Novel Epigenetic Biomarkers Mediating Bisphenol A Exposure and Metabolic Phenotypes in Female Mice.
There is compelling evidence that epigenetic modifications link developmental environmental insults to adult disease susceptibility. Animal studies have associated perinatal bisphenol A (BPA) exposure to altered DNA methylation, but these studies are often limited to candidate gene and global non-loci-specific approaches. By using an epigenome-wide discovery platform, we elucidated epigenetic alterations in liver tissue from adult mice offspring (10 months) following perinatal BPA exposure at human physiologically relevant doses (50-ng, 50-μg, and 50-mg BPA/kg diet). Biological pathway analysis identified an enrichment of significant differentially methylated regions in metabolic pathways among females. Furthermore, through the use of top enriched biological pathways, 4 candidate genes were chosen to assess DNA methylation as a mediating factor linking the association of perinatal BPA exposure to metabolic phenotypes previously observed in female offspring. DNA methylation status at Janus kinase-2 (Jak-2), retinoid X receptor (Rxr), regulatory factor x-associated protein (Rfxap), and transmembrane protein 238 (Tmem238) was used within a mediational regression analysis. DNA methylation in all four of the candidate genes was identified as a mediator in the mechanistic pathway of developmental BPA exposure and female-specific energy expenditure, body weight, and body fat phenotypes. Data generated from this study are crucial for deciphering the mechanistic role of epigenetics in the pathogenesis of chronic disease and the development of epigenetic-based prevention and therapeutic strategies for complex human disease.
Department of Environmental Health Sciences.|Department of Nutritional Sciences.
Olivia S
OS
Anderson
Department of Environmental Health Sciences.
Jung H
JH
Kim
Department of Nutritional Sciences.
Karen E
KE
Peterson
Department of Biostatistics, and.
Brisa N
BN
Sanchez
Department of Environmental Health Sciences.
Karilyn E
KE
Sant
Department of Biostatistics, and.|Department of Computational Medicine and Bioinformatics, Medical School, University of Michigan, Ann Arbor, Michigan 48109.
Maureen A
MA
Sartor
Department of Environmental Health Sciences.
Caren
C
Weinhouse
Department of Environmental Health Sciences.|Department of Nutritional Sciences.
Dana C
DC
Dolinoy
D000818:Animals; D001559:Benzhydryl Compounds / Q000633:toxicity*; D015415:Biomarkers / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects*; D052244:Endocrine Disruptors / Q000633:toxicity*; D004781:Environmental Exposure; D044127:Epigenesis, Genetic; D057890:Epigenomics; D005260:Female; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D010636:Phenols / Q000633:toxicity*; D000098826:Bisphenol A Compounds
D001559:Benzhydryl Compounds; D015415:Biomarkers; D052244:Endocrine Disruptors; D010636:Phenols; C006780:bisphenol A; D000098826:Bisphenol A Compounds