Oral Presentation ESA-SRB-NZSE-CaSR 2026 in conjunction with ENSA

Pre-conception BGP-15 rejuvenates sperm microRNA signatures and restores fetal growth and heart development in older male mice (143602)

Macarena Gonzalez 1 , Aaron Phillips 2 , Yasir Kusay 3 4 , Helle Bielefeldt-Ohmann 5 , Joshua Deluao 1 6 , Rebecca Robker 1 , Chung Hoow Kok 3 4 , Tina Bianco-Miotto 1 2 , Nicole McPherson 1 6 7
  1. Robinson Research Institute, School of Pharmacy and Biomedical Sciences, Adelaide University, Adelaide, South Australia, Australia
  2. Waite Research Institute; School of Agriculture, Food and Wine, Adelaide University, Adelaide, South Australia, Australia
  3. Centre for Cancer Biology; School of Medicine, Adelaide University, Adelaide, South Australia, Australia
  4. Genetics & Molecular Pathology, SA Pathology, Adelaide, South Australia, Australia
  5. School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Queensland, Australia
  6. Freemason's Centre for Male Health and Wellbeing, Adelaide, South Australia, Australia
  7. Genea Fertility SA, St. Andrew's Hospital, Adelaide

Background: Mammalian sperm carries molecular signals that transfer to the embryo at fertilisation and shape development during pregnancy. We previously showed that male ageing alters embryo development, causing complications such as fetal growth restriction with lasting health consequences. Whether this cargo can be modified to restore normal development is unknown. As sperm ageing involves oxidative stress and mitochondrial decline, we tested whether pre-conception treatment with BGP-15, a small molecule that improves mitochondrial function and cellular stress resistance, rejuvenates sperm microRNAs and restores normal fetal development in older males.

Methods: Young (8 weeks) or older (14 months) C57BL/6 males were untreated or given BGP-15 (50 mg/kg BW, drinking water) for 6 weeks (n=4–7 sires per group), then mated to naturally cycling females; fetuses were collected at embryonic day 18.5 for pathology analysis. Sperm was collected from sires for sncRNA-seq. Fetal heart underwent sncRNA-seq and RNA-seq for gene expression analysis.

Main results: The sperm from older males presented a characteristic microRNA signature distinct from young males, that was "rejuvenated" by BGP-15 treatment. Of four differentially expressed microRNAs, miR-155-5p, a known regulator of placental development, was elevated in older males and normalised by BGP-15. Compared with young controls, older males produced fetuses with characteristics of fetal growth restriction: larger placentas (p=0.001) and lighter bodies (p=0.0004), consistent with reduced placental efficiency. This was normalised in fetuses from BGP-15-treated older males (p=0.02 and p=0.002, respectively). Fetuses sired by older males also tended to have higher placental mineralisation (p=0.06) and had abnormal heart gene expression (p<0.05), which was again normalised by BGP-15 treatment (p=0.04 and p<0.05, respectively).

Conclusion: Pre-conception BGP-15 restored sperm microRNAs and normalised fetal growth and heart gene expression in offspring from older fathers, showing that age-driven sperm changes are not fixed and can be reversed before conception.