Fetal programming of adult hypertension in female rat offspring exposed to androgens in utero

Abstract

Aims The influence of prenatal factors on the development of arterial hypertension has gained considerable interest in recent years. We examined the effects of prenatal testosterone treatment on blood pressure in adult female rats. Further, to define the mechanisms whereby blood pressure may be raised, we examined vascular endothelial function and nitric oxide synthesis. Methods and Results Testosterone propionate (0.5mg/kg/day;SC) or vehicle was administered to pregnant Sprague-Dawley rats from gestational day 15–19. Maternal feed intake and plasma levels of steroid hormones were measured in the dams. In the female offspring, birth weight, growth rate, blood pressure, vascular reactivity, eNOS expression, and nitric oxide production were examined. In the pregnant rats, testosterone-treatment increased plasma testosterone levels by 2-fold without any significant changes in 17β-estradiol, progesterone and corticosterone levels. Testosterone-treatment did not affect maternal feed intake. The pups born to testosterone mothers were smaller in size but exhibited catch-up growth. The blood pressure in the testosterone offspring at 6 months of age was significantly higher compared to controls. Endothelium-intact mesenteric arteries from testosterone group exhibited increased contractile responses to phenylephrine, decreased vasodilation to acetylcholine and unaltered responses to sodium nitroprusside in comparison to control rats. Testosterone rats demonstrated decreased expression for eNOS, and reduced nitric oxide production. Conclusions Our data show that elevated plasma maternal testosterone levels: (1) causes low birth weight followed by catch-up growth and hypertension in female offspring; (2) alters endothelium-dependent vascular responses. The endothelial dysfunction is associated with decreased activity/expression of eNOS.

Maternal androgen excess reduces placental and fetal weights, increases placental steroidogenesis, and leads to long-term health effects in their female offspring

“…Administration of testosterone to rats in late pregnancy did not affect maternal weight gain, food intake, metabolic status, or circulating estradiol or corticosterone concentrations, and these results are consistent with previous reports in rodents (36). This suggests that the effect of testosterone on placental and fetal growth in rats is a direct effect of the testosterone and not a secondary consequence of maternal malnutrition or alterations in metabolic and steroid hormones.…”

“…Administration of testosterone during pregnancy in rats or sheep does not affect the food intake or weight gain of the dam or the maternal levels of insulin, estrogen, progesterone, glucose, or lipids (36,47). These findings indicate that the effects of prenatal androgenization on the placenta, fetus, and female offspring are not caused by changes in maternal metabolism.…”

“…It also leads to a dose-dependent reduction in birth weight in nonprimate species (25,35,36,50). Despite the recognition that excess androgen during pregnancy affects fetal development and can program for future development of adult metabolic diseases, there are few studies examining the underlying mechanisms of fetal origins of PCOS.…”

Effects of Oxidative Stress on Vascular Reactivity in the Offspring of Protein-Restricted Stroke-Prone Spontaneously Hypertensive Rats

“…[14][15][16] The female offspring of testosterone-treated dams have shown catch-up growth and elevated blood pressure which were accompanied by decreased eNOS expression and decreased NO production. 17) The birth weight in the present study was significantly lower in the PR group than in the control group, but the weight was similar at 10 weeks of age because of catch-up growth in both males and females. We also found that AChinduced relaxation, but not PE-induced contraction, was lower in the PR group.…”

Pathogenesis of polycystic ovary syndrome: multifactorial assessment from the foetal stage to menopause

“…Foetuses of animals exposed to androgen excess at the beginning of pregnancy may also exhibit an increased risk of hyperinsulinaemia and visceral obesity in infancy (Escobar-Morreale et al 2014). Although developmental programming by androgen excess might be associated with IUGR in rodents (Sathishkumar et al 2011) and sheep (Beckett et al 2014) and with low birth weight (LBW), these characteristics are not frequently found in that process in non-human primate models for PCOS (Abbott et al 2010). LH, luteinising hormone.…”