Department of Genetics, Harvard Medical School, Boston, MA, United States of America.
Wadsworth Center, New York State Department of Health, Empire State Plaza, Albany, New York, United States of America.
PLoS Genet. 2019 Feb 14;15(2):e1007975. doi: 10.1371/journal.pgen.1007975. eCollection 2019 Feb.
Chemicals that are highly prevalent in our environment, such as phthalates and pesticides, have been linked to problems associated with reproductive health. However, rapid assessment of their impact on reproductive health and understanding how they cause such deleterious effects, remain challenging due to their fast-growing numbers and the limitations of various current toxicity assessment model systems. Here, we performed a high-throughput screen in C. elegans to identify chemicals inducing aneuploidy as a result of impaired germline function. We screened 46 chemicals that are widely present in our environment, but for which effects in the germline remain poorly understood. These included pesticides, phthalates, and chemicals used in hydraulic fracturing and crude oil processing. Of the 46 chemicals tested, 41% exhibited levels of aneuploidy higher than those detected for bisphenol A (BPA), an endocrine disruptor shown to affect meiosis, at concentrations correlating well with mammalian reproductive endpoints. We further examined three candidates eliciting aneuploidy: dibutyl phthalate (DBP), a likely endocrine disruptor and frequently used plasticizer, and the pesticides 2-(thiocyanomethylthio) benzothiazole (TCMTB) and permethrin. Exposure to these chemicals resulted in increased embryonic lethality, elevated DNA double-strand break (DSB) formation, activation of p53/CEP-1-dependent germ cell apoptosis, chromosomal abnormalities in oocytes at diakinesis, impaired chromosome segregation during early embryogenesis, and germline-specific alterations in gene expression. This study indicates that this high-throughput screening system is highly reliable for the identification of environmental chemicals inducing aneuploidy, and provides new insights into the impact of exposure to three widely used chemicals on meiosis and germline function.
在我们的环境中高度普遍存在的化学物质，如邻苯二甲酸酯和农药，已被证明与生殖健康问题有关。然而，由于它们数量的快速增长以及各种当前毒性评估模型系统的局限性，快速评估它们对生殖健康的影响以及了解它们如何造成这种有害影响仍然具有挑战性。在这里，我们在秀丽隐杆线虫中进行了高通量筛选，以鉴定由于生殖系功能受损而导致非整倍体的化学物质。我们筛选了 46 种广泛存在于我们环境中的化学物质，但对其在生殖系中的作用知之甚少。这些化学物质包括农药、邻苯二甲酸酯以及用于水力压裂和原油加工的化学品。在测试的 46 种化学物质中，有 41%表现出的非整倍体水平高于内分泌干扰物双酚 A（BPA），BPA 已知会影响减数分裂，并与哺乳动物生殖终点相关的浓度密切相关。我们进一步研究了三种引起非整倍体的候选物：邻苯二甲酸二丁酯（DBP），一种可能的内分泌干扰物，也是常用的增塑剂，以及农药 2-（硫氰基甲基硫代）苯并噻唑（TCMTB）和氯菊酯。暴露于这些化学物质会导致胚胎致死率增加、DNA 双链断裂（DSB）形成增加、p53/CEP-1 依赖性生殖细胞凋亡激活、减数分裂中期二价体的染色体异常、早期胚胎发生期间染色体分离受损以及生殖系基因表达的特异性改变。这项研究表明，这种高通量筛选系统非常可靠，可以鉴定出引起非整倍体的环境化学物质，并为广泛使用的三种化学物质对减数分裂和生殖系功能的影响提供了新的见解。
