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.

Promoter DNA Methylation Regulates Murine SUR1 (Abcc8) and SUR2 (Abcc9) Expression in HL-1 Cardiomyocytes

“…In support of such a notion, TNFα a cytokine which is elevated in the failing heart, has recently been shown to induce a decrease in SERCA2 expression that correlates with promoter methylation [50]. Environmental factors, such as hypoxia, toxins or age, could cause similar changes in methylation and expression [51], [52], with alterations in K ATP current density being either detrimental or beneficial. For example, it has recently been suggested that exercise training confers a significant benefit on cardiovascular function, which correlates with an increase in cardiac SUR2A expression [53].…”

Postnatal exposure to trichloroethylene alters glutathione redox homeostasis, methylation potential, and neurotrophin expression in the mouse hippocampus

“…Low- level TCE (10 ppb) suppressed the expression of the cardiac gene Serca2a in association with hypermethylation of its promoter region (Palbykin et al ., 2011). In contrast, acute high dose TCE (1000 mg/kg/day) decreased methylation of the promoter regions for c-jun and c-myc in the liver and a corresponding increased expression of these genes was reversed by supplemental methionine (Tao et al ., 1999; Tao et al ., 2000).…”

Environmental risk factors of systemic sclerosis

“…MRL+/+ mice, when exposed to trichloroethylene, develop higher levels of overall serum IgG and increased prevalence of antinuclear antibodies [54]. Other experimental models have shown that exposure to trichloroethylene led to (1) protein modifications [55][56][57][58][59]; (2) synthesis of higher levels of IL-17 and IL-21 by splenocytes in trichloroethylene-treated mice [60]; (3) production of reactive oxygen species and increased nitric oxide by nitric oxide synthase in cultured human epidermal keratinocytes [61]; (4) Th1 T cell activation in MRL+/+ mice [62]; (5) inhibition of cellular apoptosis of naïve CD4+ and CD8+ T cells in MRL+/+ mice [63]; and (6) DNA hypermethylation on rat cardiac myoblasts [64]. Furthermore, other experimental studies have shown that exposure to benzene resulted in (1) decreased T cell population in wild/captive American kestrel birds [65]; (2) reduced number of CD4+/CD8+ T cells and B cells in exposed workers [66]; (3) increased reactive oxygen species and induction of DNA fragmentation in pump workers [67]; and (4) changes in gene transcription involved in apoptosis, oxidative stress, cellular cycle, and cytokine production in benzene-treated mice [68].…”