Grant Number:
Principal Investigator:
Faulk, Christopher Don
Institution:
University of Minnesota
Most Recent Award Year:
2015
Lifestage of Participants:
Exposure:
Prenatal
Exposures:
Metals:
Lead
Personal Care/Consumer Products:
Bisphenol A (BPA)
Health Outcomes:
Biological Sample:
Human fetal liver cells
Epigenetic Mechanisms Studied:
DNA Methylation
Abstract:
There are fifty times as many transposons as there are genes in the human genome, and through interaction of the environment and the epigenome, they can become a disruptive force in gene regulation. Since the inception of the field of epigenetics, only a handful of genes have been definitively identified as epigenetically modifiable by environmental exposures. Such loci are termed "metastable epialleles". Most of these epigenetically labile regions are linked to chance insertions of repetitive elements, causing for example, the varying fur colors of genetically identical Agouti viable yellow (Avy) mice. Early exposure to the common environmental toxicants bisphenol A (BPA) and lead (Pb) has been shown to alter the epigenome through global changes in DNA methylation at repetitive elements in mammals. Consequently, the interaction between these toxicants and the epigenome at repetitive elements can have dramatic and long lasting effects. We do not know the governing features underlying the capacity for metastability, nor do we understand how toxicant exposure affects methylation instability in transposons. The candidate's research strategy is designed to discover the extent to which environmental toxicants disrupt the necessary silencing of these selfish elements. Intriguingly, the candidate's preliminary evidence shows that two intracisternal A particle (IAP) transposons associated with metastable epialleles in mice have a higher sequence similarity to each other than to any other transposon in the genome. Thus the overall objective in this study is to determine if phylogenetic similarity predicts the instability of DNA methylation at transposons and whether early environmental insults shift the methylation pattern in mice and humans. The proposed work presents opportunity to merge repetitive element genomics with environmental epigenetics and establish good biomarkers to test exposed populations of mice and humans. First the candidate will test variability in DNA methylation of genetically similar and dissimilar transposons to determine whether sequence identity is a controlling factor in epigenetic instability (Aim 1). Those transposons found to be variably methylated will be validated in mice exposed to environmentally relevant levels of BPA or Pb throughout gestation and early life. Second, using fetal liver samples stratified by BPA exposure that have undergone next-generation sequencing, the candidate will develop an unbiased methodology to identify potentially metastable transposons in humans (Aim 2). Finally, human metastable loci candidates identified with this approach will be validated in a well-characterized ongoing epidemiological birth cohort, the Early Life Exposure in Mexico to Environmental Toxicants (ELEMENT) study (Aim 3). The successful completion of this project will result in more accurate tests of prior environmental exposures and the identification of metastable transposons susceptible to modification by environmental toxicants in both mice and humans.
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Related NIEHS-Funded Study Populations
Early Life Exposures in Mexico to Environmental Toxicants (ELEMENT)
Principal Investigator:
Hu, Howard; Peterson, Karen; Hernandez-Avila, Mauricio; Tellez-Rojo, Martha Maria
| Study Population Page Study Population c49
Institution:
University of Michigan
Location:
Mexico City, Mexico
Number of Participants::
1,653
Brief Description::
This is a group of three sequentially-enrolled, on-going, epidemiologic birth cohort studies in Mexico City with an original aim to investigate the impact of lead on child development. The research aims have since expanded to include a wide range health outcomes and environmental, nutritional, behavioral, genetic, and epigenetic risk factors. More than 1,600 mother-child pairs enrolled in the study beginning in 1994, some of whom have been followed for over two decades.