Effects of In Utero PFOS Exposure on Epigenetics and Metabolism in Mouse Fetal Livers.
Tsz Chun HoHin Ting WanWang Ka LeeThomas Ka Yam LamXiao LinTing Fung ChanKeng Po LaiChris Kong Chu WongPublished in: Environmental science & technology (2023)
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.
Keyphrases
- fatty acid
- body weight
- mass spectrometry
- single cell
- pregnant women
- poor prognosis
- genome wide
- high resolution
- dna methylation
- blood glucose
- oxidative stress
- induced apoptosis
- gene expression
- preterm infants
- liquid chromatography
- photodynamic therapy
- weight gain
- type diabetes
- long non coding rna
- binding protein
- birth weight
- cell proliferation
- endoplasmic reticulum stress
- adipose tissue
- genome wide analysis