Glucocorticoid-insulin-like growth factor 1 (GC-IGF1) axis programming mediated hepatic lipid-metabolic in offspring caused by prenatal ethanol exposure.

Prenatal ethanol exposure (PEE) could increase offspring's susceptibility to adult liver lipid-metabolism diseases. This study aimed to confirm intrauterine programming mechanism of glucocorticoid-insulin-like growth factor 1 (GC-IGF1) axis for liver dysfunction in offspring rats induced by PEE. The results showed that levels of hepatic IGF1, lipid metabolism-related enzymes (e.g. FASN and HMGCR) and serum phenotype (TG, TCH, HDL-C, and LDL-C) were low in fetal rats of PEE but high in adult offspring except for HDL-C, meanwhile, hepatic H3K9ac and expression levels of IGF1 were low in fetal rats but high in adult offspring. Furthermore, levels of serum corticosterone and hepatic glucocorticoid-activation system (mainly including expression of 11β-HSD1, GR, and C/EBPα as well as 11β-HSD1/11β-HSD2 ratio) were high in fetal rats of PEE but low or unchanged in adult offspring. The adult F2 generation of PEE maintained the same GC-IGF1 axis programming alteration as the F1 generation despite gender differences. In vitro, cortisol was proved to activate hepatocyte glucocorticoid-activation system and decrease H3K9ac and expression levels of IGF1 by GR. Therefore, PEE has a long-term effect on the offspring's liver functional development, which may be mainly related to the epigenetic programming alteration of the GC-IGF1 axis mediated by the glucocorticoid-activation system.