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      Prenatal caffeine exposure induces liver developmental dysfunction in offspring rats

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          Abstract

          We previously showed that prenatal caffeine exposure (PCE) induces intrauterine growth retardation (IUGR) and high susceptibility to nonalcoholic fatty liver disease in offspring rats, and the underlying mechanisms are associated with fetal overexposure to maternal glucocorticoids. Herein, we aimed to verify whether PCE disrupts liver development before and after birth and explore its possible programming mechanism. In vivo, reduced fetal weights and increased IUGR rates were accompanied by fetal liver developmental dysfunction in PCE rats. Increased fetal serum corticosterone and decreased insulin-like growth factor 1 (IGF1) levels were observed. Both male and female fetal livers exhibited increased glucocorticoid function-related gene (GR/C/EBPα) expression and inhibited IGF1 signaling pathway (IGF1/IGF1R/Akt2) expression. At PW6, the levels of serum corticosterone and glucocorticoid function-related genes in PCE offspring livers were decreased, while serum IGF1 and liver IGF1 signaling pathway expression were increased, accompanied by obvious catch-up growth and enhanced liver function. Furthermore, in PCE adult offspring under chronic stress, serum corticosterone and liver GR/C/EBPα expression levels were elevated, while the serum IGF1 and liver IGF1 signaling pathway levels were decreased. In vitro, cortisol (not caffeine) upregulated GR and C/EBPα expression and downregulated IGF1R expression. The IGF1R expression downregulated by cortisol was partially reversed by GR or C/EBPα knockdown. In conclusion, PCE induced liver developmental dysfunction in fetal rats and catch-up growth in IUGR offspring. The mechanisms may be closely associated with GR/C/EBPα upregulation and IGF1/IGF1R signaling pathway downregulation in the fetal liver, caused by intrauterine programming of the liver glucocorticoid-IGF1 axis induced by glucocorticoid overexposure.

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          Author and article information

          Journal
          Journal of Endocrinology
          Bioscientifica
          0022-0795
          1479-6805
          July 2019
          July 2019
          Affiliations
          [1 ]B He, Pharmacology, Basic Medical School of Wuhan University, Wuhan, China
          [2 ]Y Wen, Orthopedic Surgery, Wuhan University, Wuhan, China
          [3 ]S Hu, Pharmacology, wuhan univerisity, wuhan, China
          [4 ]G Wang, pharmacology, Wuhan University, Wuhan, China
          [5 ]W Hu, pharmacology, Wuhan University, Wuhan, China
          [6 ]J Magdalou, pharmacology, Nancy Univ, nancy, France
          [7 ]L Chen, Department of Orthopedic Surgery, Wuhan University Zhongnan Hospital Department of Chemotherapy and Radiation Therapy, Wuhan, China
          [8 ]H Wang, pharmacology, Wuhan University, Wuhan, China
          Article
          10.1530/JOE-19-0066
          31340202
          6091014a-c6ca-46a2-bed5-352654080048
          © 2019

          Free to read

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