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Principal Investigator: Cardenas, Andres
Institute Receiving Award Stanford University
Location Redwood City, CA
Grant Number R21ES035517
Funding Organization National Institute of Environmental Health Sciences
Award Funding Period 07 Sep 2023 to 31 Aug 2025
DESCRIPTION (provided by applicant): 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.
Science Code(s)/Area of Science(s) Primary: 10 - Epigenetics
Secondary: 03 - Carcinogenesis/Cell Transformation
Publications No publications associated with this grant
Program Officer Kimberly Mcallister
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