Intrauterine Programming of Glucocorticoid-Insulin-Like Growth Factor-1 Axis-Mediated Developmental Origin of Osteoporosis Susceptibility in Female Offspring Rats of Prenatal Caffeine Exposure.

Epidemiologic investigations suggest that excessive intake of caffeine during pregnancy is one of the risk factors for osteoporosis in adult offspring. However, the phenomena and mechanisms have remained obscure. This study found that prenatal caffeine exposure (PCE) leads to persistent bone dysplasia in gestational day 20 and postnatal week offspring rats and increases the susceptibility to osteoporosis in postnatal week 28 offspring rats. In the embryonic period, PCE increases the concentration of serum corticosterone and inhibits the expression of insulin-like growth factor-1 (IGF1) and osteogenic differentiation genes. After birth, the recovery of IGF1 expression in PCE offspring is unable to completely compensate osteogenic function, and chronic stress can lead to a further decrease in IGF1 expression. In vitro experiments found that corticosterone instead of caffeine restrains mineralized nodule formation and osteoblast differentiation by inhibiting IGF1 expression. The corticosterone inhibits H3K9 and H3K14 histone acetylation of IGF1 in osteoblasts through glucocorticoid receptor and CCAAT and enhancer binding protein α, respectively. In conclusion, glucocorticoid instead of caffeine inhibits bone IGF1 expression via glucocorticoid receptor and CCAAT and enhancer binding protein α and mediates the PCE-induced bone dysplasia and bone mass reduction in offspring fetal rats, which may contribute to osteoporosis susceptibility in adulthood.