The 2020 ESPINA study follow-up Exam: Fungicides, Insecticides, Inflammation and Child Development

2020年ESPINA研究后续考试：杀菌剂、杀虫剂、炎症和儿童发育

• 批准号: 10457234
• 负责人: Jose Ricardo Suarez
• 金额: $ 56.26万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-18 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10457234
• 关键词: Acetylcholinesterase; Adolescence; Adolescent; Affect; Age; Agriculture; Americas; Antifungal Agents; Azoles; Biological Markers; Blood; CCL2 gene; Child; Child Development; Child Health; Cholinesterase Inhibitors; Cognition; Cognitive; County; Cytochrome P450; Cytokeratin 18; Data Collection; Development; Disease; Drug Metabolic Detoxication; Ecuador; Environmental Health; Enzymes; Epigenetic Process; Exposure to; Fatty Liver; Flowers; Follow-Up Studies; Food; Free Radicals; Funding; Future; Gender; Hair; Health; Hepatotoxicity; Human; Impairment; In Vitro; Industrial fungicide; Inflammation; Insecticides; Interleukin-6; Investigation; Link; Liver; Measurement; Measures; Mediating; Mental Health; Methods; Microtubules; National Institute of Environmental Health Sciences; Nerve Degeneration; Neurocognition; Neurocognitive; Neurocognitive Deficit; Neurons; Organophosphates; Outcome; Participant; Patients; Performance; Pesticides; Pharmaceutical Preparations; Physiological; Plasma; Population; Prevention program; Process; Production; Prospective Studies; Quinones; Recurrence; Research; Risk Assessment; Safety; Sales; Saliva; Sampling; Serum; Specimen; Structure; TNF gene; Technology; Testing; Time; Toxic effect; Transaminases; United States National Institutes of Health; Urine; Vascular Endothelium; Work; agricultural community; agricultural pesticide; biobank; clinical practice; cognitive performance; cohort; developmental toxicity; disorder prevention; epidemiology study; experimental study; exposure pathway; follow-up; fruits and vegetables; individuals with autism spectrum disorder; inflammatory marker; inhibitor; liver inflammation; monocyte; neurobehavior; neurobehavioral; neuroinflammation; neurotoxic; novel; pesticide exposure; prenatal exposure; prospective; prospective test; pyrethroid; study population; urinary; young adult

The sales of agricultural insecticides have steadily risen in the last 20 years and the use of fungicides have skyrocketed in the last decade. Unfortunately, direct assessments of children's developmental toxicity in relation to commonly used fungicides such as Azoles or Quinone Outside Inhibitors (QoI) are unavailable because methods for their quantification in bio-specimens have only recently been developed. In experimental studies, exposures QoI fungicides, resulted in epigenetic changes related to neuro-inflammation, and higher levels of free-radicals. Azoles, another heavily used fungicide class, have also been linked with liver inflammation and toxicity in-vitro. Azole fungicides share the same structure as azole antifungals used in clinical practice, which are associated with elevations of liver enzymes in up to 20% of patients. Cholinesterase inhibitor insecticide exposures have been associated with short- and long-lasting neurobehavioral/cognitive delays in children associated. Whether continuing exposures to organophosphates or other insecticides such as neonicotinoids or pyrethroids can affect cognition in adolescence is unclear. We propose to conduct a follow-up investigation of adolescent participants (ages 16-21 y, n=535) of the Secondary Pesticide Exposure among Children and Adolescents (ESPINA) study in 2020. This NIH-funded study has examined participants in Pedro Moncayo County, Ecuador since 2008. Pedro Moncayo has one of the highest concentrations of flower plantations in the Americas. The production of flowers involves a disproportionately high use of fungicides. We plan to assess the ongoing and long-term associations of pesticide exposures with neurocognition, and inflammatory markers (systemic, neuro and liver). To our knowledge, this will be the first epidemiologic study of children/adolescents to evaluate health outcomes in relation to fungicide and neonicotinoid exposures. This prospective study capitalizes on existing blood measurements of insecticides in 2016 and acetylcholinesterase in 2008 and 2016. The specific aims are to test the following hypotheses: Urinary metabolites of insecticides in 2016 and 2020 (organophosphates, neonicotinoids, pyrethroids) and fungicides (Azoles, QoI) in 2016 are associated with: 1) higher subclinical markers of systemic and neuro inflammation (CRP, TNF, IL-6, sICAM-1, sVCAM-1, MCP-1, sCD14, sCD163); 2) Pesticides, particularly azole fungicides are associated with subclinical increases in liver inflammation markers: transaminases (AST and ALT) and cytokeratin 18. We will test concurrent and prospective associations with all inflammation markers in 2016-2018; 3) lower neur0-cognitive performance in adolescence. We will test longitudinal associations of fungicides and insecticides with neurocognitive performance, and will contrast such findings across pesticides to evaluate neurotoxic potencies. 4) As an exploratory aim: we will assess mediating or modifying effects of inflammation on pesticide-induced impaired neurobehavioral performance.

近20年来农用杀虫剂的销量稳步上升，杀菌剂的使用 在过去十年中飞速增长。不幸的是，直接评估儿童的发育毒性 与常用杀菌剂如唑类或醌类外部抑制剂 (QoI) 的关系尚不清楚 因为生物样本中的定​​量方法最近才被开发出来。实验中 研究表明，暴露 QoI 杀菌剂会导致与神经炎症相关的表观遗传变化，并且更高 自由基水平。唑类是另一种广泛使用的杀菌剂，也与肝脏有关 体外炎症和毒性。唑类杀菌剂与唑类抗真菌剂具有相同的结构 临床实践中，高达 20% 的患者肝酶升高。 胆碱酯酶抑制剂杀虫剂暴露与短期和长期的 儿童的神经行为/认知迟缓相关。是否持续接触有机磷 或其他杀虫剂（例如新烟碱类或拟除虫菊酯）是否会影响青春期的认知尚不清楚。 我们建议对青少年参与者（16-21 岁，n=535）进行跟踪调查 2020 年儿童和青少年二次农药暴露 (ESPINA) 研究。这项由 NIH 资助的研究 自 2008 年以来，一项研究对厄瓜多尔佩德罗蒙卡约县的参与者进行了调查。佩德罗蒙卡约有以下一项： 美洲花卉种植园最集中的地区。花卉的生产涉及到 杀菌剂的使用过多。我们计划评估当前和长期的关联 农药暴露与神经认知和炎症标志物（全身、神经和肝脏）。致我们的 据了解，这将是第一个针对儿童/青少年的流行病学研究，以评估儿童/青少年的健康结果 与杀菌剂和新烟碱类暴露的关系。这项前瞻性研究利用了现有的血液 2016 年杀虫剂的测量以及 2008 年和 2016 年乙酰胆碱酯酶的测量。 具体目的是检验以下假设： 2016 年杀虫剂的尿液代谢物 2016 年和 2020 年（有机磷类、新烟碱类、拟除虫菊酯类）和杀菌剂（唑类、QoI）相关 具有：1) 更高的全身和神经炎症亚临床标志物（CRP、TNF、IL-6、sICAM-1、sVCAM-1、 MCP-1、sCD14、sCD163)； 2) 农药，特别是唑类杀菌剂与亚临床增加有关 肝脏炎症标志物：转氨酶（AST 和 ALT）和细胞角蛋白 18。我们将同时测试和 2016-2018 年与所有炎症标志物的前瞻性关联； 3）神经0认知表现较低 在青春期。我们将测试杀菌剂和杀虫剂与神经认知的纵向关联 性能，并将对比不同农药的这些发现，以评估神经毒性效力。 4）作为 探索性目标：我们将评估炎症对农药引起的损伤的调节或改变作用 神经行为表现。