Arpita Kalla Vyas

Early to midgestational testosterone (T) excess adversely programs lung development in a sex-specific manner, with effects extending from fetal life into adulthood. Fetal lung transcriptomics reveal distinct sex-specific molecular responses to prenatal T exposure. Together, these findings suggest that prenatal androgen excess may represent a developmental mechanism linking fetal lung programming to persistent pulmonary remodeling in adulthood.

Using a sheep model of human translational relevance, this study provides evidence for adverse effects of early to midgestational testosterone exposure on fetal hearts persisting beyond the time of exposure to androgen excess. Moreover, the effects are more pronounced in the left ventricle compared with the right ventricle in late gestational fetuses.

In a translationally relevant ovine model of gestational hyperandrogenism we have previously reported cardiometabolic disruption in female offspring (males were not extensively studied). We hypothesized that gestational hyperandrogenism would lead to sex-specific disruption in offspring’s growth, cytokine and metabolic milieu, potential mediators of cardiometabolic disease (CMD). 100 mg Testosterone propionate (T) or vehicle (C) was administered intramuscularly twice weekly between gestational days (GD) 30–90. Two cohorts of offspring were generated, including both males and females. Fetal weight and systemic metabolomics were analyzed in the fetal cohort (GD120). Growth trajectory, systemic cytokines, and metabolomics were analyzed in the postnatal cohort. Data was analyzed using mixed model ANOVA, student T-test, and Cohen D (d) analysis. T excess led to (1) a reduction in fetal weight at GD 120 in both sexes and sex-specific perturbations in the fetal metabolome, (2) T-Female had a growth trajectory similar to males and significantly different from C-Females (age x treatment interaction p = 0.028) and (3) sex-specific alterations in cytokine milieu at birth and metabolome in the pre-pubertal period. Altered sex-specific postnatal metabolic milieu and growth trajectory, notable for catch-up growth in T-Female, could have implications for sex-specific impact on the cardiometabolic function in the lambs.

Using a sheep model of human translational relevance, this study provides evidence that excess gestational testosterone exposure such as that seen in hyperandrogenic disorders adversely impacts postpartum maternal hearts.

Gestational hyperandrogenism adversely impacts offspring health. Using an ovine model, we found that prenatal testosterone (T) excess adversely affects growth and cardiometabolic outcomes in female offspring and produces sex-specific effects on fetal myocardium. Since lipids are essential to cardiometabolic function, we hypothesized that prenatal T excess leads to sex-specific disruptions in lipid metabolism at birth. Shotgun lipidomics was performed on the plasma samples collected 48 hours after birth from female (F) and male (M) lambs of control (C) and (T) sheep (CF = 4, TF = 7, CM = 5, TM = 10) and data were analyzed by univariate analysis, multivariate dimensionality reduction modeling followed by functional enrichment, and pathway analyses. Biosynthesis of phosphatidylserine was the major pathway responsible for sex differences in controls. Unsupervised and supervised models showed separation between C and T in both sexes with glycerophospholipids and glycerolipids classes being responsible for the sex differences between C and T. T excess increased cholesterol in females while decreasing phosphatidylcholine levels in male lambs. Specifically, T excess: 1) suppressed the phosphatidylethanolamine N-methyltransferase (PEMT) phosphatidylcholine synthesis pathway overall and in TM lambs as opposed to suppression of carnitine levels overall and TF lambs; and 2) activated biosynthesis of ether-linked (O-)phosphatidylethanolamine and O-phosphatidylcholine from O-diacylglycerol overall and in TF lambs. Higher cholesterol levels could underlie adverse cardiometabolic outcomes in TF lambs, whereas suppressed PEMT pathway in TM lambs could lead to endoplasmic reticulum stress and defective lipid transport. These novel findings point to sex-specific effects of prenatal T excess on lipid metabolism in newborn lambs, a precocial ovine model of translational relevance.

Cardiovascular disease affects 1% to 4% of the nearly 4 million pregnancies in the United States each year and is the primary cause of pregnancy-related mortality. Adverse pregnancy outcomes are associated with cardiovascular complications during pregnancy persisting into the postpartum period. Recently, investigations have identified an altered sex hormone milieu, such as in the case of hyperandrogenism, as a causative factor in the development of gestational cardiovascular dysfunction. The mechanisms involved in the development of cardiovascular disease in postpartum women are largely unknown. Animal studies have attempted to recapitulate adverse pregnancy outcomes to investigate causal relationships and molecular underpinnings of adverse gestational cardiac events and progression to the development of cardiovascular disease postpartum. This review will focus on summarizing clinical and animal studies detailing the impact of adverse pregnancy outcomes, including preeclampsia, gestational diabetes mellitus, and maternal obesity, on gestational cardiometabolic dysfunction and postpartum cardiovascular disease. Specifically, we will highlight the adverse impact of gestational hyperandrogenism and its potential to serve as a biomarker for maternal gestational and postpartum cardiovascular dysfunctions.

Adverse in-utero insults during fetal life alters offspring’s developmental trajectory, including that of the cardiovascular system. Gestational hyperandrogenism is once such adverse in-utero insult. Gestational testosterone (T)-treatment, an environment of gestational hyperandrogenism, manifests as hypertension and pathological left ventricular (LV) remodeling in adult ovine offspring. Furthermore, sexual dimorphism is noted in cardiomyocyte number and morphology in fetal life and at birth. This study investigated transcriptional changes and potential biomarkers of prenatal T excess-induced adverse cardiac programming. Genome-wide coding and non-coding (nc) RNA expression were compared between prenatal T-treated (T propionate 100 mg intramuscular twice weekly from days 30 to 90 of gestation; Term: 147 days) and control ovine LV at day 90 fetus in both sexes. Prenatal T induced differential expression of mRNAs in the LV of female (2 down, 5 up) and male (3 down, 1 up) (FDR < 0.05, absolute log2 fold change > 0.5); pathways analysis demonstrated 205 pathways unique to the female, 382 unique to the male and 23 common pathways. In the male, analysis of ncRNA showed differential regulation of 15 lncRNAs (14 down, 1 up) and 27 snoRNAs (26 down and 1 up). These findings suggest sexual dimorphic modulation of cardiac coding and ncRNA with gestational T excess.

Vitamin A intoxication secondary to over-the-counter nutritional supplements and from its use in acne treatment has been described. However, there have been very few case reports of chronic hypervitaminosis A leading to hypercalcemia in the pediatric population. This paper describes a boy with hypercalcemia secondary to chronic vitamin A intoxication in the context of vitamin A usage for therapy of autism. In addition to discontinuation of vitamin A, hyperhydration, and furosemide, the hypercalcemia in this patient required the use of prednisone and pamidronate to normalize the calcium.