title: Trichloroethylene induces methylation of the Serca2 promoter in H9c2 cells and embryonic heart.
abstract: Trichloroethylene (TCE) is a halogenated hydrocarbon used as a solvent in industrial settings and in house-cleaning products. Exposure to TCE has been linked to increased risk for congenital heart malformations in both human and animal models. Previous studies showed TCE exposure reduced the expression and function of the ATP-dependent calcium pump, Serca2a, which is important for regulating calcium flux in myocytes and maintaining physiological cardiac function. In this study, we investigated whether TCE reduced Serca2a expression by altering the methylation status of its proximal promoter region. Low doses of TCE exposure (10 ppb) induced DNA hyper methylation in the Serca2 promoter region in cardiac myoblast cells and rat embryonic cardiac tissue. TCE exposure induced DNA methylation in a region of the Serca2 promoter which is the target for SP1 binding site essential for regulation of Serca2a transcriptional activity. Chromatin immunoprecipitation data confirmed that TCE exposure reduced the binding of SP1 to the Serca2 promoter region adjacent to the methylated CpG dimer. Finally, low-dose TCE exposure reduced the concentration of S-adenosyl-methionine in exposed cells and embryos. These cumulative data indicate that epigenetic mechanisms, including DNA methylation, may be important in mediating the teratogenic effects of TCE in embryonic heart.
authors.affiliation: Department of Nutritional Sciences, University of Arizona, Shantz, Tucson, AZ 85721, USA.
authors.forename: Brittany
authors.initials: B
authors.lastname: Palbykin
authors.forename: Jamie
authors.initials: J
authors.lastname: Borg
authors.forename: Patricia T
authors.initials: PT
authors.lastname: Caldwell
authors.forename: Josh
authors.initials: J
authors.lastname: Rowles
authors.forename: Andreas J
authors.initials: AJ
authors.lastname: Papoutsis
authors.forename: Donato F
authors.initials: DF
authors.lastname: Romagnolo
authors.forename: Ornella I
authors.initials: OI
authors.lastname: Selmin
mesh_terms: D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D018899:CpG Islands; D019175:DNA Methylation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D005865:Gestational Age; D006321:Heart / Q000187:drug effects* / Q000196:embryology; D008969:Molecular Sequence Data; D032386:Myoblasts, Cardiac / Q000187:drug effects* / Q000201:enzymology; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000201:enzymology; D011401:Promoter Regions, Genetic / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012436:S-Adenosylmethionine / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics* / Q000378:metabolism; D012997:Solvents / Q000633:toxicity*; D016329:Sp1 Transcription Factor / Q000378:metabolism; D013997:Time Factors; D014241:Trichloroethylene / Q000633:toxicity*
chemical_list: C506948:Atp2a2 protein, rat; D012997:Solvents; D016329:Sp1 Transcription Factor; D014241:Trichloroethylene; D012436:S-Adenosylmethionine; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases