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

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.

Grant Number: 5R21ES035517-02
NIH Institute/Center: NIH
Principal Investigator: Andres Cardenas