Increase in endogenous estradiol in the progeny of obese rats is associated with precocious puberty and altered follicular development in adulthood

Abstract

Maternal obesity during pregnancy has been related with several pathological states in offspring. However, the impact of maternal obesity on reproductive system on the progeny is beginning to be elucidated. In this work, we characterize the effect of maternal obesity on puberty onset and follicular development in adult offspring in rats. We also propose that alterations in ovarian physiology observed in offspring of obese mothers are due to increased levels of estradiol during early development. Offspring of control dams and offspring of dams exposed to a high-fat diet (HF) were studied at postnatal days (PND) 1, 7, 14, 30, 60, and 120. Body weight and onset of puberty were measured. Counting of ovarian follicles was performed at PND 60 and 120. Serum estradiol, estriol, androstenedione, FSH, LH, and insulin levels were measured by ELISA. Hepatic CYP3A2 expression was determined by Western blot. HF rats had a higher weight than controls at all ages and they also had a precocious puberty. Estradiol levels were increased while CYP3A2 expression was reduced from PND 1 until PND 60 in HF rats compared to controls. Estriol was decreased at PND60 in HF rats. Ovaries from HF rats had a decrease in antral follicles at PND60 and PND120 and an increase in follicular cysts at PND60 and PND120. In this work, we demonstrated that maternal obesity in rats alters follicular development and induces follicular cysts generation in the adult offspring. We observed that maternal obesity produces an endocrine disruption through increasing endogenous estradiol in early life. A programmed failure in hepatic metabolism of estradiol is probably the cause of its increase.

Detrimental effect of maternal and post-weaning high-fat diet on the reproductive function in the adult female offspring rat: roles of insulin-like growth factor 2 and the ovarian circadian clock

“…This endocrine system has likely evolved to prevent the premature and inappropriate development of primordial follicles. A previous study has shown that maternal obesity increases serum E 2 at PND1, PND7, and until PND 60 in the female offspring [13]. We also found higher plasma E 2 levels in 6-month-old progeny from HF-fed dams; the higher estradiol may cause abnormal follicular development.…”

“…Taken together, we postulate that the increased estradiol level is involved in Igf2 -induced upregulation of the FSH receptor, rather than through downregulation of Igf2r , and the lower plasma LH level in HF-fed dams (i.e., the HF/C and HF/HF groups) may result from a negative feedback loop by inhibiting the production of gonadotropin in the hypothalamus because of high plasma E 2 status. In addition, diet-induced maternal obesity and hyperestrogenism were both reported with advanced puberty-onset and estrous cycle disruption in adult female offspring [13, 45]. Our study may provide a possible explanation for maternal HF nutrition resulting in hyperestrogenism via an Igf2 -induced upregulation effect in the ovary, which subsequently causes further female offspring reproductive dysfunction in adult life.…”

“…Additionally, previous studies showed that diet-induced maternal obesity or a post-weaning HF diet can cause early onset of puberty and estrous cycle abnormalities in female progeny [8–10]. However, limited data are available on the long-term effects of HF exposure during gestation, lactation, and early life, especially on ovarian follicular development and steroidal hormones [11–13]. …”

The Association between High Fat Diet around Gestation and Metabolic Syndrome-related Phenotypes in Rats: A Systematic Review and Meta-Analysis

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Nutritional adversity, sex and reproduction: 30 years of DOHaD and what have we learned?

“…Changes in offspring sex steroid concentrations may also influence ovarian follicle development. Offspring from HFD-fed rats demonstrated elevated estradiol levels between day 1 and 60 of postnatal life, in association with a loss of ovarian antral follicles, increased follicular cysts as well as changes in hepatic metabolism of estradiol (Ambrosetti et al 2016). Finally, recent work suggests that improving maternal insulin sensitivity during an obese pregnancy has positive impacts on offspring ovarian function (Álvarez et al 2018).…”