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.
journal_name
Endocrinologyjournal_title
Endocrinologyauthors
Shu L,Meng Q,Diamante G,Tsai B,Chen YW,Mikhail A,Luk H,Ritz B,Allard P,Yang Xdoi
10.1210/en.2018-00817subject
Has Abstractpub_date
2019-02-01 00:00:00pages
409-429issue
2eissn
0013-7227issn
1945-7170pii
5250673journal_volume
160pub_type
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