Programming of Epigenetic Clocks and Biomarkers from Early-life Arsenic Exposure

项目总结 全世界数以百万计的人接触到砷，主要来自受污染的饮用水来源， 包括美国的许多地区。砷是一种已知的人类致癌物质，接触一直是 与其他慢性疾病相关，包括糖尿病、心血管和呼吸系统疾病风险 突显其免疫调节作用的新证据。有证据表明，接触砷 影响表观遗传编程，并被认为是砷暴露和潜伏期之间的潜在联系 许多相关的健康影响，包括癌症。关于砷的毒性可能包括 表观遗传失调主要在成人横断面和出生队列中进行测试，随访有限。 以测试表观遗传变化的持久性或临床相关性。拟议的项目将 利用智利北部最大城市安托法加斯塔的一项大型流行病学研究的样本和数据， 那里有大量的砷水浓度记录。1958年，两条砷浓度较高的河流 被转移到研究地区作为饮用水的主要来源，这一高暴露时期结束了 1970年，安装了一座砷水处理厂。结果，有13年的时间 其中平均砷浓度为860ug/L，而治疗前后的水平(&lt；10ug/L)要低得多 句号。这一悲惨的情景为研究人们健康影响的潜伏期提供了一个自然的实验 与智利其他地区的有效比较人群暴露于高水平的砷。从这里开始的研究 该地区报告了强烈的前瞻性关联，并有证据表明，早期接触砷与 随着肺癌、膀胱癌和肾癌的增加以及心肌梗塞风险的增加，慢性 肾脏疾病、支气管扩张症和呼吸道症状。这些联系在几十年后才显现出来 在采取缓解措施后几十年，暴露高峰期在暴露人群中持续存在 有人了。我们正在利用已经从早期接触过的和未接触过的人身上收集的样本 配对研究参与者，测试几十年后中年(中位年龄)表观遗传学中断的持久性 ~50年)。我们将评估暴露的个体是否在多个表观遗传中加速了表观遗传衰老 反映生物老化、发病率和死亡风险的不同方面的时钟。此外，我们将测试是否 接触者对白细胞组成和DNA甲基化特征有不同的估计。我们会 关键协变量的匹配和控制，例如当前的尿砷水平、 成年期、饮食、吸烟、体重指数、性别和社会经济地位。此方法将使我们能够测试延迟 在白细胞DNA甲基化中捕获的表观遗传中断与最近和当前的砷无关 曝光。如果成功，我们的研究将证明，在生命早期接触砷可以持续 规划表观遗传生物标记物，这些标记物与几十年后的发病率和死亡率密切相关。

PROJECT SUMMARY Millions of individuals around the world are exposed to arsenic, mostly from contaminated drinking water sources, including many areas in the U.S. Arsenic is a known human carcinogen, and exposure has been consistently associated with other chronic diseases including diabetes, cardiovascular and respiratory disease risk with emerging evidence highlighting its immunomodulatory effects. There is evidence that arsenic exposure influences epigenetic programming and proposed to be a potential link between arsenic exposure and the latency of many associated health effects, including cancer. The leading hypothesis that arsenic’s toxicity might involve epigenetic dysregulation has been tested mostly in adult cross-sectional and birth cohorts with limited follow-up of participants to test for persistence or clinical relevance of epigenetic changes. The proposed project will leverage samples and data from a large epidemiological study in Antofagasta, the largest city in Northern Chile, where extensive arsenic water concentration records exist. In 1958, two rivers with high arsenic concentrations were diverted into the study region as the primary source of drinking water and this high exposure period ended in 1970 when an arsenic water treatment plant was installed. As a result, there was a thirteen-year period in which average arsenic concentrations were 860 µg/L, with much lower levels (<10 µg/L) before and after the period. This tragic scenario provided a natural experiment to study the latency of health effects among people exposed to high levels of arsenic with valid comparison populations from the rest of Chile. Studies from this region have reported strong prospective associations and evidence that early-life arsenic exposure is associated with increases in lung, bladder, and kidney cancers as well as increased risk of myocardial infarction, chronic renal disease, bronchiectasis, and respiratory symptoms. These associations were only evident decades after the peak exposure period and persisted among the exposed population decades after mitigation measures were taken. We are leveraging already collected samples from individuals exposed in early-life and unexposed matched study participants to test for persistence of epigenetic disruption decades later in mid-life (median age ~ 50 years). We will evaluate if exposed individuals have accelerated epigenetic aging across multiple epigenetic clocks that reflect different aspects of biological aging, morbidity, and mortality risk. Additionally, we will test if exposed individuals have different estimates of leukocyte composition and DNA methylation signatures. We will match and control for key covariates, such as current urinary arsenic levels, historical arsenic exposure in adulthood, diet, smoking, BMI, sex, and socioeconomic status. This approach will enable us to test for latency of epigenetic disruption captured in DNA methylation of leukocytes independent of recent and current arsenic exposure. If successful, our study will demonstrate that exposure to arsenic during early-life can persistently program epigenetic biomarkers that are strongly associated with morbidity and mortality decades later.