Elevated Androgen Levels During Pregnancy Impair Fetal Growth Due to Placental Insufficiency and Programs for Adult Hypertension in Rats. (2009)

Fetal/neonatal insults lead to low birth weight and adult-onset diseases like hypertension, obesity, diabetes, etc. Pregnant women with elevated testosterone levels and their problems with low birth weight and adverse health consequences are rapidly increasing. Studies indicate that pregnant mothers can be inadvertently exposed to elevated androgens due to (a) exposure to environmental pollutants and anabolic steroids, (b) disorders like preeclampsia, pregnancy-associated-hypertension and adrenal hyperplasia and (c) lifestyle activities, such as, caffeine, alcohol or nicotine intake, strenuous exercise, and increased stress. Also, African American and PCOS mothers have higher plasma testosterone levels with greater percentage of placental complications, low birth weight babies and adult cardiovascular dysfunction observed in these populations. Based on these epidemiological data, we hypothesis that elevated maternal androgens may impair placental function and fetal growth, and program for adult cardiovascular dysfunction. Pregnant Sprague-Dawley rats were daily administered with testosterone propionate (TP; 0.5 mg kg-1 bodyweight, subcutaneously) in sesame oil or oil alone during gestational days (GD) 15-19. In the dams, changes in hormone levels, and placental size and morphology were determined. Placental transfer of amino acids and glucose to the fetus were assessed using [14C]methyl-aminoisobutyric acid (MeAIB, 10 μCi kg-1) and 3-O-methyl-D-[3H]glucose (50 μCi kg-1), respectively to rats on GD 21. Expression of amino acid and glucose transporters, SNAT-1, -2, -4, and GLUT-1 and -3 were determined by Western blot and/or real-time RT-PCR. In the offspring, birth weight and temporal changes in body weight and blood pressure were determined in both sexes. TP injection caused two-fold increase in testosterone levels in TP dams. There were no significant changes in estrogen, progesterone and corticosterone levels. Placental size was reduced with smaller and distorted labyrinth zone and compressed spongiotrophoblasts in TP dams. Placental transport measurements showed a significant reduction in placental uptake (counts per minute (c.p.m.) (g placenta)-1), placental transport (c.p.m. (g fetus)-1) and placental transport capacity (fetal c.p.m. (g placenta)-1) of MeAIB by 20%, 26% and 19%, respectively in TP dams compared to controls. No significant difference in glucose transport was observed. There is a significant decrease in placental mRNA and protein expression of SNAT2 but other transporters in TP placentas were not affected. Birth weights of pups were lower by 22% in TP rats compared to controls and the growth curves of the two groups remained significantly different through adulthood. Mean BP was significantly higher in both genders of TP offspring compared to their respective controls. However, the male offspring had an early onset (i.e., at 4 mo) and more severe hypertension compared to female siblings. Exposure to testosterone during pregnancy causes placental insufficiency by deceasing the expression and function of system A transporters, which might contribute fetal growth retardation and programming of organ function. Understanding of these mechanisms will aid in the development of effective diagnostic tools and interventions to prevent or decrease the risk of low birth weight and improve adult health. (poster)