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National Institute of Environmental Health Sciences

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Your Environment. Your Health.

Publication Detail

Title: Sex-specific DNA methylation and associations with in utero tobacco smoke exposure at nuclear-encoded mitochondrial genes.

Authors: King, Dillon E; Sparling, Anna Clare; Lloyd, Dillon; Satusky, Matthew Joseph; Martinez, Mackenzie; Grenier, Carole; Bergemann, Christina Michelle; Maguire, Rachel; Hoyo, Cathrine; Meyer, Joel Newman; Murphy, Susan K

Published In Epigenetics, (2022 Dec)

Abstract: Sex-linked differences in mitochondrial ATP production, enzyme activities, and reactive oxygen species generation have been reported in multiple tissue and cell types. While the effects of reproductive hormones underlie many of these differences, regulation of sexually dimorphic mitochondrial function has not been fully characterized. We hypothesized that sex-specific DNA methylation contributes to sex-specific expression of nuclear genes that influence mitochondrial function. Herein, we analysed DNA methylation data specifically focused on nuclear-encoded mitochondrial genes in 191 males and 190 females. We found 596 differentially methylated sites (DMSs) (FDR p < 0.05), corresponding to 324 genes, with at least a 1% difference in methylation between sexes. To investigate the potential functional significance, we utilized gene expression microarray data. Of the 324 genes containing DMSs, 17 showed differences in gene expression by sex. Particularly striking was that ATP5G2, encoding subunit C of ATP synthase, contains seven DMSs and exhibits a sex difference in expression (p = 0.04). Finally, we also found that alterations in DNA methylation associated with in utero tobacco smoke exposure were sex-specific in these nuclear-encoded mitochondrial genes. Interestingly, the level of sex differences in DNA methylation at nuclear-encoded mitochondrial genes and the level of methylation changes associated with smoke exposure were less prominent than that of other genes. This suggests more conservative regulation of DNA methylation at these nuclear-encoded mitochondrial genes as compared to others. Overall, our findings suggest that sex-specific DNA methylation may help establish sex differences in expression and function and that sex-specific alterations in DNA methylation in response to exposures could contribute to sex-variable toxicological responses.

PubMed ID: 35238269 Exiting the NIEHS site

MeSH Terms: Adenosine Triphosphate; DNA Methylation*; Female; Genes, Mitochondrial; Hormones; Humans; Male; Maternal Exposure*; Reactive Oxygen Species; Sex Factors*; Tobacco Smoke Pollution*

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