Kidney developmental effects of metal-herbicide mixtures: Implications for chronic kidney disease of unknown etiology
Kidney developmental effects of metal-herbicide mixtures: Implications for chronic kidney disease of unknown etiology
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DOI：
10.1016/j.envint.2020.106019
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发表时间：
2020-11-01
影响因子：
11.8
通讯作者：
Jayasundara, Nishad
中科院分区：
文献类型：
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作者：
Babich, Remy;Ulrich, Jake C.;Jayasundara, Nishad
原因不明的慢性肾脏疾病(CKDu)是一个新出现的全球问题，影响到美洲和南亚的几个农业社区。环境污染物，如饮用水中的重金属(如Cd、As、Pb和V)和有机农药(如草甘膦)，被假设在儿童疾病的发生和发展中发挥作用。然而，对饮用水中的化学污染物以及这些化合物及其混合物对肾脏发育和功能的影响仍不清楚。在这里，我们对CKDu受影响最严重的国家之一斯里兰卡的沉积物和饮用水进行了有针对性和无针对性的化学分析。使用斑马鱼Danio Rerio，一个毒理学和肾脏疾病的模型，然后我们检查了暴露于(I)来自CKDu地方性和非地方性地区的环境样品和(Ii)Cd、As、V、Pb和草甘膦作为单独的化合物和混合的混合物对肾脏发育的影响。我们发现，饮用水受到各种有机化学物质的污染，包括肾毒性化合物和重金属，但污染水平被认为是安全的。组织学研究和检测肾脏发育标志物(Pax2a)和肾脏损伤标志物(Kim1)的基因表达分析显示，新的金属和草甘膦-金属混合物对肾脏发育具有特异性作用。线粒体功能障碍与肾衰竭直接相关，混合特异性线粒体毒性检测显示，与来自流行区的环境样本一起治疗后，线粒体功能发生了变化。总而言之，我们表明，饮用水中的金属，即使在安全水平上，也会在早期阻碍肾脏发育，增强对草甘膦等其他农用化学品的易感性。饮用水对线粒体的污染作用可进一步促进肾功能障碍的进展，我们的线粒体检测可能有助于识别CKDu的风险区域。
Chronic kidney disease of unknown etiology (CKDu) is an emerging global concern affecting several agricultural communities in the Americas and South Asia. Environmental contaminants such as heavy metals (e.g., Cd, As, Pb, and V) and organic pesticides (e.g., glyphosate) in the drinking water have been hypothesized to play a role in childhood onset and progression of this disease. However, a comprehensive analysis of chemical contaminants in the drinking water and effects of these compounds and their mixtures on kidney development and function remains unknown. Here, we conducted targeted and non-targeted chemical analyses of sediment and drinking water in CKDu affected regions in Sri Lanka, one of the most affected countries. Using zebrafish Danio rerio, a toxicology and kidney disease model, we then examined kidney developmental effects of exposure to (i) environmentally derived samples from CKDu endemic and non-endemic regions and (ii) Cd, As, V, Pb, and glyphosate as individual compounds and in mixtures. We found that drinking water is contaminated with various organic chemicals including nephrotoxic compounds as well as heavy metals, but at levels considered safe for drinking. Histological studies and gene expression analyses examining markers of kidney development (pax2a) and kidney injury (kim1) showed novel metal and glyphosate-metal mixture specific effects on kidney development. Mitochondrial dysfunction is directly linked to kidney failure, and examination of mixture specific mitochondrial toxicity showed altered mitochondrial function following treatment with environmental samples from endemic regions. Collectively, we show that metals in drinking water, even at safe levels, can impede kidney development at an early age, potentiating increased susceptibility to other agrochemicals such as glyphosate. Drinking water contaminant effects on mitochondria can further contribute to progression of kidney dysfunction and our mitochondrial assay may help identify regions at risk of CKDu.