Department of Environmental Health Sciences, School of Public Health, University of Michigan, Ann Arbor, MI, USA.
Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, MI, USA.
Environ Res. 2020 May;184:109259. doi: 10.1016/j.envres.2020.109259. Epub 2020 Feb 19.
Miscarriage is a prevalent public health issue and many events occur before women are aware of their pregnancy, complicating research design. Thus, risk factors for miscarriage are critically understudied. Our goal was to identify environmental chemicals with a high number of interactions with miscarriage genes, based on known toxicogenomic responses.
We used miscarriage (MeSH: D000022) and chemical gene lists from the Comparative Toxicogenomics Database in human, mouse, and rat. We assessed enrichment for gene ontology biological processes among the miscarriage genes. We prioritized chemicals (n = 25) found at Superfund sites or in the blood or urine pregnant women. For chemical-disease gene sets of sufficient size (n = 13 chemicals, n = 20 comparisons), chi-squared enrichment tests and proportional reporting ratios (PRR) were calculated. We cross-validated enrichment results.
Miscarriage was annotated with 121 genes and overrepresented in inflammatory response (q = 0.001), collagen metabolic process (q = 1 × 10), cell death (q = 0.02), and vasculature development (q = 0.005) pathways. The number of unique genes annotated to a chemical ranged from 2 (bromacil) to 5607 (atrazine). In humans, all chemicals tested were highly enriched for miscarriage gene overlap (all p < 0.001; parathion PRR = 7, cadmium PRR = 6.5, lead PRR = 3.9, arsenic PRR = 3.5, atrazine PRR = 2.8). In mice, highest enrichment (p < 0.001) was observed for naphthalene (PRR = 16.1), cadmium (PRR = 12.8), arsenic (PRR = 11.6), and carbon tetrachloride (PRR = 7.7). In rats, we observed highest enrichment (p < 0.001) for cadmium (PRR = 8.7), carbon tetrachloride (PRR = 8.3), and dieldrin (PRR = 5.3). Our findings were robust to 1000 permutations each of variable gene set sizes.
We observed chemical gene sets (parathion, cadmium, naphthalene, carbon tetrachloride, arsenic, lead, dieldrin, and atrazine) were highly enriched for miscarriage genes. Exposures to chemicals linked to miscarriage, and thus linked to decreased probability of live birth, may limit the inclusion of fetuses susceptible to adverse birth outcomes in epidemiology studies. Our findings have critical public health implications for successful pregnancies and the interpretation of adverse impacts of environmental chemical exposures on pregnancy.
流产是一个普遍存在的公共卫生问题，许多事件发生在女性意识到怀孕之前，这使得研究设计变得复杂。因此，流产的风险因素研究严重不足。我们的目标是根据已知的毒理基因组反应，确定与流产基因有大量相互作用的环境化学物质。
我们使用了流产（MeSH：D000022）和比较毒理基因组数据库中的人类、小鼠和大鼠的化学基因列表。我们评估了流产基因中基因本体生物过程的富集情况。我们优先考虑在超级基金场址或孕妇血液或尿液中发现的化学物质（n=25）。对于化学-疾病基因集（n=13 种化学物质，n=20 种比较），计算了卡方富集检验和比例报告比（PRR）。我们交叉验证了富集结果。
流产与 121 个基因相关，并在炎症反应（q=0.001）、胶原蛋白代谢过程（q=1×10）、细胞死亡（q=0.02）和血管发育（q=0.005）途径中过度表达。与一种化学物质相关的独特基因数量从 2 个（溴草隆）到 5607 个（莠去津）不等。在人类中，所有测试的化学物质都高度富集了流产基因重叠（均 p<0.001；对硫磷 PRR=7，镉 PRR=6.5，铅 PRR=3.9，砷 PRR=3.5，莠去津 PRR=2.8）。在小鼠中，萘（PRR=16.1）、镉（PRR=12.8）、砷（PRR=11.6）和四氯化碳（PRR=7.7）观察到最高的富集（p<0.001）。在大鼠中，我们观察到最高的富集（p<0.001）为镉（PRR=8.7）、四氯化碳（PRR=8.3）和狄氏剂（PRR=5.3）。我们的发现经过了 1000 次变量基因集大小的随机排列，结果仍然稳健。
我们观察到化学物质基因集（对硫磷、镉、萘、四氯化碳、砷、铅、狄氏剂和莠去津）与流产基因高度富集。与流产相关的化学物质暴露，因此与活产概率降低相关，可能会限制易受不良出生结局影响的胎儿被纳入流行病学研究。我们的发现对成功怀孕和解释环境化学物质暴露对怀孕的不良影响具有重要的公共卫生意义。
