Intrauterine arsenic exposure induces glucose metabolism disorders in adult offspring by targeting TET2-mediated DNA hydroxymethylation reprogramming of HNF4α in developing livers, an effect alleviated by ascorbic acid.

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  • Additional Information
    • Source:
      Publisher: Elsevier Country of Publication: Netherlands NLM ID: 9422688 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1873-3336 (Electronic) Linking ISSN: 03043894 NLM ISO Abbreviation: J Hazard Mater Subsets: MEDLINE
    • Publication Information:
      Original Publication: Amsterdam : Elsevier,
    • Subject Terms:
      Arsenic*/toxicity ; Ascorbic Acid*/therapeutic use ; Dioxygenases*/metabolism ; Glucose Metabolism Disorders*/chemically induced ; Glucose Metabolism Disorders*/genetics ; Glucose Metabolism Disorders*/metabolism; Animals ; Mice ; DNA ; DNA Methylation ; DNA-Binding Proteins ; Glucose/metabolism ; Liver/metabolism
    • Abstract:
      Exposure to arsenic during gestation has lasting health-related effects on the developing fetus, including an increase in the risk of metabolic disease later in life. Epigenetics is a potential mechanism involved in this process. Ten-eleven translocation 2 (TET2) has been widely considered as a transferase of 5-hydroxymethylcytosine (5hmC). Here, mice were exposed, via drinking water, to arsenic or arsenic combined with ascorbic acid (AA) during gestation. For adult offspring, intrauterine arsenic exposure exhibited disorders of glucose metabolism, which are associated with DNA hydroxymethylation reprogramming of hepatic nuclear factor 4 alpha (HNF4α). Further molecular structure analysis, by SEC-UV-DAD, SEC-ICP-MS, verified that arsenic binds to the cysteine domain of TET2. Mechanistically, arsenic reduces the stability of TET2 by binding to it, resulting in the decrease of 5hmC levels in Hnf4α and subsequently inhibiting its expression. This leads to the disorders of expression of its downstream key glucose metabolism genes. Supplementation with AA blocked the reduction of TET2 and normalized the 5hmC levels of Hnf4α, thus alleviating the glucose metabolism disorders. Our study provides targets and methods for the prevention of offspring glucose metabolism abnormalities caused by intrauterine arsenic exposure.
      Competing Interests: Declaration of Competing Interest The authors declare no competing financial interests.
      (Copyright © 2024 Elsevier B.V. All rights reserved.)
    • Contributed Indexing:
      Keywords: Ascorbic acid; Glucose metabolism disorders; Hepatic nuclear factor 4 alpha; Intrauterine arsenic exposure; Ten-eleven translocation 2
    • Accession Number:
      N712M78A8G (Arsenic)
      PQ6CK8PD0R (Ascorbic Acid)
      EC 1.13.11.- (Dioxygenases)
      9007-49-2 (DNA)
      0 (DNA-Binding Proteins)
      IY9XDZ35W2 (Glucose)
    • Publication Date:
      Date Created: 20240107 Date Completed: 20240214 Latest Revision: 20240712
    • Publication Date:
      20240712
    • Accession Number:
      10.1016/j.jhazmat.2023.133405
    • Accession Number:
      38185084