Oral Presentation ESA-SRB-ANZBMS 2024 in conjunction with ENSA

Paternal miR-146a regulates female receptivity to embryo implantation and fetal viability in mice (#44)

Hon Yeung (Dexter) Chan 1 , Kerrie L Foyle 1 , Peck Yin Chin 1 , Ricky A Matias 1 , Nicole O McPherson 1 , David J Sharkey 1 , John E Schjenken 1 2 3 , Sarah A Robertson 1
  1. Robinson Research Institute & School of Biomedicine, University of Adelaide, Adelaide, SA 5005, Australia
  2. Hunter Medical Research Institute, Infertility and Reproductive Research Program, New Lambton Heights, NSW 2305, Australia
  3. School of Environmental and Life Sciences, Discipline of Biological Sciences, The University of Newcastle, University Drive, Callaghan, NSW 2308, Australia

In mammals, male seminal fluid delivered at mating impacts the female reproductive tract immune response to influence fertility and the trajectory of fetal development. Fertility is boosted by permissive factors in semen including TGFB, while inhibitory factors such as interferon-G that arise under inflammatory circumstances can impair fertility. Male reproductive tract miR-146a expression and abundance in seminal fluid is upregulated after inflammatory challenge. We thus hypothesised that miR-146a is a novel inhibitory regulator of the female reproductive tract immune response that has consequences for pregnancy outcomes. To assess the impact of paternal miR-146a on pregnancy outcomes, miR-146a-null mutant male mice were mated with BALB/c females. Uterine T cell populations were assessed by flow cytometry on day (d) 3.5 post-coitum (pc). Pregnancy outcomes were measured on d5.5pc and d17.5pc. Neonatal outcomes were assessed at birth and offspring weight was measured fortnightly until week 16 post-partum. miR-146a-/- male-sired litters contained 19% more viable fetuses on d17.5pc (n=28-30/group, P<0.05), with no change in fetal weight but an 8.0% decrease in mean placental weight suggesting improved placental efficiency. A second post-implantation (d5.5pc) cohort showed a similar increase in litter size (n=14-18/group, P=0.03). In a third cohort evaluated at birth, there was no change in litter size, implying a 21% loss of pups in late gestation or early neonatal period in litters sired by miR-146a-/- males, compared with <5% loss in miR-146a+/+ mating (n=10-17/group). Gestation length and offspring survival and growth trajectory to 16 weeks were not affected by paternal genotype. Flow cytometry analysis revealed a 40% reduction in uterine CD3+ T cells after mating with miR-146a-/- males (n=10-16/group, P=0.02). Collectively, these findings indicate that paternal miR-146a directly or indirectly attenuates uterine receptivity to modulate the number of embryos permitted to implant, through a mechanism that involves effects on the female immune response.