Sex-Specific Alterations in Cardiac DNA Methylation in Adult Mice by Perinatal Lead Exposure

Svoboda, Laurie K.; Wang, Kai; Jones, Tamara R.; Colacino, Justin A.; Sartor, Maureen A.; Dolinoy, Dana C.

doi:10.3390/ijerph18020577

Cited by 15 publications

(15 citation statements)

References 88 publications

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“…Few studies, however, have investigated the effects of Pb on the cardiac epigenome. We recently discovered that perinatal Pb exposure results in sex-specific changes in DNA methylation in the hearts of offspring mice that are present in adulthood, long after cessation of the exposure [ 146 ]. The implications of these changes for cardiac health are under investigation.…”

Section: Introductionmentioning

confidence: 99%

Developmental toxicant exposures and sex-specific effects on epigenetic programming and cardiovascular health across generations

Svoboda

Ishikawa

Dolinoy

2022

Environmental Epigenetics

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Despite substantial strides in diagnosis and treatment, cardiovascular diseases (CVDs) continue to represent the leading cause of death in the US and around the world, resulting in significant morbidity and loss of productive years of life. It is increasingly evident that environmental exposures during early development can influence CVD risk across the life course. CVDs exhibit marked sexual dimorphism, but how sex interacts with environmental exposures to affect cardiovascular health is a critical and understudied area of environmental health. Emerging evidence suggests that developmental exposures may have multi- and transgenerational effects on cardiovascular health, with potential sex differences; however, further research in this important area is urgently needed. Lead (Pb), phthalate plasticizers, and perfluoroalkyl substances (PFAS) are ubiquitous environmental contaminants with numerous adverse human health effects. Notably, recent evidence suggests that developmental exposure to each of these toxicants has sex-specific effects on cardiovascular outcomes, but the underlying mechanisms, and their effects on future generations, require further investigation. This Review Article will highlight the role for the developmental environment in influencing cardiovascular health across generations, with a particular emphasis on sex differences and epigenetic mechanisms In particular, we will focus on the current evidence for adverse multi and transgenerational effects of developmental exposures to Pb, phthalates, and PFAS, and highlight areas where further research is needed.

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Section: Introductionmentioning

confidence: 99%

Developmental toxicant exposures and sex-specific effects on epigenetic programming and cardiovascular health across generations

Svoboda

Ishikawa

Dolinoy

2022

Environmental Epigenetics

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“…At weaning on postnatal day 21, approximately 1 male and 1 female offspring per litter (n = 7 mice per condition) were sacrificed for tissue harvest. A second cohort of mice (approximately 1 male and 1 female per litter) was sacrificed at 5 months of age (n = 6 mice per condition), and data from these mice have been published previously [ 44 ]. All animals had access to food and drinking water ad libitum throughout the experiment while housed in polycarbonate-free cages.…”

Section: Methodsmentioning

confidence: 99%

“…Enhanced Reduced Representation Bisulfite Sequencing (ERRBS) was utilized to examine changes in DNA methylation with Pb exposure in this study (N = 7 per sex, per condition). Our previously published study of animals at 5 months of age included 6 animals per sex, per condition [ 44 ]. ERRBS permits the quantitative detection of base-pair resolution DNA methylation at CpG-rich regions in the genome [ 50 ].…”

Section: Methodsmentioning

confidence: 99%

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Perinatal Lead Exposure Promotes Sex-Specific Epigenetic Programming of Disease-Relevant Pathways in Mouse Heart

Svoboda

Wang

Goodrich

et al. 2023

Toxics

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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.

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“…Pb is a known neurotoxic substance that may impair spatial learning and memory by damaging hippocampal long-term enhancement (LTP) and damage hippocampal neurons [ 2 ]. Pb exposure has been linked to high blood pressure, myocardial infarction, stroke, and arrhythmias in humans and animals [ 3 ]. It has been found that Pb exposure may cause cellular oxidative stress, ECG abnormalities, and elevated blood pressure, which may cause cardiovascular disease [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

Alleviating Effects of Black Soybean Peptide on Oxidative Stress Injury Induced by Lead in PC12 Cells via Keap1/Nrf2/TXNIP Signaling Pathway

Wen

et al. 2022

Nutrients

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Many researchers have found that Pb exposure can cause oxidative stress damage to the body’s tissue. Black soybean peptide (BSP) has a variety of physiological functions, especially in terms of oxidative stress. Nevertheless, the mitigation function of BSPs on Pb-induced oxidative stress damage in PC12 cells has not been clearly defined. In this study, cell viability was detected by CCK8. Oxidative stress indicators, such as ROS, GSH/GSSG, MDA, SOD, CAT, GPx, and GR, were tested with biochemical kit. Protein expression of Keap1, Nrf2, and TXNIP was measured by Western blot. Compared with the control group, Pb reduced the cell viability of PC12 cells. However, BSP treatment significantly increased the viability of PC12 cells induced by lead exposure (p < 0.05). Lead can enrich the contents of MDA and ROS, but decrease the amount of CAT, SOD, GR, GPx, and GSH/GSSG in PC12 cells, while BSP can alleviate it (p < 0.05). Lead can enhance the expression of Keap1 and TXNIP proteins, but reduce Nrf2 expression. In contrast, BSPs reversed this phenomenon (p < 0.05). BSPs can alleviate oxidative stress injury induced by lead in PC12 cells through the Keap1/Nrf2/TXNIP signaling pathway.

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Sex-Specific Alterations in Cardiac DNA Methylation in Adult Mice by Perinatal Lead Exposure

Cited by 15 publications

References 88 publications

Developmental toxicant exposures and sex-specific effects on epigenetic programming and cardiovascular health across generations

Developmental toxicant exposures and sex-specific effects on epigenetic programming and cardiovascular health across generations

Perinatal Lead Exposure Promotes Sex-Specific Epigenetic Programming of Disease-Relevant Pathways in Mouse Heart

Alleviating Effects of Black Soybean Peptide on Oxidative Stress Injury Induced by Lead in PC12 Cells via Keap1/Nrf2/TXNIP Signaling Pathway

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