Environmental Health Perspectives ( IF 10.4 ) Pub Date : 2022-8-10 , DOI: 10.1289/ehp10576 Aseel Eid 1 , Isha Mhatre-Winters 1, 2 , Ferass M Sammoura 1 , Melissa K Edler 2, 3, 4 , Richard von Stein 5 , Muhammad M Hossain 1, 5 , Yoonhee Han 1 , Miriam Lisci 6 , Kristina Carney 6 , Mary Konsolaki 6, 7 , Ronald P Hart 8 , Joan W Bennett 9 , Jason R Richardson 1, 5, 10
Abstract
Background:
The interaction of aging-related, genetic, and environmental factors is thought to contribute to the etiology of late-onset, sporadic Alzheimer’s disease (AD). We previously reported that serum levels of p,p′-dichlorodiphenyldichloroethylene (DDE), a long-lasting metabolite of the organochlorine pesticide dichlorodiphenyltrichloroethane (DDT), were significantly elevated in patients with AD and associated with the risk of AD diagnosis. However, the mechanism by which DDT may contribute to AD pathogenesis is unknown.
Objectives:
This study sought to assess effects of DDT exposure on the amyloid pathway in multiple in vitro and in vivo models.
Methods:
Cultured cells (SH-SY5Y and primary neurons), transgenic flies overexpressing amyloid beta (), and C57BL/6J and 3xTG-AD mice were treated with DDT to assess impacts on the amyloid pathway. Real time quantitative polymerase chain reaction, multiplex assay, western immunoblotting and immunohistochemical methods were used to assess the effects of DDT on amyloid precursor protein (APP) and other contributors to amyloid processing and deposition.
Results:
Exposure to DDT revealed significantly higher APP mRNA and protein levels in immortalized and primary neurons, as well as in wild-type and AD-models. This was accompanied by higher levels of secreted in SH-SY5Y cells, an effect abolished by the sodium channel antagonist tetrodotoxin. Transgenic flies and 3xTG-AD mice had more pathology following DDT exposure. Furthermore, loss of the synaptic markers synaptophysin and PSD95 were observed in the cortex of the brains of 3xTG-AD mice.
Discussion:
Sporadic Alzheimer’s disease risk involves contributions from genetic and environmental factors. Here, we used multiple model systems, including primary neurons, transgenic flies, and mice to demonstrate the effects of DDT on APP and its pathological product . These data, combined with our previous epidemiological findings, provide a mechanistic framework by which DDT exposure may contribute to increased risk of AD by impacting the amyloid pathway. https://doi.org/10.1289/EHP10576
中文翻译:
DDT 对淀粉样前体蛋白水平和淀粉样 β 病理学的影响:与阿尔茨海默病风险的机制联系
摘要
背景:
衰老相关、遗传和环境因素的相互作用被认为是导致迟发性、散发性阿尔茨海默病 (AD) 的病因。我们之前报道过,p,p'-二氯二苯基二氯乙烯 (DDE) 是一种有机氯农药二氯二苯基三氯乙烷 (DDT) 的长效代谢物,在 AD 患者中显着升高,并且与 AD 诊断的风险相关。然而,DDT 可能导致 AD 发病的机制尚不清楚。
目标:
本研究试图在多种体外和体内模型中评估 DDT 暴露对淀粉样蛋白途径的影响。
方法:
培养细胞(SH-SY5Y 和原代神经元),过表达β淀粉样蛋白的转基因果蝇(),并对 C57BL/6J 和 3xTG-AD 小鼠进行 DDT 治疗,以评估对淀粉样蛋白通路的影响。实时定量聚合酶链反应、多重分析、蛋白质免疫印迹和免疫组织化学方法用于评估 DDT 对淀粉样蛋白前体蛋白 (APP) 和其他对淀粉样蛋白加工和沉积的贡献者的影响。
结果:
暴露于 DDT 后,在永生化和原代神经元以及野生型和 AD 模型中,APP mRNA 和蛋白质水平显着升高。这伴随着更高水平的分泌在 SH-SY5Y 细胞中,钠通道拮抗剂河豚毒素消除了这种作用。转基因果蝇和 3xTG-AD 小鼠有更多DDT 暴露后的病理学。此外,在 3xTG-AD 小鼠的大脑皮层中观察到突触标志物突触素和 PSD95 的丢失。
讨论:
散发性阿尔茨海默病风险涉及遗传和环境因素的贡献。在这里,我们使用了多个模型系统,包括原代神经元、转基因果蝇和小鼠,来证明 DDT 对 APP 及其病理产物的影响. 这些数据与我们之前的流行病学发现相结合,提供了一个机制框架,通过该框架,滴滴涕暴露可能通过影响淀粉样蛋白途径而导致 AD 风险增加。https://doi.org/10.1289/EHP10576