Succinate dehydrogenase inhibitors (SDHIs) are the most widely used fungicides against plant parasitic fungi. They act by blocking the enzyme succinate dehydrogenase (SDH), a key component of mitochondrial respiration, which is highly conserved throughout evolution. Recently, it has been reported that some SDHIs used in many fungicides do not only inhibit the SDH activity of target fungi but can also block several non-target human cells in in vitro models. This study reveals a lack of SDHI species specificity and so points to a major health risk for exposed organisms, including humans. Despite the frequent detection of SDHIs in the environment and on harvested products and their increasing use in modern agriculture, their potential toxic effects in vivo, especially on neurodevelopment, are still under-evaluated. Here, we assessed the neurotoxicity of bixafen, one of the latest-generation SDHIs, which had never been tested during neurodevelopment. For this purpose, we used a well-known vertebrate model for toxicity testing, namely zebrafish transparent embryos, and live imaging using transgenic lines labelling the brain and spinal cord. Here we show that bixafen causes microcephaly and defects on motor neuron axon outgrowth and their branching during development. Our findings show that the central nervous system is highly sensitive to bixafen, thus demonstrating for the first time in vivo that an SDHI, bixafen, widely used in agriculture, is neurotoxic in vertebrates and causes neurodevelopmental defects. This work adds to our knowledge of the toxic effect of SDHIs on neurodevelopment and may help us take the appropriate precautions to ensure protection against the neurotoxic effects of these substances.

中文翻译：

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Bixafen是一种琥珀酸脱氢酶抑制剂杀菌剂，在发育过程中会引起小头畸形和运动神经元轴突缺陷

琥珀酸脱氢酶抑制剂（SDHIs）是针对植物寄生性真菌使用最广泛的杀真菌剂。它们通过阻止琥珀酸脱氢酶（SDH）来起作用，该酶是线粒体呼吸的关键组成部分，在整个进化过程中高度保守。近来，已经报道了许多杀真菌剂中使用的一些SDHIs不仅抑制靶真菌的SDH活性，而且在体外模型中还可以阻断几种非靶标人类细胞。这项研究揭示了SDHI物种缺乏特异性，因此指出了包括人类在内的暴露生物的主要健康风险。尽管在环境和收获产品中经常检测到SDHIs，并且在现代农业中越来越多地使用SDHI，但它们在体内的潜在毒性作用，尤其是对神经发育的潜在作用，仍被低估。这里，我们评估了比沙芬（一种最新一代的SDHIs）的神经毒性，该药物从未在神经发育过程中进行过测试。为此，我们使用了众所周知的脊椎动物模型进行毒性测试，即斑马鱼透明胚胎，并使用标记大脑和脊髓的转基因品系进行了实时成像。在这里，我们显示了比沙芬引起小头畸形和运动神经元轴突生长及其发育过程中分支的缺陷。我们的发现表明，中枢神经系统对bixafen高度敏感，因此首次在体内证明了SDHI，bixafen（广泛用于农业）在脊椎动物中具有神经毒性并引起神经发育缺陷。