Carcinogenesis of Nickel and Epigenetic Control

New York University School Of Medicine, New York NY

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Abstract

DESCRIPTION (provided by applicant): This grant will investigate and map epigenetic changes induced in CD3+ T lymphocytes of humans exposed to carcinogenic nickel compounds from a nickel refinery in Jinchang, China. Workers in this nickel refinery have very high exposure to carcinogenic nickel compounds and have a 4-fold higher incidence of lung cancer than the general population of China. We will determine the effect of nickel ion exposure on peripheral blood T lymphocytes induced to proliferate with PHA in vitro. Using the Solexa/Illumina ChIP-Seq method, we will map whole genome changes in a gene activating mark H3K4 trime, and a gene silencing mark, H3K9 dime, as well as gene expression changes using Affymetrix gene chips and whole genomic mapping of DNA methylation changes. We will first determine whether there are epigenetic changes induced by nickel exposure in vivo by examining 15 unexposed vs.15 highly exposed workers at the age of 54. These workers in China retire at age 55, so this law allows us to investigate the persistence of epigenetic changes induced by Ni ions after the exposure ceases. We will also examine inter- and intra-individual variation in these epigenetic marks and gene expression changes over time. We will also study the persistence of the epigenetic marks in the same 15 unexposed individuals or those 15 previously exposed after they retire at age 55 and again at ages 56 and 57 when their exposure to nickel will have stopped. We will also examine a dose response relationship between nickel exposure and the epigenetic marks and gene expression changes by recruiting 30 unexposed individuals, as well as 30 exposed to lower (<1 mg/M3) or 30 individuals with a higher level of nickel exposure (>1 mg/M3). We will attempt to control confounders by study design, since all the participants will be at the same age, same sex, similar BMI, and non-smokers. Other confounders such as demographic factors and alcohol intake will also be examined and controlled. This study will help us understand whole genomic changes in several epigenetic marks and gene expression induced by human exposure to carcinogenic nickel compounds. PUBLIC HEALTH RELEVANCE: It is very difficult to find a population exposed to carcinogenic nickel compounds in the United States. Thus, we take advantage of this unique opportunity to study the effect of nickel compound exposure in humans on whole genomic epigenetic marks. We will address how these marks change with exposure and whether they are persistent and inheritable through cell division.