Zika virus (ZIKV) infection during pregnancy can lead to a set of congenital malformations known as Congenital ZIKV syndrome (CZS), whose main feature is microcephaly. The geographic distribution of CZS in Brazil during the 2015–2017 outbreak was asymmetrical, with a higher prevalence in the Northeast and Central‐West regions of the country, despite the ubiquitous distribution of the vector Aedes aegypti, indicating that environmental factors could influence ZIKV vertical transmission and/or severity. Here we investigate the involvement of the most used agrochemicals in Brazil with CZS. First, we exposed human neuroblastoma SK‐N‐AS cells to the 15 frequently used agrochemical molecules or derivative metabolites able to cross the blood–brain barrier. We found that a derived metabolite from a widely used herbicide in the Central‐West region, 2,4‐dichlorophenoxyacetic acid (2,4D), exacerbates ZIKV neurotoxic effects in vitro. We validate this observation by demonstrating vertical transmission leading to microcephaly in the offspring of immunocompetent C57BL/6J mice exposed to water contaminated with 0.025 mg/L of 2,4D. Newborn mice whose dams were exposed to 2,4D and infected with ZIKV presented a smaller brain area and cortical plate size compared to the control. Also, embryos from animals facing the co‐insult of ZIKV and 2,4D exposition presented higher Caspase 3 positive cells in the cortex, fewer CTIP2+ neurons and proliferative cells at the ventricular zone, and a higher viral load. This phenotype is followed by placental alterations, such as vessel congestion, and apoptosis in the labyrinth and decidua. We also observed a mild spatial correlation between CZS prevalence and 2,4D use in Brazil's North and Central‐West regions, with R2 = 0.4 and 0.46, respectively. Our results suggest that 2,4D exposition facilitates maternal vertical transmission of ZIKV, exacerbating CZS, possibly contributing to the high prevalence of this syndrome in Brazil's Central‐West region compared to other regions.

中文翻译：

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产前接触除草剂 2,4-二氯苯氧乙酸 (2,4D) 会加剧寨卡病毒的体外和体内神经毒性


怀孕期间感染寨卡病毒（ZIKV）可导致一系列先天性畸形，称为先天性 ZIKV 综合征（CZS），其主要特征是小头畸形。 2015-2017年爆发期间，巴西CZS的地理分布不对称，尽管媒介埃及伊蚊分布广泛，但该国东北部和中西部地区的患病率较高，这表明环境因素可能影响ZIKV垂直传播传播和/或严重程度。在这里，我们调查了巴西最常用的农用化学品与 CZS 的关系。首先，我们将人神经母细胞瘤 SK-N-AS 细胞暴露于 15 种常用的能够穿过血脑屏障的农化分子或衍生代谢物。我们发现，中西部地区广泛使用的除草剂 2,4-二氯苯氧基乙酸 (2,4D) 的衍生代谢物在体外会加剧寨卡病毒的神经毒性作用。我们通过证明垂直传播导致暴露于 0.025 mg/L 2,4D 污染的水的免疫活性 C57BL/6J 小鼠的后代出现小头畸形来验证这一观察结果。与对照组相比，暴露于 2,4D 并感染 ZIKV 的新生小鼠的大脑区域和皮质板尺寸较小。此外，面临 ZIKV 和 2,4D 暴露共同攻击的动物的胚胎在皮质中呈现出更高的 Caspase 3 阳性细胞，在心室区呈现出更少的 CTIP2+ 神经元和增殖细胞，以及更高的病毒载量。这种表型之后是胎盘改变，例如血管充血以及迷路和蜕膜中的细胞凋亡。我们还观察到巴西北部和中西部地区 CZS 患病率与 2,4D 使用之间存在轻微的空间相关性，R2 分别 = 0.4 和 0.46。 我们的结果表明，2,4D 暴露促进了 ZIKV 的母体垂直传播，加剧了 CZS，可能导致巴西中西部地区与其他地区相比该综合征的高患病率。