Developmental programming: exposure to testosterone excess disrupts steroidal and metabolic environment in pregnant sheep.

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TitleDevelopmental programming: exposure to testosterone excess disrupts steroidal and metabolic environment in pregnant sheep.
Publication TypeJournal Article
Year of Publication2015
AuthorsB Salloum A, Veiga-Lopez A, Abbott DH, Burant CF, Padmanabhan V
JournalEndocrinology
Volume156
Issue6
Pagination2323-37
Date Published2015 Jun
ISSN1945-7170
KeywordsAnimals, Birth Weight, Blood Glucose, Female, Flutamide, Insulin, Pregnancy, Progesterone, Reproduction, Sheep, Steroids, Testosterone, Thiazolidinediones
Abstract

Gestational exposure to excess T leads to intrauterine growth restriction, low birth weight, and adult metabolic/reproductive disorders in female sheep. We hypothesized that as early mediators of such disruptions, gestational T disrupts steroidal and metabolic homeostasis in both the mother and fetus by both androgenic and metabolic pathways. Maternal blood samples were measured weekly for levels of insulin, glucose, and progesterone from four groups of animals: control; gestational T (twice weekly im injections of 100 mg of T propionate from d 30 to d 90 of gestation); T plus an androgen antagonist, flutamide (15 mg/kg·d oral; T-Flutamide); and T plus the insulin sensitizer, rosiglitazone (0.11 mg/kg·d oral; T-Rosi) (n = 10-12/group). On day 90 of gestation, maternal and umbilical cord samples were collected after a 48-hour fast from a subset (n = 6/group) for the measurement of steroids, free fatty acids, amino acids, and acylcarnitines. Gestational T decreased maternal progesterone levels by 36.5% (P < .05), which was prevented by flutamide showing direct androgenic mediation. Gestational T also augmented maternal insulin levels and decreased medium chained acylcarnitines, suggesting increased mitochondrial fatty acid oxidation. These changes were prevented by rosiglitazone, suggesting alterations in maternal fuel use. Gestational T-induced increases in fetal estradiol were not prevented by either cotreatment. Gestational T disrupted associations of steroids with metabolites and progesterone with acylcarnitines, which was prevented either by androgen antagonist or insulin sensitizer cotreatment. These findings suggest a future combination of these treatments might be required to prevent alteration in maternal/fetal steroidal and metabolic milieu(s).

DOI10.1210/en.2014-2006
Alternate JournalEndocrinology
PubMed ID25763641
PubMed Central IDPMC4430607
Grant ListDK089503 / DK / NIDDK NIH HHS / United States
P01 HD44232 / HD / NICHD NIH HHS / United States
T32 DK071212-08 / DK / NIDDK NIH HHS / United States
U24 DK097153 / DK / NIDDK NIH HHS / United States