Perinatal Lead Exposure Promotes Sex-Specific Epigenetic Programming of Disease-Relevant Pathways in Mouse Heart
Environmental contaminants such as the metal lead (Pb) are associated with cardiovascular disease, but the underlying molecular mechanisms are poorly understood. In particular, little is known about how exposure to Pb during early development impacts the cardiac epigenome at any point across the lif...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-01-01
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| Series: | Toxics |
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| Online Access: | https://www.mdpi.com/2305-6304/11/1/85 |
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| author | Laurie K. Svoboda Kai Wang Jaclyn M. Goodrich Tamara R. Jones Justin A. Colacino Karen E. Peterson Martha M. Tellez-Rojo Maureen A. Sartor Dana C. Dolinoy |
| author_facet | Laurie K. Svoboda Kai Wang Jaclyn M. Goodrich Tamara R. Jones Justin A. Colacino Karen E. Peterson Martha M. Tellez-Rojo Maureen A. Sartor Dana C. Dolinoy |
| author_sort | Laurie K. Svoboda |
| collection | DOAJ |
| description | Environmental contaminants such as the metal lead (Pb) are associated with cardiovascular disease, but the underlying molecular mechanisms are poorly understood. In particular, little is known about how exposure to Pb during early development impacts the cardiac epigenome at any point across the life course and potential differences between sexes. In a mouse model of human-relevant perinatal exposures, we utilized RNA-seq and Enhanced Reduced Representation Bisulfite Sequencing (ERRBS) to investigate the effects of Pb exposure during gestation and lactation on gene expression and DNA methylation, respectively, in the hearts of male and female mice at weaning. For ERRBS, we identified differentially methylated CpGs (DMCs) or differentially methylated 1000 bp regions (DMRs) based on a minimum absolute change in methylation of 10% and an FDR < 0.05. For gene expression data, an FDR < 0.05 was considered significant. No individual genes met the FDR cutoff for gene expression; however, we found that Pb exposure leads to significant changes in the expression of gene pathways relevant to cardiovascular development and disease. We further found that Pb promotes sex-specific changes in DNA methylation at hundreds of gene loci (280 DMCs and 99 DMRs in males, 189 DMCs and 121 DMRs in females), and pathway analysis revealed that these CpGs and regions collectively function in embryonic development. In males, differential methylation also occurred at genes related to immune function and metabolism. We then investigated whether genes exhibiting differential methylation at weaning were also differentially methylated in hearts from a cohort of Pb-exposed mice at adulthood. We found that a single gene, Galnt2, showed differential methylation in both sexes and time points. In a human cohort investigating the influence of prenatal Pb exposure on the epigenome, we also observed an inverse association between first trimester Pb concentrations and adolescent blood leukocyte DNA methylation at a locus in GALNT2, suggesting that this gene may represent a biomarker of Pb exposure across species. Together, these data, across two time points in mice and in a human birth cohort study, collectively demonstrate that Pb exposure promotes sex-specific programming of the cardiac epigenome, and provide potential mechanistic insight into how Pb causes cardiovascular disease. |
| first_indexed | 2024-03-09T11:05:55Z |
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| id | doaj.art-2972c769fe584d8e8ebbf25f8da924f3 |
| institution | Directory Open Access Journal |
| issn | 2305-6304 |
| language | English |
| last_indexed | 2024-03-09T11:05:55Z |
| publishDate | 2023-01-01 |
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| series | Toxics |
| spelling | doaj.art-2972c769fe584d8e8ebbf25f8da924f32023-12-01T00:56:14ZengMDPI AGToxics2305-63042023-01-011118510.3390/toxics11010085Perinatal Lead Exposure Promotes Sex-Specific Epigenetic Programming of Disease-Relevant Pathways in Mouse HeartLaurie K. Svoboda0Kai Wang1Jaclyn M. Goodrich2Tamara R. Jones3Justin A. Colacino4Karen E. Peterson5Martha M. Tellez-Rojo6Maureen A. Sartor7Dana C. Dolinoy8Environmental Health Sciences, University of Michigan School of Public Health, Ann Arbor, MI 48109, USADepartment of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI 48109, USAEnvironmental Health Sciences, University of Michigan School of Public Health, Ann Arbor, MI 48109, USAEnvironmental Health Sciences, University of Michigan School of Public Health, Ann Arbor, MI 48109, USAEnvironmental Health Sciences, University of Michigan School of Public Health, Ann Arbor, MI 48109, USANutritional Sciences, University of Michigan School of Public Health, Ann Arbor, MI 48109, USACenter for Research on Nutrition and Health, National Institute of Public Health, Cuernavaca 62100, MexicoDepartment of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI 48109, USAEnvironmental Health Sciences, University of Michigan School of Public Health, Ann Arbor, MI 48109, USAEnvironmental contaminants such as the metal lead (Pb) are associated with cardiovascular disease, but the underlying molecular mechanisms are poorly understood. In particular, little is known about how exposure to Pb during early development impacts the cardiac epigenome at any point across the life course and potential differences between sexes. In a mouse model of human-relevant perinatal exposures, we utilized RNA-seq and Enhanced Reduced Representation Bisulfite Sequencing (ERRBS) to investigate the effects of Pb exposure during gestation and lactation on gene expression and DNA methylation, respectively, in the hearts of male and female mice at weaning. For ERRBS, we identified differentially methylated CpGs (DMCs) or differentially methylated 1000 bp regions (DMRs) based on a minimum absolute change in methylation of 10% and an FDR < 0.05. For gene expression data, an FDR < 0.05 was considered significant. No individual genes met the FDR cutoff for gene expression; however, we found that Pb exposure leads to significant changes in the expression of gene pathways relevant to cardiovascular development and disease. We further found that Pb promotes sex-specific changes in DNA methylation at hundreds of gene loci (280 DMCs and 99 DMRs in males, 189 DMCs and 121 DMRs in females), and pathway analysis revealed that these CpGs and regions collectively function in embryonic development. In males, differential methylation also occurred at genes related to immune function and metabolism. We then investigated whether genes exhibiting differential methylation at weaning were also differentially methylated in hearts from a cohort of Pb-exposed mice at adulthood. We found that a single gene, Galnt2, showed differential methylation in both sexes and time points. In a human cohort investigating the influence of prenatal Pb exposure on the epigenome, we also observed an inverse association between first trimester Pb concentrations and adolescent blood leukocyte DNA methylation at a locus in GALNT2, suggesting that this gene may represent a biomarker of Pb exposure across species. Together, these data, across two time points in mice and in a human birth cohort study, collectively demonstrate that Pb exposure promotes sex-specific programming of the cardiac epigenome, and provide potential mechanistic insight into how Pb causes cardiovascular disease.https://www.mdpi.com/2305-6304/11/1/85heartcardiovascular diseaseDNA methylationepigeneticDevelopmental Origins of Health and Disease (DOHaD)toxicoepigenetics |
| spellingShingle | Laurie K. Svoboda Kai Wang Jaclyn M. Goodrich Tamara R. Jones Justin A. Colacino Karen E. Peterson Martha M. Tellez-Rojo Maureen A. Sartor Dana C. Dolinoy Perinatal Lead Exposure Promotes Sex-Specific Epigenetic Programming of Disease-Relevant Pathways in Mouse Heart Toxics heart cardiovascular disease DNA methylation epigenetic Developmental Origins of Health and Disease (DOHaD) toxicoepigenetics |
| title | Perinatal Lead Exposure Promotes Sex-Specific Epigenetic Programming of Disease-Relevant Pathways in Mouse Heart |
| title_full | Perinatal Lead Exposure Promotes Sex-Specific Epigenetic Programming of Disease-Relevant Pathways in Mouse Heart |
| title_fullStr | Perinatal Lead Exposure Promotes Sex-Specific Epigenetic Programming of Disease-Relevant Pathways in Mouse Heart |
| title_full_unstemmed | Perinatal Lead Exposure Promotes Sex-Specific Epigenetic Programming of Disease-Relevant Pathways in Mouse Heart |
| title_short | Perinatal Lead Exposure Promotes Sex-Specific Epigenetic Programming of Disease-Relevant Pathways in Mouse Heart |
| title_sort | perinatal lead exposure promotes sex specific epigenetic programming of disease relevant pathways in mouse heart |
| topic | heart cardiovascular disease DNA methylation epigenetic Developmental Origins of Health and Disease (DOHaD) toxicoepigenetics |
| url | https://www.mdpi.com/2305-6304/11/1/85 |
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