Epidemiological investigations have shown that fetuses with
intrauterine growth retardation (IUGR) are susceptible to adult
metabolic syndrome. Clinical investigations and experiments have demonstrated that
caffeine is a definite inducer of IUGR, as children who ingest
caffeine-containing food or drinks are highly susceptible to adult
obesity and
hypertension. Our goals for this study were to investigate the effect of prenatal
caffeine ingestion on the functional development of the fetal hippocampus and the hypothalamic-pituitary-adrenal (HPA) axis and to clarify an intrauterine HPA axis-associated neuroendocrine alteration induced by
caffeine. Pregnant Wistar rats were intragastrically administered 20, 60, and 180 mg/kg · d
caffeine from gestational days 11-20. The results show that prenatal
caffeine ingestion significantly decreased the expression of fetal hypothalamus
corticotrophin-releasing
hormone. The fetal adrenal cortex changed into slight and the expression of fetal adrenal
steroid acute regulatory
protein (StAR) and
cholesterol side-chain cleavage enzyme (P450scc), as well as the level of fetal adrenal endogenous
corticosterone (CORT), were all significantly decreased after
caffeine treatment. Moreover,
caffeine ingestion significantly increased the levels of maternal and fetal blood CORT and decreased the expression of placental 11β-hydroxysteroid dehydrogenase-2 (11β-HSD-2). Additionally, both in vivo and in vitro studies show that
caffeine can downregulate the expression of fetal hippocampal 11β-HSD-2, promote the expression of 11β-hydroxysteroid
dehydrogenase 1 and
glucocorticoid receptor (GR), and enhance DNA methylation within the hippocampal 11β-HSD-2 promoter. These results suggest that prenatal
caffeine ingestion inhibits the development of the fetal HPA axis, which may be associated with the fetal overexposure to maternal
glucocorticoid and activated
glucocorticoid metabolism in the fetal hippocampus. These results will be beneficial in elucidating the developmental toxicity of
caffeine and in exploring the fetal origin of adult HPA axis dysfunction and
metabolic syndrome susceptibility for offspring with IUGR induced by
caffeine.