title: Maternal ghrelin deficiency compromises reproduction in female progeny through altered uterine developmental programming.
abstract: Ghrelin has a well-known role in the regulation of appetite, satiety, energy metabolism, and reproduction; however ghrelin has not been implicated in reproductive tract development. We examined the effect of ghrelin deficiency on the developmental programming of female fertility. We observed that female wild-type mice born of ghrelin heterozygote dams (i.e. exposed in utero to ghrelin deficiency) had diminished fertility and produced smaller litters. We demonstrate that exposure to in utero ghrelin deficiency led to altered developmental programming of the reproductive tract. The number of ovarian follicles, corpora lutea, and embryos produced were identical in both exposed and unexposed mice. However wild-type embryos transferred to uteri of mice exposed to in utero ghrelin deficiency had a 60% reduction in the rate of embryo implantation compared with those transferred to wild-type unexposed uteri. We identified significant alterations in the uterine expression of four genes critical for implantation and a defect in uterine endometrial proliferation. Taken together, these results demonstrate that the mechanism of subfertility was abnormal endometrial function. In utero exposure to decreased levels of ghrelin led to defects in developmental programming of the uterus and subsequent subfertility in wild-type offspring.
authors.affiliation: Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
authors.forename: J Ryan
authors.initials: JR
authors.lastname: Martin
authors.forename: Sarah B
authors.initials: SB
authors.lastname: Lieber
authors.forename: James
authors.initials: J
authors.lastname: McGrath
authors.forename: Marya
authors.initials: M
authors.lastname: Shanabrough
authors.forename: Tamas L
authors.initials: TL
authors.lastname: Horvath
authors.forename: Hugh S
authors.initials: HS
authors.lastname: Taylor
mesh_terms: D000818:Animals; D010064:Embryo Implantation / Q000235:genetics; D005260:Female; D005298:Fertility / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental; D054439:Ghrelin / Q000097:blood / Q000172:deficiency / Q000235:genetics*; D006579:Heterozygote; D000080905:Homeobox A10 Proteins; D018398:Homeodomain Proteins / Q000235:genetics; D007150:Immunohistochemistry; D008098:Litter Size / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D012098:Reproduction / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics; D014599:Uterus / Q000196:embryology / Q000254:growth & development / Q000378:metabolism*; D051153:Wnt Proteins / Q000235:genetics; D000099260:Empty Spiracles Homeobox Proteins
chemical_list: D054439:Ghrelin; D000080905:Homeobox A10 Proteins; D018398:Homeodomain Proteins; D018809:Proliferating Cell Nuclear Antigen; D014157:Transcription Factors; D051153:Wnt Proteins; D000099260:Empty Spiracles Homeobox Proteins; C490508:Wnt7a protein, mouse; C092119:Hoxa10 protein, mouse