Environmentally-relevant exposure to diethylhexyl phthalate (DEHP) alters regulation of double-strand break formation and crossover designation leading to germline dysfunction in Caenorhabditis elegans.,PLOS Genetics

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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.
PLOS Genetics ( IF 4.0 ) Pub Date : 2020-01-09 , DOI: 10.1371/journal.pgen.1008529
Luciann Cuenca ₁ , Nara Shin ₁ , Laura I Lascarez-Lagunas ₁ , Marina Martinez-Garcia ₁ , Saravanapriah Nadarajan ₁ , Rajendiran Karthikraj ₂ , Kurunthachalam Kannan _{2,

3} , Mónica P Colaiácovo ₁

Affiliation

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.

中文翻译：

与环境相关的邻苯二甲酸二乙基己酯（DEHP）暴露会改变双链断裂形成和交叉标记的调控，导致秀丽隐杆线虫的种系功能障碍。

暴露于邻苯二甲酸二乙基己基酯（DEHP）是生产含聚乙烯基塑料的最丰富的增塑剂，已导致男性和女性生殖健康不良。尽管已广泛研究了DEHP对生殖健康的影响，但在多细胞生物的背景下，暴露于与环境相关的DEHP及其代谢产物水平影响雌性生殖的分子机制仍然不清楚。使用秀丽隐杆线虫种系作为研究生殖毒性的模型，我们表明暴露于环境相关水平的DEHP及其代谢产物导致减数分裂双链断裂（DSB）增加，DSB修复进程改变，p53 / CEP-1活化依赖的生殖细胞凋亡，前一期晚期染色体重塑中的缺陷，diakinesis卵母细胞中异常的染色体形态，增加的染色体非分离性和早期胚胎发生过程中的缺陷。暴露于DEHP会导致核的子集在粗线中后期保持在DSB允许状态，在交叉（CO）指定/形成中表现出缺陷。此外，这些细胞核显示SYP-4（一种突触复合物（SC）蛋白）的Polo样激酶-1/2（PLK-1 / 2）依赖性磷酸化降低。此外，DEHP暴露导致prmt-5表达中的种系特异性变化，该变化编码一个精氨酸甲基转移酶，并且增加了SC长度，并改变了X染色体上的CO指定水平。综上所述，我们的数据提出了一个模型，通过该模型设置了一个依赖PLK-1 / 2的负反馈回路来关闭减数分裂DSB，以及染色体结构的改变，

更新日期：2020-02-18

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