Prenatal undernutrition affects the phenotypes of PCOS model rats

in Journal of Endocrinology
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Although polycystic ovary syndrome (PCOS) is among the most common endocrine disorders in women of reproductive age, its etiology remains poorly understood. From the perspective of developmental origins of health and disease, some studies have investigated the relationship between low birth weight and the prevalence of PCOS and/or PCOS phenotypes in humans; however, the results of these studies were inconclusive. Here, we evaluated the effects of prenatal undernutrition on the metabolic and reproductive phenotypes of dihydrotestosterone-induced PCOS model rats. The PCOS model rats showed increased body weight, food intake, fat weight, adipocyte size and upregulation of inflammatory cytokines in adipose tissue; prenatal undernutrition exacerbated these metabolic changes. Prenatal undernutrition also increased the gene expression of hypothalamic orexigenic factor and decreased the gene expression of anorexigenic factor in the PCOS model rats. In addition, the PCOS model rats exhibited irregular cyclicity, polycystic ovaries and disrupted gene expression of ovarian steroidogenic enzymes. Interestingly, prenatal undernutrition attenuated these reproductive changes in the PCOS model rats. Our results suggest that in dihydrotestosterone-induced PCOS model rats, prenatal undernutrition exacerbates the metabolic phenotypes, whereas it improves the reproductive phenotypes and that such phenotypic changes may be induced by the alteration of some peripheral and central factors.

 

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    Effects of prenatal undernutrition on maternal body weight (BW) change, birth weight and BW change of female offspring. (A and B) BW and BW change (% of the BW at gestational day 14) during gestational days (Day) were significantly lower in the undernourished dams than in the normally nourished dams. (C) The birth weight was significantly lower in the UN group than in the NN group. (D) The BW of the offspring was significantly lower in the UN group than in the NN group from postnatal days (PND) 7 to 21; however, this difference was not observed on PND 28. The data of both sexes were included for the calculation of the mean birth weight, whereas only the data of females were included for the calculation of the mean BW and BW change after PND 7. Data are expressed as the mean ± standard error (s.e.); n = 9–10 per group. Statistical analysis was performed using ANOVA followed by the Tukey–Kramer post hoc test or Student’s t test. *P < 0.05 and **P < 0.01 vs the normally nourished dams or the NN group (Student’s t test). NN, offspring from normally nourished dams; UN, offspring from undernourished dams.

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    Effects of prenatal undernutrition on body weight (BW) regulation and feeding in DHT-induced PCOS model rats. (A, B, C and D) The BW, BW change, cumulative food intake (FI) and feed efficiency were significantly higher in the DHT-administered rats than in the control rats in both NN and UN groups. These parameters were also significantly higher in the UN-DHT group than in the NN-DHT group. Feed efficiency was calculated as total BW gained/cumulative FI. Data are expressed as the mean ± standard error (s.e.); n = 9 or 10 per group. Statistical analysis was performed using ANOVA followed by the Tukey–Kramer post hoc test. *P < 0.05 and **P < 0.01. DHT, 5α-dihydrotestosterone; NN, offspring from normally nourished dams; PND, postnatal day; UN, offspring from undernourished dams.

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    Effects of prenatal undernutrition on fat weights and adipocyte sizes in DHT-induced PCOS model rats. Samples were taken at 10 weeks of age (after 6-week administration). (A) The visceral fat weight on the day of sampling was significantly heavier in the DHT-administered rats than in the control rats in the UN group. The subcutaneous and total fat weights were significantly heavier in the DHT-administered rats than in the control rats in both NN and UN groups. In addition, the visceral, subcutaneous and total fat weights were significantly higher in the UN-DHT group than in the NN-DHT group. (B) The visceral adipocyte size was significantly larger in the DHT-administered rats than in the control rats in the UN group. The visceral adipocyte size was significantly larger in the UN-DHT group than in the NN-DHT group. (C) The subcutaneous adipocyte size was significantly larger in the DHT-administered rats than in the control rats in both NN and UN groups. Data are expressed as the mean ± standard error (s.e.); n = 9 or 10 per group. Statistical analysis was performed using ANOVA followed by the Tukey-Kramer post hoc test. *P < 0.05 and **P < 0.01. DHT, 5α-dihydrotestosterone; NN, offspring from normally nourished dams; UN, offspring from undernourished dams.

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    Effects of prenatal undernutrition on serum hormonal levels and gene expression levels of inflammatory cytokines in DHT-induced PCOS model rats. Samples were taken at 10 weeks of age (after 6-week administration). (A) The serum leptin level on the day of sampling was significantly higher in the DHT-administered rats than in the control rats in the UN group. (B) The IL-1 and TNF-α mRNA levels in visceral fat were significantly higher in the DHT-administered rats than in the control rats in the UN group. In addition, the mRNA levels of these factors were significantly higher in the UN-DHT group than in the NN-DHT group. (C) The IL-1 and IL-6 mRNA levels in subcutaneous fat were significantly higher in the DHT-administered rats than in the control rats in the UN group. (D) The hepatic IL-1, TNF-α and IL-6 mRNA levels were not significantly different between the DHT-administered rats and control rats in both NN and UN groups. The expression levels were normalized by dividing by 18S rRNA (fat) or glyceraldehyde 3-phosphate dehydrogenase (liver) mRNA levels. Data are expressed as the mean ± standard error (s.e.); n = 9 or 10 per group. Statistical analysis was performed using ANOVA followed by the Tukey–Kramer post hoc test. *P < 0.05 and **P < 0.01. DHT, 5α-dihydrotestosterone; NN, offspring from normally nourished dams; UN, offspring from undernourished dams.

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    Effects of prenatal undernutrition on estrous cyclicity in DHT-induced PCOS model rats. (A) The estrous cyclicity in two representative rats from each group is shown. (B) Vaginal epithelial smears were obtained over 12 days starting from 4 weeks after implantation of a DHT-filled tube or empty tube (8 weeks of age). The numbers of estrus stage and diestrus stage during 12 days were significantly smaller and larger, respectively, in the DHT-administered rats than in the control rats in the NN group. In addition, these parameters in the NN-DHT group were significantly smaller and larger, respectively, than those in the UN-DHT group. Data are expressed as the mean ± standard error (s.e.); n = 9 or 10 per group. Statistical analysis was performed using ANOVA followed by the Tukey–Kramer post hoc test. *P < 0.05 and **P < 0.01. DHT, 5α-dihydrotestosterone; D, diestrus; E, estrus; M, metestrus; NN, offspring from normally nourished dams; P, proestrus; UN, offspring from undernourished dams.

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    Effects of prenatal undernutrition on ovarian morphology in DHT-induced PCOS model rats. Samples were taken at 10 weeks of age (after 6-week administration). (A) The ovarian morphology in representative rats from each group is shown. The ovaries of rats in the NN-DHT and UN-DHT groups exhibited polycystic morphology. (B) The ovarian weight and the number of corpora lutea were significantly lower and smaller, respectively, in the DHT-administered rats than in the control rats in the NN group. In addition, these parameters were significantly lower and smaller, respectively, in the NN-DHT group than those in the UN-DHT group. The number of cystic follicles was significantly larger in the DHT-administered rats than in the control rats in the NN group. Data are expressed as the mean ± standard error (s.e.). n = 9 or 10 per group. Statistical analysis was performed using ANOVA followed by the Tukey-Kramer post hoc test. **P < 0.01. DHT, 5α-dihydrotestosterone; NN, offspring from normally nourished dams; UN, offspring from undernourished dams.

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    Effects of prenatal undernutrition on serum hormonal levels and gene expression levels of ovarian steroidogenic enzymes in DHT-induced PCOS model rats. Samples were taken at 10 weeks of age (after 6-week administration). (A) The serum luteinizing hormone (LH) level was significantly lower in the DHT-administered rats than in the control rats in the UN group. Conversely, the serum follicle-stimulating hormone (FSH), testosterone and estradiol (E2) levels were not different between DHT-administered rats and control rats in both NN and UN groups. (B) The mRNA levels of ovarian steroidogenic acute regulatory protein (StAR) and cholesterol side-chain cleavage enzyme (P450scc) were significantly lower in the DHT-administered rats than in the control rats in the NN group. The mRNA levels of these factors were significantly lower in the NN-DHT group than in the UN-DHT group. The ovarian mRNA levels of 17β-hydroxysteroid dehydrogenase (17β-HSD) and steroidogenic factor-1/nuclear receptor subfamily 5, group A, member 1 (SF-1/NR5A1) were significantly higher in the DHT-administered rats than in the control rats in the NN group. The expression levels were normalized by dividing by β-actin mRNA levels. Data are expressed as the mean ± standard error (s.e.). n = 9 or 10 per group. Statistical analysis was performed using ANOVA followed by the Tukey–Kramer post hoc test. *P < 0.05 and **P < 0.01. DHT, 5α-dihydrotestosterone; NN, offspring from normally nourished dams; UN, offspring from undernourished dams.

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    Effects of prenatal undernutrition on gene expression levels of hypothalamic factors in DHT-induced PCOS model rats. Samples were taken at 10 weeks of age (after 6-week administration). The hypothalamic pp-orexin mRNA level was significantly higher in the UN-DHT group than in the NN-DHT group. The leptin receptor (OBRb) mRNA level was significantly higher in the DHT-administered rats than in the control rats in the NN group but not in the UN group. The hypothalamic serotonin 2C receptor (5HT2CR) mRNA level was significantly lower in the UN-DHT group than in the NN-DHT group. The hypothalamic Kiss1 mRNA level was significantly lower in the DHT-administered rats than in the control rats in both NN and UN groups, whereas the hypothalamic gonadotropin-releasing hormone (GnRH) mRNA level did not differ. The expression levels were normalized by dividing by glyceraldehyde 3-phosphate dehydrogenase mRNA levels. Data are expressed as the mean ± standard error (s.e.). n = 9 or 10 per group. Statistical analysis was performed using ANOVA followed by the Tukey–Kramer post hoc test. **P < 0.01. DHT, 5α-dihydrotestosterone; NN, offspring from normally nourished dams; NPY, neuropeptide Y; UN, offspring from undernourished dams.

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