Infertility in transgenic mice overexpressing the bovine growth hormone gene: disruption of the neuroendocrine control of prolactin secretion during pregnancy.
Transgenic female mice overexpressing the bovine growth hormone (bGH) gene with the phosphoenolpyruvate carboxykinase (PEPCK) promoter exhibit severe reproductive deficits. Although these animals ovulate and conceive normally, pregnancy is arrested due to luteal failure, leading to the loss of embryos during early gestation. The results of replacement therapy suggested that luteal failure was secondary to prolactin (PRL) deficiency. The objective of this study was to examine the neuroendocrine control of PRL secretion during early pregnancy in PEPCKbGH-1 transgenic mice. Normal and transgenic littermates were killed by decapitation on Day 7 postcoitum (p.c.) at 1500, 1800, or 2100 h, i.e., the period including the expected diurnal PRL surge in pregnant mice. In normal females, plasma PRL levels were significantly elevated at 1800 h when compared to the levels measured at 1500 or 2100 h, but no temporal variation in PRL levels was found in transgenic mice. In normal females, the content of dopamine in the median eminence was reduced at 1800 h, i.e., at the time of the PRL surge. In contrast, no temporal changes were detected in the median eminence dopamine content in transgenic mice. Twice-daily injections of domperidone, a dopamine receptor blocker, increased the incidence of pregnancy in transgenic females. After treatment with aromatic amino acid decarboxylase inhibitor NSD-1015 on Day 7 p.c., plasma levels of PRL were similarly elevated in transgenic and normal females. However, the accumulation of 5-hydroxytryptophan (5-HTP) in the medial basal hypothalamus after this treatment was significantly smaller in transgenic than in normal females.(ABSTRACT TRUNCATED AT 250 WORDS)
Cecim
M
M
Department of Physiology, Southern Illinois University School of Medicine, Carbondale 62901-6512, USA.
Fadden
C
C
Kerr
J
J
Steger
R W
RW
Bartke
A
A
D006916:5-Hydroxytryptophan / Q000378:metabolism; D000818:Animals; D065105:Aromatic Amino Acid Decarboxylase Inhibitors; D002417:Cattle; D004294:Domperidone / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D013006:Growth Hormone / Q000235:genetics / Q000502:physiology*; D006834:Hydrazines / Q000494:pharmacology; D007031:Hypothalamus / Q000502:physiology*; D007247:Infertility, Female / Q000209:etiology*; D008473:Median Eminence / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000235:genetics; D011247:Pregnancy; D011388:Prolactin / Q000378:metabolism*; D011401:Promoter Regions, Genetic
D065105:Aromatic Amino Acid Decarboxylase Inhibitors; D006834:Hydrazines; D004294:Domperidone; D011388:Prolactin; D013006:Growth Hormone; C004297:3-hydroxybenzylhydrazine; D006916:5-Hydroxytryptophan; D010729:Phosphoenolpyruvate Carboxykinase (GTP); D004298:Dopamine