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

在过去的20年里，农用杀虫剂的销售稳步上升， 在过去的十年里急剧上升。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）的关系 因为最近才开发出在生物样本中定量它们的方法。实验性 研究表明，暴露于QoI杀菌剂，导致与神经炎症相关的表观遗传变化， 自由基水平。唑类，另一种大量使用的杀真菌剂，也与肝脏有关 炎症和毒性。唑类杀真菌剂具有与在杀真菌剂中使用的唑类抗真菌剂相同的结构。 临床实践中，这与高达20%的患者的肝酶升高有关。 胆碱酯酶抑制剂杀虫剂暴露与短期和长期 儿童神经行为/认知延迟相关。是否持续接触有机磷 或其他杀虫剂如烟碱类或拟除虫菊酯是否会影响青春期的认知能力尚不清楚。 我们建议对青少年参与者（年龄16-21岁，n=535）进行随访调查， 2020年儿童和青少年二次农药暴露（ESPINA）研究。这个NIH资助的 自2008年以来，厄瓜多尔Pedro Moncayo县的研究对参与者进行了调查。佩德罗·蒙卡约有一个 是美洲花卉种植园最集中的地方花卉的生产涉及一个 不成比例地大量使用杀真菌剂。我们计划评估以下因素的持续和长期关联： 农药暴露与神经认知和炎症标志物（全身，神经和肝脏）。对我们 知识，这将是第一个流行病学研究的儿童/青少年，以评估健康结果， 与杀真菌剂和类烟碱暴露的关系。这项前瞻性研究利用现有的血液 2016年对杀虫剂的测量以及2008年和2016年对乙酰胆碱酯酶的测量。 具体目的是检验以下假设：2016年杀虫剂的尿代谢物 2016年的2020年（有机磷酸酯、烟碱类、拟除虫菊酯）和杀真菌剂（唑类、QoI）相关 具有：1）更高的全身和神经炎症的亚临床标志物（CRP、TNF、IL-6、sICAM-1、sVCAM-1， MCP-1、sCD 14、sCD 163）; 2）杀虫剂，特别是唑类杀真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。我们将测试并发和 2016-2018年与所有炎症标志物的前瞻性相关性; 3）神经认知性能降低 在青春期。我们将测试杀真菌剂和杀虫剂与神经认知功能的纵向关联， 性能，并将比较这些结果在农药，以评估神经毒性的潜力。4)作为 探索性目的：我们将评估炎症对杀虫剂诱导的受损的 神经行为表现

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.