ARRA IMPACT REPORT:
Epigenetics


Public Health Burden
Exposure to environmental chemicals can have adverse health effects, particularly when the exposures occur during specific developmental windows. In some cases, decades can pass between the exposure and the onset of disease. One mechanism by which this may occur is through alteration of epigenetic gene regulation. Epigenetics refers to the regulation of gene expression by chemical modifications that attach directly to DNA or by chemical modifications to the special packaging proteins that associate with DNA, rather than by mutations to the DNA code. Recipients of this group of ARRA awards sought to understand how environmental exposures affected epigenetic programming and how path ways associated with epigenetic modifications might be exploited for the development of prevention/intervention strategies and therapeutic approaches.

Basic Research
Genome-wide DNA Methylation Analyses to Three Organophosphate Pesticides: Researchers at Northwestern University conducted in vitro genome-wide DNA methylation analyses (techniques to measure changes in DNA methylation, one type of epigenetic modification) on DNA samples obtained from cells exposed to three organophosphate pesticides: fonofos, parathion, and terbufos. Previous epidemiology studies linked all three pesticides to human cancers.With ARRA support, researchers observed 712 genes with comparable DNA methylation changes for all three pesticides in addition to specific DNA methylation changes to each pesticide. Gene ontology analysis demonstrated that some of these genes are implicated in carcinogenesis, some have functions directly related to causing cancer, and some are functionally unknown. A genome-wide examination of DNA methylation in the same cells revealed that the insecticide diazinon caused significant DNA methylation changesin 984 genes.1

Effects of Endocrine-disrupting Chemicals on the Brain’s Neuroendocrine System: Another research program, based at the University of Texas – Austin, investigated how exposure to endocrine-disrupting chemicals can have epigenetic effects on the brain’s neuroendocrine systems, which regulate reproductive and other endocrine functions, using a rat model. In utero exposure to low doses of polychlorinated biphenyls (PCBs) led to sex-dependent effects in the hypothalamus, as well as altered neuroendocrine gene and protein expression. These changes were observable as soon as one day after birth, and may underlie physiological and phenotypic differences in exposed animals observed later in life.2

Therapeutics
Early Childhood Exposure to ‘Methyl-rich’ Diets: Research conducted by investigators at Duke University focused on the central hypothesis that in utero and early childhood exposure to ‘methyl-rich’ diets increases the risk of abnormal DNA methylationin special regions of DNA that are critical for the normal shutting down of the expression of one copy of certain genes, a phenomenon call “imprinting.” Abnormal DNA methylation disrupts the imprinting of IGF2, DLK1, and other imprinted genes. Because both copies of the gene become active, this may increase concentrations of growth factors they encode, which can lead to rapid weight gain in children. An ARRA supplement allowed the parent study to complete recruitment within two years by hiring new staff. A data technician and a part time post-doctoral fellow were hired to sequence the differentially methylated region controlling the expression of DLK1. Overall findings have shown that the nurturing gene, PEG3, and several other genes are dramatically altered by early postnatal lead exposure. This perturbation has been shown to be associated with lower IQ and a risk of criminal behavior in adulthood.3

Intervention
Folate and Colorectal Cancer: Avery common gene polymorphism (C677T) of the methylenetetrahydrofolate reductase (MTHFR) gene is known to exert a bipolar effect with respect to the risk of developing colorectal cancer, and this effect is mediated by the B-vitamin, folate. The C677T gene variant conveys protection when folate status is sufficient but increases risk when folate status is low. Biochemical characterization of a mouse model containing a conditional knockout of the MTHFR gene suggests that it may recapitulate the human homozygous variant. A grant allowed the production of offspring from a cross between the conditional MTHFR knockout with Apc1638N mice, a strain that is predisposed to intestinal carcinogenesis. Experiments with these mice will determine whether the down regulation of MTHFR activity alters the effect of intestinal tumor development similarly to what is observed in humans. These MTHFR animals are available publically to interested investigators. Knowledge from this grant could inform the implementation of folic acid fortification programs and identify genetically susceptible individuals that would benefit most from a folate dietary intervention.4

Contributing NIH Institutes & Centers

  • National Institute of Environmental Health Sciences (NIEHS)