EDC 可能会产生不良健康后果。
EDC,是美国第二大常用的农业除草剂,也是最常见的除草剂。
饮用水供应中的阿特拉津污染物受到美国环境保护署 (EPA) 的监管。
饮用水中的浓度为十亿分之三 (ppb; µg/L),但浓度高于此规定
实验室和流行病学研究报告了各种内分泌干扰和限制。
大多数研究结果集中在下丘脑-垂体-性腺轴上,但是
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
总体而言,研究支持莠去津影响多个内分泌轴和假设。
下丘脑毒性目标,但其机制尚未明确阐明,值得进一步研究。
此外,目前美国环保署关于莠去津的内分泌干扰作用的报道相互矛盾。
我们使用斑马鱼模型系统的研究表明,最大污染物水平 (MCL) 为 3 ppb。
胚胎阿特拉津暴露浓度范围为当前 US EPA MCL 的 1/10 倍至 10 倍,导致
与神经和生殖系统发育相关的基因的表达改变
与神经元相关的 microRNA (miRNA) 的功能、细胞周期和癌变;
分化和成熟以及癌症;整体低甲基化;以及幼虫头部长度的改变。
此外,我们观察到胚胎暴露于莠去津的成虫产卵成功率下降。
这些成年女性的卵巢黄体酮和卵泡闭锁也有所增加,并且
大脑中血清素代谢和血清素周转与不同分子相关的基因改变。
在成年女性的脑组织中观察到内分泌和中枢神经系统的通路
这些研究支持胚胎时期的阿特拉津暴露足以导致日后的不良后果。
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目标,我们试图确定其机制。
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
我们将评估过去对多个内分泌轴的研究的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
以及下丘脑-垂体界面的轴突生长改变。
项目成果
期刊论文数量(0)
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会议论文数量(0)
专利数量(0)
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Jennifer L Freeman其他文献
Differential Developmental Neurotoxicity and Tissue Uptake of the Per- and Polyfluoroalkyl Substance Alternatives, GenX and PFBS.
全氟烷基和多氟烷基物质替代品 GenX 和 PFBS 的不同发育神经毒性和组织吸收。
- DOI:
- 发表时间:
2023 - 期刊:
- 影响因子:11.4
- 作者:
Ola G. Wasel;Hanna King;Y. Choi;Linda S Lee;Jennifer L Freeman - 通讯作者:
Jennifer L Freeman
Jennifer L Freeman的其他文献
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{{ truncateString('Jennifer L Freeman', 18)}}的其他基金
Mechanisms of gene-environment interaction in developmental lead exposure leading to Alzheimer's disease phenotypes
发育期铅暴露导致阿尔茨海默病表型的基因-环境相互作用机制
- 批准号:
10591095 - 财政年份:2022
- 资助金额:
$ 7.18万 - 项目类别:
Mechanisms of gene-environment interaction in developmental lead exposure leading to Alzheimer's disease phenotypes
发育期铅暴露导致阿尔茨海默病表型的基因-环境相互作用机制
- 批准号:
10707380 - 财政年份:2022
- 资助金额:
$ 7.18万 - 项目类别:
Developmental neuroendocrine toxicity targeting the kisspeptin pathway
针对 Kisspeptin 通路的发育神经内分泌毒性
- 批准号:
10608824 - 财政年份:2022
- 资助金额:
$ 7.18万 - 项目类别:
Developmental Origins of Neurotoxicity of the PFAS GenX
X 代 PFAS 神经毒性的发育起源
- 批准号:
10218403 - 财政年份:2021
- 资助金额:
$ 7.18万 - 项目类别:
Developmental Origins of Neurotoxicity of the PFAS GenX
X 代 PFAS 神经毒性的发育起源
- 批准号:
10392474 - 财政年份:2021
- 资助金额:
$ 7.18万 - 项目类别:
Molecular biomarkers of exposure to an endocrine disrupting herbicide
接触内分泌干扰性除草剂的分子生物标志物
- 批准号:
8496349 - 财政年份:2010
- 资助金额:
$ 7.18万 - 项目类别:
Molecular biomarkers of exposure to an endocrine disrupting herbicide
接触内分泌干扰性除草剂的分子生物标志物
- 批准号:
7940339 - 财政年份:2010
- 资助金额:
$ 7.18万 - 项目类别:
Molecular biomarkers of exposure to an endocrine disrupting herbicide
接触内分泌干扰性除草剂的分子生物标志物
- 批准号:
7940339 - 财政年份:2010
- 资助金额:
$ 7.18万 - 项目类别:
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