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首页> 外文期刊>PLoS Genetics >Environmentally-relevant exposure to diethylhexyl phthalate (DEHP) alters regulation of double-strand break formation and crossover designation leading to germline dysfunction in Caenorhabditis elegans
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Environmentally-relevant exposure to diethylhexyl phthalate (DEHP) alters regulation of double-strand break formation and crossover designation leading to germline dysfunction in Caenorhabditis elegans

机译：邻苯二甲酸二乙基己酯（DEHP）的环境相关接触改变双链断裂形成和交叉指定，导致<斜线> Caenorhabditis elegans

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Exposure to diethylhexyl phthalate (DEHP), the most abundant plasticizer used in the production of polyvinyl-containing plastics, has been associated to adverse reproductive health outcomes in both males and females. While the effects of DEHP on reproductive health have been widely investigated, the molecular mechanisms by which exposure to environmentally-relevant levels of DEHP and its metabolites impact the female germline in the context of a multicellular organism have remained elusive. Using the Caenorhabditis elegans germline as a model for studying reprotoxicity, we show that exposure to environmentally-relevant levels of DEHP and its metabolites results in increased meiotic double-strand breaks (DSBs), altered DSB repair progression, activation of p53/CEP-1-dependent germ cell apoptosis, defects in chromosome remodeling at late prophase I, aberrant chromosome morphology in diakinesis oocytes, increased chromosome non-disjunction and defects during early embryogenesis. Exposure to DEHP results in a subset of nuclei held in a DSB permissive state in mid to late pachytene that exhibit defects in crossover (CO) designation/formation. In addition, these nuclei show reduced Polo-like kinase-1/2 (PLK-1/2)-dependent phosphorylation of SYP-4, a synaptonemal complex (SC) protein. Moreover, DEHP exposure leads to germline-specific change in the expression of prmt- 5, which encodes for an arginine methyltransferase, and both increased SC length and altered CO designation levels on the X chromosome. Taken together, our data suggest a model by which impairment of a PLK-1/2-dependent negative feedback loop set in place to shut down meiotic DSBs, together with alterations in chromosome structure, contribute to the formation of an excess number of DSBs and altered CO designation levels, leading to genomic instability.
机译：暴露于邻苯二甲酸二乙基己酯（DeHP），最丰富的增塑剂，用于生产聚乙烯族塑料，与男性和女性的不利生殖健康结果有关。虽然DEHP对生殖健康的影响得到了广泛研究，但是在多细胞生物体背景下暴露于环境相关水平的分子机制及其代谢产物的影响尤为难以实现。使用CaenorhabditisEgbans种系作为学习再生毒性的模型，我们表明暴露于环境相关水平的DeHP及其代谢物导致降低人的双链（DSB）的增加，改变了DSB修复进展，激活P53 / Cep-1 - 依赖性生殖细胞凋亡，晚期预先发生的染色体重塑中的缺陷，在高管瘤卵母细胞中的异常染色体形态，早期胚胎发生过程中的染色体不分离和缺陷。暴露于DEHP在中期嗜睡状态下在DSB允许状态下保持的核子集中，其在跨越交叉（CO）指定/地层中表现出缺陷。此外，这些核显示出较少的酚类激酶-1 / 2（PLK-1/2） - SYP-4的依赖性磷酸化，一种Sypaponemal复合物（SC）蛋白。此外，DeHP暴露导致PRMT-5表达的细菌特异性变化，其编码精氨酸甲基转移酶，并且均增加了X染色体上的SC长度和改变的CO指定水平。我们的数据建议了一种模型，通过该模型将PLK-1/2依赖性负反馈回路损伤损伤，以便关闭减数分裂性DSB，以及染色体结构的改变，有助于形成多余的DSB和改变的CO指定水平，导致基因组不稳定。

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