Exogenous transforming growth factor beta1 replacement and fertility in male Tgfb1 null mutant mice.
Analysis of Tgfb1 null mutant mice has demonstrated that the cytokine transforming growth factor beta1 (TGFB1) has essential non-redundant roles in fertility. The present study attempted to alleviate the infertility phenotype of Tgfb1 null mutant male mice by administration of exogenous TGFB1, either orally by colostrum feeding or subcutaneously by delivery of recombinant human latent TGFB1 (rhLTGFB1) via osmotic mini-pumps. Bovine colostrum and fresh unpasteurised bovine milk were found to be rich sources of TGFB1 and TGFB2; however, feeding Tgfb1 null mutant mice colostrum for 2 days failed to raise serum levels of TGFB1. Administration of rhLTGFB1 (approximately 150 microg in total) over 14 days to Tgfb1 null mutant mice resulted in detectable TGFB1 in serum; however, mean levels remained 10-fold less than in Tgfb1 heterozygous mice. After 7 days and 14 days of rhLTGFB1 administration, serum testosterone, spontaneous non-contact erections and mating behaviour were assessed. Despite the increased serum TGFB1, administration of rhLTGFB1 to Tgfb1 null mutant mice failed to improve these fertility parameters. It is concluded that sustained restoration of circulating latent TGFB1 to levels approaching the normal physiological range does not rescue the infertility phenotype caused by TGFB1 deficiency. Reproductive function in male Tgfb1 null mutant mice may not respond to systemic TGFB1 supplementation due to a requirement for local sources of TGFB1 at the site of action in the reproductive tract, or perturbed development during the neonatal period or puberty such that adult reproductive function is permanently impaired.
McGrath
Leanne J
LJ
Discipline of Obstetrics and Gynaecology and Research Centre for Reproductive Health, University of Adelaide, Adelaide, SA 5005, Australia.
Ingman
Wendy V
WV
Robker
Rebecca L
RL
Robertson
Sarah A
SA
D000284:Administration, Oral; D000818:Animals; D002417:Cattle; D003126:Colostrum / Q000737:chemistry; D005260:Female; D005298:Fertility / Q000187:drug effects / Q000235:genetics; D005838:Genotype; D006801:Humans; D015918:Infusion Pumps, Implantable; D055104:Infusions, Subcutaneous; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D008892:Milk / Q000737:chemistry; D010410:Penile Erection; D010641:Phenotype; D011247:Pregnancy; D011994:Recombinant Proteins / Q000008:administration & dosage; D012726:Sexual Behavior, Animal; D013739:Testosterone / Q000097:blood; D013997:Time Factors; D053773:Transforming Growth Factor beta1 / Q000008:administration & dosage / Q000032:analysis / Q000235:genetics / Q000378:metabolism*
D011994:Recombinant Proteins; C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; D053773:Transforming Growth Factor beta1; D013739:Testosterone