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、死胎、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几代人，而不仅仅是直接接触的个体，这表明环境毒素具有跨代影响。尽管有这些迹象，很少有研究关注EDCs对生殖系的直接影响。此外，虽然人类暴露于恒定和可变的EDC混合物中，但大多数EDC研究仅侧重于单一化学品的影响。因此，了解这些化学品之间的加性、协同作用和拮抗作用对于了解它们对人类健康构成的风险至关重要。因为这对人类来说是一项艰巨的任务，我将结合秀丽隐杆线虫和小鼠的研究，测试在蠕虫中快速筛选的有效性，作为一种建立常见污染物之间关系和评估化学混合物对生殖细胞影响的方法。我的研究将特别集中在一类具有良好特征的EDCs，即邻苯二甲酸酯，它是邻苯二甲酸的烷基二酯和广泛使用的增塑剂，在各种消费、医疗和建筑产品中都有发现。利用最近在人类母体尿液中发现的六种特定邻苯二甲酸盐，我们的初步研究发现，个体暴露于BBP、DBP、DEP、DiBP、DiNP和DEHP显著增加秀丽隐线虫卵发生过程中的染色体不分离和生殖细胞凋亡。在本提案中，我的目标是进一步表征这两种邻苯二甲酸盐（BBP和DEP）对染色体形态发生、减数分裂进程、种系特异性基因表达和雌性和雄性种系染色质景观的个体影响。最后，我的目标是确定所有六种邻苯二甲酸盐组合的影响，因为它们存在于我们的环境中，并评估这些影响是如何在物种之间保持的。这些拟议的研究不仅将阐明这些邻苯二甲酸盐对雌性和雄性生殖系的个体和组合影响，而且还将阐明利用秀丽隐杆线虫快速评估和预测环境毒素对高等生物的影响的有效性。

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.