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Environmental factors play an important role in the etiology of cardiovascular diseases. Cardiovascular diseases exhibit marked sexual dimorphism; however, the sex-specific effects of environmental exposures on cardiac health are incompletely understood. Perinatal and adult exposures to the metal lead (Pb) are linked to several adverse cardiovascular outcomes, but the sex-specific effects of this toxicant on the heart have received little attention. Perinatal environmental exposures can lead to disease through disruption of the normal epigenetic programming that occurs during early development. Using a mouse model of human-relevant perinatal environmental exposure, we investigated the effects of exposure to Pb during gestation and lactation on DNA methylation in the hearts of adult offspring mice (n = 6 per sex). Two weeks prior to mating, dams were assigned to control or Pb acetate (32 ppm) water, and exposure continued until offspring were weaned at three weeks of age. Enhanced reduced-representation bisulfite sequencing was used to measure DNA methylation in the hearts of offspring at five months of age. Although Pb exposure stopped at three weeks of age, we discovered hundreds of differentially methylated cytosines (DMCs) and regions (DMRs) in males and females at five months of age. DMCs/DMRs and their associated genes were sex-specific, with a small, but statistically significant subset overlapping between sexes. Pathway analysis revealed altered methylation of genes important for cardiac and other tissue development in males, and histone demethylation in females. Together, these data demonstrate that perinatal exposure to Pb induces sex-specific changes in cardiac DNA methylation that are present long after cessation of exposure, and highlight the importance of considering sex in environmental epigenetics and mechanistic toxicology studies.
Laurie K. Svoboda; Kai Wang; Tamara R. Jones; Justin A. Colacino; Maureen A. Sartor; Dana C. Dolinoy. Sex-Specific Alterations in Cardiac DNA Methylation in Adult Mice by Perinatal Lead Exposure. International Journal of Environmental Research and Public Health 2021, 18, 577 .
AMA StyleLaurie K. Svoboda, Kai Wang, Tamara R. Jones, Justin A. Colacino, Maureen A. Sartor, Dana C. Dolinoy. Sex-Specific Alterations in Cardiac DNA Methylation in Adult Mice by Perinatal Lead Exposure. International Journal of Environmental Research and Public Health. 2021; 18 (2):577.
Chicago/Turabian StyleLaurie K. Svoboda; Kai Wang; Tamara R. Jones; Justin A. Colacino; Maureen A. Sartor; Dana C. Dolinoy. 2021. "Sex-Specific Alterations in Cardiac DNA Methylation in Adult Mice by Perinatal Lead Exposure." International Journal of Environmental Research and Public Health 18, no. 2: 577.
Genomic imprinting, a phenomenon by which genes are expressed in a monoallelic, parent-of-origin-dependent fashion, is critical for normal brain development. Expression of imprinted genes is regulated via epigenetic mechanisms, including DNA methylation (5-methylcytosine, 5mC), and disruptions in imprinting can lead to disease. Early-life exposure to the endocrine disrupting chemical bisphenol A (BPA) is associated with abnormalities in brain development and behavior, as well as with disruptions in epigenetic patterning, including 5mC and DNA hydroxymethylation (5-hydroxymethylcytosine, 5hmC). Using an established mouse model of perinatal environmental exposure, the objective of this study was to examine the effects of perinatal BPA exposure on epigenetic regulation of imprinted gene expression in adult mice. Two weeks prior to mating, dams were assigned to control chow or chow containing an environmentally relevant dose (50 µg/kg) of BPA. Exposure continued until offspring were weaned at post-natal day 21, and animals were followed until 10 months of age. Expression of three imprinted genes—Pde10a, Ppp1r9a, and Kcnq1, as well as three genes encoding proteins critical for regulation of 5mC and 5hmC—Dnmt1, Tet1, and Tet2, were evaluated in the right cortex and midbrain using qRT-PCR. Perinatal BPA exposure was associated with a significant increase in adult Kcnq1 (p = 0.04) and Dnmt1 (p = 0.02) expression in the right cortex, as well as increased expression of Tet2 in the midbrain (p = 0.03). Expression of Tet2 and Kcnq1 were positively correlated in the midbrain. Analysis of 5mC and 5hmC at the Kcnq1 locus was conducted in parallel samples using standard and oxidative bisulfite conversion followed by pyrosequencing. This analysis revealed enrichment of both 5mC and 5hmC at this locus in both brain regions. No significant changes in 5mC and 5hmC at Kcnq1 were observed with perinatal BPA exposure. Together, these data suggest that perinatal BPA exposure results in altered expression of Kcnq1, Dnmt1, and Tet2 in the adult mouse brain. Further studies with larger sample sizes are necessary to understand the mechanistic basis for these changes, as well as to determine the implications they have for brain development and function.
Maureen A. Malloy; Joseph J. Kochmanski; Tamara R. Jones; Justin A. Colacino; Jaclyn M. Goodrich; Dana C. Dolinoy; Laurie K. Svoboda. Perinatal Bisphenol A Exposure and Reprogramming of Imprinted Gene Expression in the Adult Mouse Brain. Frontiers in Genetics 2019, 10, 1 .
AMA StyleMaureen A. Malloy, Joseph J. Kochmanski, Tamara R. Jones, Justin A. Colacino, Jaclyn M. Goodrich, Dana C. Dolinoy, Laurie K. Svoboda. Perinatal Bisphenol A Exposure and Reprogramming of Imprinted Gene Expression in the Adult Mouse Brain. Frontiers in Genetics. 2019; 10 ():1.
Chicago/Turabian StyleMaureen A. Malloy; Joseph J. Kochmanski; Tamara R. Jones; Justin A. Colacino; Jaclyn M. Goodrich; Dana C. Dolinoy; Laurie K. Svoboda. 2019. "Perinatal Bisphenol A Exposure and Reprogramming of Imprinted Gene Expression in the Adult Mouse Brain." Frontiers in Genetics 10, no. : 1.