Obesity during human pregnancy predisposes offspring to obesity and cardiovascular disease in postnatal life. In a sheep model of maternal overnutrition/obesity we have previously reported myocardial inflammation and fibrosis, as well as cardiac dysfunction in late term fetuses, in association with chronically elevated blood cortisol. Significant research has suggested a link between elevated glucocorticoid exposure in utero and hypertension and cardiovascular disease postnatally. Here we examined the effects of maternal obesity on myocardial inflammation and fibrosis of their adult offspring. Adult male offspring from control (CON) mothers fed 100% of National Research Council (NRC) recommendations (n = 6) and male offspring from obese mothers (MO) fed 150% NRC (n = 6), were put on a 12-week ad libitum feeding challenge then necropsied. At necropsy, plasma cortisol and left and right ventricular thickness were markedly increased (P<0.05) in adult male MO offspring. Myocardial collagen content and collagen-crosslinking were greater (P<0.05) in MO offspring compared to CON offspring in association with increased mRNA and protein expression of glucocorticoid receptors (GR). No group difference was found in myocardial mineralocorticoids receptor (MR) protein expression. Further, mRNA expression for the proinflammatory cytokines: cluster of differentiation (CD)-68, transforming growth factor (TGF)-β1, and tumor necrosis factor (TNF)-α were increased (P < 0.05), and protein expression of CD-68, TGF-β1, and TNF-α tended to increase (P<0.10) in MO vs. CON offspring. These data provide evidence for MO-induced programming of elevated plasma cortisol and myocardial inflammation and fibrosis in adult offspring potentially through increased GR.

Perturbed in utero hormone milieu leads to intrauterine growth retardation (IUGR), a known risk factor for left ventricular (LV) dysfunction later in life. Gestational testosterone (T) excess predisposes offspring to IUGR and leads to LV myocardial disarray and hypertension in adult females. However, the early impact of T excess on LV programming and if it is female specific is unknown. LV tissues were obtained at day 90 gestation from days 30–90 T-treated or control fetuses (n = 6/group/sex) and morphometric and molecular analyses were conducted. Gestational T treatment increased cardiomyocyte number only in female fetuses. T excess upregulated receptor expression of insulin and insulin-like growth factor. Furthermore, in a sex-specific manner, T increased expression of phosphatidylinositol 3-kinase (PI3K) while downregulating phosphorylated mammalian target of rapamycin (pmTOR)-to-mTOR ratio suggestive of compensatory response. T excess 1) upregulated atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), markers of stress and cardiac hypertrophy and 2) upregulated estrogen receptors1 (ESR1) and 2 (ESR2), but not in androgen receptor (AR). Thus, gestational T excess upregulated markers of cardiac stress and hypertrophy in both sexes while inducing cardiomyocyte hyperplasia only in females, likely mediated via insulin and estrogenic programming. NEW & NOTEWORTHY The present study demonstrates sex-specific effects of gestational T excess between days 30 and 90 of gestation on the cardiac phenotype. Furthermore, the sex-specific programming is likely secondary to perturbation in both estrogen and insulin signaling pathways collectively. These findings are supportive of the role of androgen excess to serve as early biomarkers of CVD and could be critical in identifying therapeutic targets for LV hypertrophy and predict long-term CVD.

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.

Lipids play a critical role in neonate development and breastmilk is the newborn’s major source of lipids. Milk lipids directly influence the neonate plasma lipid profile. The milk lipidome is dynamic, influenced by maternal factors and related to the maternal plasma lipidome. The close inter-relationship between the maternal plasma, milk and neonate plasma lipidomes is critical to understanding maternal-child health and nutrition. In this exploratory study, lipidomes of blood and breast milk from Suffolk sheep and matched lamb blood (n = 13), were profiled on day 34 post birth by untargeted mass spectrometry. Comparative multivariate analysis of the three matrices identified distinct differences in lipids and class of lipids amongst them. Paired analysis identified 346 differential lipids (DL) and 31 correlated lipids (CL) in maternal plasma and milk, 340 DL and 32 CL in lamb plasma and milk and 295 DL and 16 CL in maternal plasma and lamb plasma. Conversion of phosphatidic acid to phosphatidyl inositol was the most active pathway in lamb plasma compared to maternal plasma. This exploratory study illustrates the partitioning of lipids across maternal plasma, milk and lamb plasma and the dynamic relationship between them, reiterating the need to study these three matrices as one biological system.

Changes in cardiometabolic functions contribute to increased morbidity and mortality after chronic spinal cord injury. Despite many advancements in discovering SCI-induced pathologies, the cardiometabolic risks and divergences in severity-related responses have yet to be elucidated. Here, we examined the effects of SCI severity on functional recovery and cardiometabolic functions following moderate (50 kdyn) and severe (75 kdyn) contusions in the thoracic-8 (T8) vertebrae in mice using imaging, morphometric, and molecular analyses. Both severities reduced hindlimbs motor functions, body weight (g), and total body fat (%) at all-time points up to 20 weeks post-injury (PI), while only severe SCI reduced the total body lean (%). Severe SCI increased liver echogenicity starting from 12 weeks PI, with an increase in liver fibrosis in both moderate and severe SCI. Severe SCI mice showed a significant reduction in left ventricular internal diameters and LV volume at 20 weeks PI, associated with increased LV ejection fraction as well as cardiac fibrosis. These cardiometabolic dysfunctions were accompanied by changes in the inflammation profile, varying with the severity of the injury, but not in the lipid profile nor cardiac or hepatic tyrosine hydroxylase innervation changes, suggesting that systemic inflammation may be involved in these SCI-induced health complications.

Exposure to glucocorticoid levels higher than appropriate for current developmental stages induces offspring metabolic dysfunction. Overfed/obese (OB) ewes and their fetuses display elevated blood cortisol, while fetal Adrenocorticotropic hormone (ACTH) remains unchanged. We hypothesized that OB pregnancies would show increased placental 11β hydroxysteroid dehydrogenase 2 (11β-HSD2) that converts maternal cortisol to fetal cortisone as it crosses the placenta and increased 11β-HSD system components responsible for peripheral tissue cortisol production, providing a mechanism for ACTH-independent increase in circulating fetal cortisol. Control ewes ate 100% National Research Council recommendations (CON) and OB ewes ate 150% CON diet from 60 days before conception until necropsy at day 135 gestation. At necropsy, maternal jugular and umbilical venous blood, fetal liver, perirenal fat, and cotyledonary tissues were harvested. Maternal plasma cortisol and fetal cortisol and cortisone were measured. Fetal liver, perirenal fat, cotyledonary 11β-HSD1, hexose-6-phosphate dehydrogenase (H6PD), and 11β-HSD2 protein abundance were determined by Western blot. Maternal plasma cortisol, fetal plasma cortisol, and cortisone were higher in OB vs. CON (p < 0.01). 11β-HSD2 protein was greater (p < 0.05) in OB cotyledonary tissue than CON. 11β-HSD1 abundance increased (p < 0.05) in OB vs. CON fetal liver and perirenal fat. Fetal H6PD, an 11β-HSD1 cofactor, also increased (p < 0.05) in OB vs. CON perirenal fat and tended to be elevated in OB liver (p < 0.10). Our data provide evidence for increased 11β-HSD system components responsible for peripheral tissue cortisol production in fetal liver and adipose tissue, thereby providing a mechanism for an ACTH-independent increase in circulating fetal cortisol in OB fetuses.