Perinatal DEHP exposure induces sex- and tissue-specific DNA methylation changes in both juvenile and adult mice

Abstract

Di(2-ethylhexyl) phthalate (DEHP) is a type of phthalate plasticizer found in a variety of consumer products and poses a public health concern due to its metabolic and endocrine disruption activities. Dysregulation of epigenetic modifications, including DNA methylation, has been shown to be an important mechanism for the pathogenic effects of prenatal exposures, including phthalates. In this study, we used an established mouse model to study the effect of perinatal DEHP exposure on the DNA methylation profile in liver (a primary target tissue of DEHP) and blood (a common surrogate tissue) of both juvenile and adult mice. Despite exposure ceasing at 3 weeks of age (PND21), we identified thousands of sex-specific differential DNA methylation events in 5-month old mice, more than identified at PND21, both in blood and liver. Only a small number of these differentially methylated cytosines (DMCs) overlapped between the time points, or between tissues (i.e. liver and blood), indicating blood may not be an appropriate surrogate tissue to estimate the effects of DEHP exposure on liver DNA methylation. We detected sex-specific DMCs common between 3-week and 5-month samples, pointing to specific DNA methylation alterations that are consistent between weanling and adult mice. In summary, this is the first study to assess the genome-wide DNA methylation profiles in liver and blood at two different aged cohorts in response to perinatal DEHP exposure. Our findings cast light on the implications of using surrogate tissue instead of target tissue in human population-based studies and identify epigenetic biomarkers for DEHP exposure.

Toxicoepigenetics and Environmental Health: Challenges and Opportunities

“…Our recent work in TaRGET II demonstrates that changes in DNA methylation after perinatal exposure to lead or the plasticizer di-2-ethylhexyl phthalate are highly tissue-and sexdependent, with little concordance between liver and blood. 156,184,281 Our findings are in keeping with recent work in human subjects, which found correlation in DNA methylation between blood and the liver at only a minority of CpG sites within 35 hemostatic genes. 282 Additional studies have demonstrated limited correlation in DNA methylation between human blood and other tissues.…”

“…Indeed, as chemical exposures may cause precocious aging of the epigenome, a single cross-sectional study of adult tissues may miss important exposure-related changes . Moreover, biomarkers of environmental exposures and disease may differ based on age …”

“…72 Moreover, biomarkers of environmental exposures and disease may differ based on age. 184 Marginalized Status and Environment. In addition to the intrinsic characteristics of sex and age, external factors also differentially affect epigenomic programming and disease risk in response to environmental exposures and are important considerations in toxicoepigenetics studies.…”

Impact of Endocrine Disruptors upon Non-Genetic Inheritance

“…The impact of DEHP exposure on reproduction and social behavior is not only transgenerational but also dose-specific in both males and females [ 79 ]. In addition, the perinatal exposure of both juvenile and adult mice to DEHP induces sex- and tissue-specific DNA methylation alterations [ 80 ]. DEHP exposure during gestation increased DNMT3a and DNMT3b ( Figure 3 ) expression in adult rat testes of F1 and in offspring, suggesting that epimutations may be a potential mechanism of DEHP-mediated testicular toxicity [ 81 ].…”

Effects of Prenatal Phthalate Exposure and Childhood Exercise on Maternal Behaviors in Female Rats at Postpartum: A Role of Oxtr Methylation in the Hypothalamus

“…Several studies suggest that prenatal exposure to DEHP might induce developmental toxicity and endocrine disruption by altering DNA methylation in several tissues, such as the liver, blood cells, heart, and brain [ 55 , 56 , 57 ]. However, few studies have reported the epigenetic modification of prenatal DEHP exposure on the hypothalamic Oxtr gene.…”