Assessing the effects of exposures to phthalates in both the female and male germlines

流行病学和实验数据表明，接触内分泌干扰物（EDCs）与生殖健康问题有关，包括不孕症，流产，死产，出生缺陷和胎儿发育改变。有趣的是，EDC暴露引起的一些影响已被证明会影响直接暴露个体以外的几代人，这表明环境毒素具有跨代影响。尽管有这些迹象，但很少有研究关注内分泌干扰物对生殖细胞的直接影响。此外，虽然人类暴露于恒定和可变的EDC混合物，但大多数EDC研究仅关注单一化学品的影响。因此，了解这些化学品之间的累加、协同和拮抗效应对于了解它们对人类健康构成的风险至关重要。因为这是一个艰巨的任务，在人类，我将联合收割机的研究在C。elegans和小鼠，以测试蠕虫中快速筛选作为建立常见污染物之间关系和评估化学混合物对生殖系影响的方法的效力。我的研究将特别关注一类特征良好的内分泌干扰物，即邻苯二甲酸酯，这是邻苯二甲酸的烷基二酯，广泛用于各种消费品，医疗和建筑产品中的增塑剂。使用最近在人类母体尿液中发现的六种特定邻苯二甲酸酯，我们的初步研究发现，个体暴露于BBP、DBP、DEP、DiBP、DiNP和DEHP显著增加了C.优雅在这项提案中，我的目标是进一步表征这些邻苯二甲酸酯（BBP和DEP）对染色体形态发生，减数分裂进程，生殖系特异性基因表达和染色质景观在女性和男性生殖系的个人影响。最后，我的目标是确定所有六种邻苯二甲酸酯组合的影响，因为它们存在于我们的环境中，并评估这些影响如何在物种之间保持。这些拟议的研究不仅将阐明这些邻苯二甲酸酯对雌性和雄性生殖系的个体和组合效应，而且还将阐明使用C。elegans快速评估和预测环境毒素对高等生物的影响。

Epidemiological and experimental data suggest that exposure to endocrine disrupting chemicals (EDCs) are linked to reproductive health issues including infertility, miscarriages, stillbirths, birth defects, and altered fetal development. Interestingly, some effects induced by EDC exposure have been shown to impact generations that extend beyond directly exposed individuals, suggesting that environmental toxins have transgenerational effects. Despite these indications, few studies have focused on the direct effects of EDCs on the germline. Furthermore, while humans are exposed to constant and variable mixtures of EDCs, most EDC studies have focused solely on the effects of single chemicals. Thus, understanding the additive, synergistic, and antagonistic effects between and among these chemicals is critical to understanding the risks they pose to human health. Because this is a daunting task in humans, I will combine studies in C. elegans and mice to test the efficacy of rapid screening in worms as a method of establishing relationships among common contaminants and assessing effects of chemical mixtures on the germline. My studies will focus specifically on a well characterized class of EDCs, namely phthalates, which are alkyl diesters of phthalic acid and widely used plasticizers found in various consumer, medical, and building products. Using six specific phthalates recently identified in human maternal urine, our preliminary studies found that individual exposure to BBP, DBP, DEP, DiBP, DiNP, and DEHP significantly increases chromosome nondisjunction and germ cell apoptosis during oogenesis in C. elegans. In this proposal, I aim to further characterize the individual effects of two of these phthalates (BBP and DEP) on chromosome morphogenesis, meiotic progression, germline-specific gene expression, and the chromatin landscape in both the female and male germlines. Lastly, I aim to determine the effects of all six phthalates in combination, as they exist in our environment, and assess how these effects are conserved across species. These proposed studies will not only shed light on the individual and combinatorial effects of these phthalates on both the female and male germlines, but the efficacy of using C. elegans to rapidly assess and predict the effects of environmental toxins on higher order organisms.