(P-233) Human INHBB Gene Variant (C.1079T>C:P.Met360Thr) Is Disruptive for Pregnancy and Labouring in Female Mice

Abstract Authors: Shreya Maskey1,2; Georgia Goodchild1; Anne E. O'Connor3; Amy Winship1; Jessica Stringer1; Karla Hutt1; Helena Parkington1; Don F. Conrad4,5; Kenneth I. Aston5,6; Craig Harrison1; Moira K. O'Bryan3; Kelly Walton2

1Monash Biomedicine Discovery Institute, Monash University, Clayton, Australia

2School of Biomedical Sciences, The University of Queensland, Brisbane, Australia

3School of BioSciences and Bio21 Institute, Faculty of Science, University of Melbourne, Parkville, Australia

4Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, USA

5Genetics of Male Infertility Initiative, GEMINI, Portland, USA

6Department of Surgery (Urology Division) University of Utah School of Medicine, Salt Lake City, USA

Abstract Text: Ovarian-derived inhibin A and inhibin B (α/β dimers) suppress follicle-stimulating hormone (FSH) production at the pituitary by blunting receptor activation by the activins (β/β dimers). This hypothalamic-pituitary-gonadal (HPG) loop is integral to reproductive function, and consequently, imbalances in inhibin/activin can negatively impact fertility. In a recent study, human INHBB gene variant (c.1079T >C:p.Met360Thr), identified in an infertile man, was shown to significantly reduce serum activin B levels and alter testis germ cell content in corresponding Inhbb^M364T/M364T male mice. Here, we aimed to determine if the identified INHBB gene variation also altered female reproductive function. To address this, we examined ovarian and uterine function in Inhbb^M364T/M364T adult female mice and Inhbb^WT/WT littermate controls. As observed in the Inhbb^M364T/M364T male mice, female Inhbb^M364T/M364T mice tended to have reduced (p=0.62) circulating levels of activin B as well as significantly reduced (p< 0.01) activin A levels relative to Inhbb^WT/WT littermates. Despite the reduction in serum activins, serum FSH levels and ovulation rates were comparable between Inhbb^M364T/M364T and Inhbb^WT/WT. However, pregnant Inhbb^M364T/M364T dams were found to carry significantly more (p< 0.01) and significantly smaller (p< 0.01) foetuses to late gestation (17.5 days post coitus) relative to Inhbb^WT/WT pregnant controls. Furthermore, Inhbb^M364T/M364T females were found to experience dystocia, with significantly extended gestation periods (p< 0.05) and labour (p< 0.01) relative to Inhbb^WT/WT pregnant controls. In these female mice, dystocia is attributed to weakened uterine contractility. Our findings support that the inhibin βB-subunit is essential for maintenance of pregnancy and normal labouring in females.