Intrauterine endogenous high glucocorticoids program ovarian dysfunction in female offspring secondary to prenatal caffeine exposure

Abstract

Ovarian dysfunction has an intrauterine origin, and prenatal caffeine exposure (PCE) could lead to abnormal follicle counts in offspring after birth. However, the effect of PCE on offspring ovarian function and its mechanism of intrauterine programming have not been reported thus far. In this study, pregnant Wistar rats were intragastrically administered caffeine (30 and 120 mg/kg·d) at gestational days 9-20 (GD9-20). Certain tests were performed on the blood, ovaries and hypothalamus of female offspring at different time points. PCE female offspring had ovarian dysfunction in adulthood compared with the control. Further results showed that in utero ovarian morphological development and estradiol synthesis were inhibited but rapidly increased during puberty in the PCE group. The histone 3 lysine 27 acetylation (H3K27ac) level of the insulin-like growth factor 1 (IGF1) promoter region and its expression were decreased in the ovary, which was due to exposure to high levels of fetal blood corticosterone, and the H3K27ac level of IGF1 and its expression shifted to increase after birth with a decrease in serum corticosterone levels. Chronic stress led to increased serum corticosterone levels in adult offspring, whereas ovarian morphological development, the H3K27ac level of IGF1 and its expression, and estradiol synthesis were significantly inhibited. Moreover, the activity of the hypothalamic-pituitary-ovarian (HPO) axis was increased in the early postnatal period of PCE offspring, and chronic stress reversed these changes. In the KGN cell line, it was found that cortisol could promote the translocation of the glucocorticoid receptor (GR) into the nucleus and upregulate histone deacetylase 10 (HDAC10) to inhibit the H3K27ac level of IGF1 and its expression and estradiol synthesis. In summary, PCE is associated with ovarian dysfunction in female adult offspring, and the potential mechanism is related to intrauterine high glucocorticoid exposure by activating the GR and recruiting HDAC10 to affect ovarian glucocorticoid-IGF1 axis programming and to inhibit estradiol synthesis.

Keywords: Epigenetic modification; Glucocorticoid; Insulin-like growth factor 1; Ovarian dysfunction; Prenatal caffeine exposure.