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

Siyu Liu; Kai Wang; Laurie K Svoboda; Christine A Rygiel; Kari Neier; Tamara R Jones; Raymond G Cavalcante; Justin A Colacino; Dana C Dolinoy; Maureen A Sartor

doi:10.1093/eep/dvab004

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

Environ Epigenet. 2021 May 10;7(1):dvab004. doi: 10.1093/eep/dvab004. eCollection 2021.

Authors

Siyu Liu¹, Kai Wang¹, Laurie K Svoboda², Christine A Rygiel², Kari Neier², Tamara R Jones², Raymond G Cavalcante³, Justin A Colacino^{2

4}, Dana C Dolinoy^{2

4}, Maureen A Sartor^{1

5}

Affiliations

¹ Department of Computational Medicine and Bioinformatics, University of Michigan, 500 S State St., Ann Arbor, MI 48109, USA.
² Environmental Health Sciences, University of Michigan, 500 S State St., Ann Arbor, MI 48109, USA.
³ Epigenomics Core, University of Michigan, 500 S State St., Ann Arbor, MI 48109, USA.
⁴ Nutritional Sciences, University of Michigan, 500 S State St., Ann Arbor, MI 48109, USA.
⁵ Department of Biostatistics, University of Michigan, 500 S State St., Ann Arbor, MI 48109, USA.

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.

Keywords: DEHP exposure; DNA methylation; bisulfite sequencing; blood; liver; mouse model; perinatal.

Abstract

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