title: Prenatal programming: adverse cardiac programming by gestational testosterone excess.
abstract: Adverse events during the prenatal and early postnatal period of life are associated with development of cardiovascular disease in adulthood. Prenatal exposure to excess testosterone (T) in sheep induces adverse reproductive and metabolic programming leading to polycystic ovarian syndrome, insulin resistance and hypertension in the female offspring. We hypothesized that prenatal T excess disrupts insulin signaling in the cardiac left ventricle leading to adverse cardiac programming. Left ventricular tissues were obtained from 2-year-old female sheep treated prenatally with T or oil (control) from days 30-90 of gestation. Molecular markers of insulin signaling and cardiac hypertrophy were analyzed. Prenatal T excess increased the gene expression of molecular markers involved in insulin signaling and those associated with cardiac hypertrophy and stress including insulin receptor substrate-1 (IRS-1), phosphatidyl inositol-3 kinase (PI3K), Mammalian target of rapamycin complex 1 (mTORC1), nuclear factor of activated T cells -c3 (NFATc3), and brain natriuretic peptide (BNP) compared to controls. Furthermore, prenatal T excess increased the phosphorylation of PI3K, AKT and mTOR. Myocardial disarray (multifocal) and increase in cardiomyocyte diameter was evident on histological investigation in T-treated females. These findings support adverse left ventricular remodeling by prenatal T excess.
authors.affiliation: Department of Pediatrics and Human Development, Michigan State University, E. Lansing, MI, 48824, USA.
authors.forename: Arpita K
authors.initials: AK
authors.lastname: Vyas
authors.affiliation: Department of Pediatrics and Human Development, Michigan State University, E. Lansing, MI, 48824, USA.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Hoang
authors.affiliation: Department of Pediatrics, University of Michigan, Ann Arbor, MI, 48109, USA.
authors.forename: Vasantha
authors.initials: V
authors.lastname: Padmanabhan
authors.affiliation: Pathobiology Department, College of Veterinary Medicine, Nursing and Allied Health, Tuskegee University, Tuskegee, AL, 36088, USA.
authors.forename: Ebony
authors.initials: E
authors.lastname: Gilbreath
authors.affiliation: Pathobiology and Diagnostic Investigation, College of Veterinary Medicine, Michigan State University, USA.
authors.forename: Kristy A
authors.initials: KA
authors.lastname: Mietelka
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006973:Hypertension / Q000139:chemically induced; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D011085:Polycystic Ovary Syndrome / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism; D012756:Sheep; D015398:Signal Transduction / Q000187:drug effects; D013739:Testosterone / Q000009:adverse effects*
chemical_list: D015415:Biomarkers; D007328:Insulin; D013739:Testosterone