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

Abstract

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.

Developmental origins of Parkinson’s disease risk: perinatal exposure to the organochlorine pesticide dieldrin leads to sex-specific DNA modifications in critical neurodevelopmental pathways in the mouse midbrain

“…In line with this, our previous study identified sex-specific effects of dieldrin on neuroinflammatory gene expression and the data here expand on that with sex-specific effects on DNA modification in genes with critical functions in glia (Gezer et al, 2020). More generally, these data add to evidence of the sex-specific nature of epigenetic responses to developmental exposures, reiterating the importance of considering sex when investigating the epigenetic mechanisms driving disease development (Svoboda et al, 2022b,Hilz and Gore, 2022,McCabe et al, 2017.…”

Effects of Developmental Lead and Phthalate Exposures on DNA Methylation in Adult Mouse Blood, Brain, and Liver Identifies Tissue- and Sex-Specific Changes with Implications for Genomic Imprinting

“…These findings highlight the need to evaluate sex-specific effects in toxicoepigenetic studies. 52,53 A greater degree of DMR similarity was seen between exposure types, with 1-7% of total DMRs appearing in both Pb and DEHP-exposed tissues, depending on the sex and tissue ( Figure 2D ) . General trends in DMR directionality were not conserved across tissue types, adding complexity to comparisons of changes in DNAm patterns between target and surrogate tissues ( Figure 2E ).…”

Effects of Developmental Lead and Phthalate Exposures on DNA Methylation in Adult Mouse Blood, Brain, and Liver: A Focus on Genomic Imprinting by Tissue and Sex

“…These findings highlight the need to evaluate sex-specific effects in toxicoepigenetic studies. 53 , 54 General trends in DMR directionality were also not conserved across tissue types ( Figure 2E ), adding complexity to comparisons of changes in DNAm patterns between target and surrogate tissues. Although the majority of DMRs in blood from DEHP-exposed male and female mice was largely hypermethylated (65% in both cases), DMRs in the corresponding target tissues displayed either an approximate even distribution of hyper- and hypomethylated DMRs (as in male cortex and female liver) or with a majority of DMRs that were hypomethylated (as in female cortex and male liver).…”