| Title: | Short- and long-term effects of perinatal phthalate exposures on metabolic pathways in the mouse liver |
| Author(s): | Neier K; Montrose L; Chen K; Malloy MA; Jones TR; Svoboda LK; Harris C; Song PXK; Pennathur S; Sartor MA; Dolinoy DC; |
| Address: | "Environmental Health Sciences, University of Michigan, Ann Arbor, 1415 Washington Heights 48109 MI, USA. Biostatistics, University of Michigan, Ann Arbor, 1415 Washington Heights 48109 MI, USA. Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, 1500 East Medical Center Drive 48109 MI, USA. Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, 1137 E. Catherine St. 48109 MI, USA. Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, 100 Washtenaw Avenue 48109 MI, USA. Nutritional Sciences, University of Michigan, Ann Arbor, 1415 Washington Heights 48109 MI, USA" |
| ISSN/ISBN: | 2058-5888 (Electronic) 2058-5888 (Linking) |
| Abstract: | "Phthalates have been demonstrated to interfere with metabolism, presumably by interacting with peroxisome proliferator-activated receptors (PPARs). However, mechanisms linking developmental phthalate exposures to long-term metabolic effects have not yet been elucidated. We investigated the hypothesis that developmental phthalate exposure has long-lasting impacts on PPAR target gene expression and DNA methylation to influence hepatic metabolic profiles across the life course. We utilized an established longitudinal mouse model of perinatal exposures to diethylhexyl phthalate and diisononyl phthalate, and a mixture of diethylhexyl phthalate+diisononyl phthalate. Exposure was through the diet and spanned from 2 weeks before mating until weaning at postnatal day 21 (PND21). Liver tissue was analyzed from the offspring of exposed and control mice at PND21 and in another cohort of exposed and control mice at 10 months of age. RNA-seq and pathway enrichment analyses indicated that acetyl-CoA metabolic processes were altered in diisononyl phthalate-exposed female livers at both PND21 and 10 months (FDR = 0.0018). Within the pathway, all 13 significant genes were potential PPAR target genes. Promoter DNA methylation was altered at three candidate genes, but persistent effects were only observed for Fasn. Targeted metabolomics indicated that phthalate-exposed females had decreased acetyl-CoA at PND21 and increased acetyl-CoA and acylcarnitines at 10 months. Together, our data suggested that perinatal phthalate exposures were associated with short- and long-term activation of PPAR target genes, which manifested as increased fatty acid production in early postnatal life and increased fatty acid oxidation in adulthood. This presents a novel molecular pathway linking developmental phthalate exposures and metabolic health outcomes" |
| Keywords: | DNA methylation endocrine disrupting chemicals liver metabolism metabolomics transcriptomics; |
| Notes: | "PubMed-not-MEDLINENeier, Kari Montrose, Luke Chen, Kathleen Malloy, Maureen A Jones, Tamara R Svoboda, Laurie K Harris, Craig Song, Peter X K Pennathur, Subramaniam Sartor, Maureen A Dolinoy, Dana C eng P30 ES017885/ES/NIEHS NIH HHS/ U01 ES026697/ES/NIEHS NIH HHS/ T32 HD079342/HD/NICHD NIH HHS/ P30 DK089503/DK/NIDDK NIH HHS/ P20 GM109095/GM/NIGMS NIH HHS/ P01 ES022844/ES/NIEHS NIH HHS/ T32 ES007062/ES/NIEHS NIH HHS/ R35 ES031686/ES/NIEHS NIH HHS/ England 2021/01/05 Environ Epigenet. 2020 Dec 23; 6(1):dvaa017. doi: 10.1093/eep/dvaa017. eCollection 2020" |
