Oral Presentation ESA-SRB-APEG-NZSE 2022

Human INHBB Gene Variant (c.1079T>C:p.Met360Thr) is disruptive for pregnancy and labouring in female mice (#87)

Kelly L Walton 1 , Shreya Maskey 2 , Anne E O'Connor 3 , Georgia Goodchild 2 , Amy Winship 2 , Jessica Stringer 2 , Karla Hutt 2 , Helena Parkington 2 , Don F Conrad 4 5 , Ki Aston 4 6 , Craig A Harrison 2 , Moira K O'Bryan 3
  1. The University of Queensland, Brisbane, QLD, Australia
  2. Monash University, Clayton, VIC, Australia
  3. School of BioSciences and Bio21 Institute, Faculty of Science, University of Melbourne , Melbourne , Victoria, Australia
  4. Genetics of Male Infertility Initiative, GEMINI, Portland, USA
  5. Oregon Health and Science University, Beverton, OR, US
  6. University of Utah School of Medicine, Utah, USA

Ovarian-derived inhibin A and inhibin B (α/β dimers) act in an endocrine manner to suppress pituitary production of follicle-stimulating hormone (FSH), by blocking the actions of activins (β/β dimers). This hypothalamic-pituitary-gonadal (HPG) loop is integral to reproductive function, and consequently, imbalances in inhibin/activin can impact fertility. In a recent study, we showed that a human INHBB gene variant (c.1079T>C:p.Met360Thr), identified in an infertile man, significantly reduced serum activin B levels and altered testis germ cell content in corresponding InhbbM364T/M364T male mice. This study aimed to determine if the identified INHBB gene variation also had consequences for female reproductive function. To address, we examined ovarian and uterine function in InhbbM364T/M364T adult female mice. As seen InhbbM364T/M364T male mice, female InhbbM364T/M364T mice displayed reduced levels of circulating activin B, and also activin A relative to wildtype littermates. Despite this, ovarian folliculogenesis and ovulation rates were comparable. Interestingly, InhbbM364T/M364T females had a greater number of implantation sites at late gestation, and a significant pre-disposition to dystocia, with extended gestation periods and labours relative to wildtype litter mates. Dystocia in these females appears to be attributed to disrupted uterine contractility. This study provides evidence that reduced circulating levels of activins A/B are detrimental to pregnancy outcomes in females.