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Endocrinology. 2019 Feb 1;160(2):409-429. doi: 10.1210/en.2018-00817.

Prenatal Bisphenol A Exposure in Mice Induces Multitissue Multiomics Disruptions Linking to Cardiometabolic Disorders.

Author information

1
Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, California.
2
Molecular, Cellular, and Integrative Physiology Interdepartmental Program, University of California, Los Angeles, Los Angeles, California.
3
Molecular Toxicology Interdepartmental Program, University of California, Los Angeles, Los Angeles, California.
4
Department of Epidemiology, Fielding School of Public Health, University of California, Los Angeles, Los Angeles, California.
5
Institute for Society and Genetics, University of California, Los Angeles, Los Angeles, California.
6
Institute for Quantitative and Computational Biosciences, University of California, Los Angeles, Los Angeles, California.

Abstract

The health impacts of endocrine-disrupting chemicals (EDCs) remain debated, and their tissue and molecular targets are poorly understood. In this study, we leveraged systems biology approaches to assess the target tissues, molecular pathways, and gene regulatory networks associated with prenatal exposure to the model EDC bisphenol A (BPA). Prenatal BPA exposure at 5 mg/kg/d, a dose below most reported no-observed-adverse-effect levels, led to tens to thousands of transcriptomic and methylomic alterations in the adipose, hypothalamus, and liver tissues in male offspring in mice, with cross-tissue perturbations in lipid metabolism as well as tissue-specific alterations in histone subunits, glucose metabolism, and extracellular matrix. Network modeling prioritized main molecular targets of BPA, including Pparg, Hnf4a, Esr1, Srebf1, and Fasn as well as numerous less studied targets such as Cyp51 and long noncoding RNAs across tissues, Fa2h in hypothalamus, and Nfya in adipose tissue. Lastly, integrative analyses identified the association of BPA molecular signatures with cardiometabolic phenotypes in mouse and human. Our multitissue, multiomics investigation provides strong evidence that BPA perturbs diverse molecular networks in central and peripheral tissues and offers insights into the molecular targets that link BPA to human cardiometabolic disorders.

PMID:
30566610
PMCID:
PMC6349005
[Available on 2019-12-18]
DOI:
10.1210/en.2018-00817
[Indexed for MEDLINE]

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