| Autor: |
Ho TC; Croucher Institute for Environmental Sciences, Department of Biology, Hong Kong Baptist University, Kowloon 999077, Hong Kong SAR, China.; State Key Laboratory in Environmental and Biological Analysis, Hong Kong Baptist University, Kowloon 999077, Hong Kong SAR, China., Wan HT; Croucher Institute for Environmental Sciences, Department of Biology, Hong Kong Baptist University, Kowloon 999077, Hong Kong SAR, China., Lee WK; Croucher Institute for Environmental Sciences, Department of Biology, Hong Kong Baptist University, Kowloon 999077, Hong Kong SAR, China., Lam TKY; State Key Laboratory in Environmental and Biological Analysis, Hong Kong Baptist University, Kowloon 999077, Hong Kong SAR, China., Lin X; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States., Chan TF; School of Life Sciences, State Key Laboratory of Agrobiotechnology, Bioinformatics Centre, The Chinese University of Hong Kong, New Territories 999077, Hong Kong SAR, China., Lai KP; Key Laboratory of Environmental Pollution and Integrative Omics, Education Department of Guangxi Zhuang Autonomous Region, Guilin Medical University, Guilin 541100, China., Wong CKC; Croucher Institute for Environmental Sciences, Department of Biology, Hong Kong Baptist University, Kowloon 999077, Hong Kong SAR, China.; State Key Laboratory in Environmental and Biological Analysis, Hong Kong Baptist University, Kowloon 999077, Hong Kong SAR, China. |
| Abstrakt: |
Prenatal exposure to perfluorooctanesulfonate (PFOS) increases fetus' metabolic risk; however, the investigation of the underlying mechanism is limited. In this study, pregnant mice in the gestational days (GD, 4.5-17.5) were exposed to PFOS (0.3 and 3 μg/g of body weight). At GD 17.5, PFOS perturbed maternal lipid metabolism and upregulated metabolism-regulating hepatokines ( Angptl4, Angptl8, and Selenop ). Mass-spectrometry imaging and whole-genome bisulfite sequencing revealed, respectively, selective PFOS localization and deregulation of gene methylation in fetal livers, involved in inflammation, glucose, and fatty acid metabolism. PCR and Western blot analysis of lipid-laden fetal livers showed activation of AMPK signaling, accompanied by significant increases in the expression of glucose transporters ( Glut2/4 ), hexose-phosphate sensors ( Retsat and ChREBP ), and the key glycolytic enzyme, pyruvate kinase ( Pk ) for glucose catabolism. Additionally, PFOS modulated the expression levels of PPARα and PPARγ downstream target genes, which simultaneously stimulated fatty acid oxidation ( Cyp4a14, Acot , and Acox ) and lipogenesis ( Srebp1c , Acaca , and Fasn ). Using human normal hepatocyte (MIHA) cells, the underlying mechanism of PFOS-elicited nuclear translocation of ChREBP, associated with a fatty acid synthesizing pathway, was revealed. Our finding implies that in utero PFOS exposure altered the epigenetic landscape associated with dysregulation of fetal liver metabolism, predisposing postnatal susceptibility to metabolic challenges. |
