Differential neonatal testosterone imprinting of GH-dependent liver proteins and genes in female mice

Abstract

Abnormal exposure to steroid hormones within a critical developmental period elicits permanent alterations in female reproductive physiology in rodents, but the impact on the female GH axis and the underlying sexual differences in hepatic enzymes have not been described in detail. We have investigated the effect of neonatal androgenization of female mice (achieved by s.c. injection of 100 mg testosterone propionate (TP) on the day of birth: TP females) on the GHRH-somatostatin-GH axis and downstream GH targets, which included female and male predominant liver enzymes and secreted proteins. At 4 months of age, an organizational effect of neonatal testosterone was evidenced on hypothalamic Ghrh mRNA level but not on somatostatin (stt) mRNA level. Ghrh mRNA levels were higher in males than in females, but not in TP females. Increased expression in TP females correlated with increased pituitary GH content and somatotrope population, increased serum and liver IGF-I concentration, and ultimately higher body weight. Murine urinary proteins (MUPs) that were excreted at higher levels in male urine, and whose expression requires pulsatile occupancy of liver GH receptors, were not modified in TP females and neither was liver Mup 1/2/6/8 mRNA expression. Furthermore, a male predominant liver gene (Cyp2d9) was not masculinized in TP females either, whereas two female predominant genes (Cyp2b9 and Cyp2a4) were defeminized. These data support the hypothesis that neonatal steroid exposure contributes to the remodeling of the GH axis and defeminization of hepatic steroid-metabolizing enzymes, which may compromise liver physiology.

Transient Exposure of Neonatal Female Mice to Testosterone Abrogates the Sexual Dimorphism of Abdominal Aortic Aneurysms

“…Adult ApoE-/- females administered vehicle or testosterone as neonates were infused with either saline or AngII (1,000 ng/kg/min) for 28 days. In agreement with previous reports, 34, 35 neonatal administration of testosterone resulted in a modest but significant increase in body weights of adult females (Online Table V for AngII-infused groups). However, there was no significant effect of testosterone on systolic blood pressure, blood monocyte counts, serum cholesterol concentrations (Online Table V), or lipoprotein cholesterol distribution (Online Figure I) in adult females infused with AngII at different rates.…”

Maternal transfer of BDE-47 to offspring and neurobehavioral development in C57BL/6J mice

“…Gonadotropic hormones (e.g., testosterone) are thought to promote higher levels of MUP proteins in adult males, so sex differences might not be expected until puberty (approximately PND 28) [7,42,74]. This hypothesis is also supported by a report that MUP proteins are equivalent between sexes at 1 month of age, but by 4 months males have significantly higher levels than females [51]. …”

GH/STAT5 signaling during the growth period in livers of mice overexpressing GH

“…cDNA was obtained using iScript cDNA synthesis kit (Bio-Rad), and the relative expression of the genes was analyzed by quantitative RT-PCR (qRT-PCR) as previously described (Ramirez, et al 2010). Table 1 shows the sequence of the primer sets used, obtained from Invitrogen.…”