E-Poster Presentation ESA-SRB-ANZBMS 2021

NMN supplementation rescues fertility and bone strength in chemotherapy-treated mice (#545)

Maria B Marinova 1 2 , Wing-Hong Jonathan Ho 1 3 , Michael J Bertoldo 1 2 , Vedran Lovric 4 , Kaisa Selesniemi 5 , Amelia Brown 2 , Derek Wong 1 , David A Sinclair 5 , Kirsty Walters 2 , William R Walsh 4 , Robert B Gilchrist 2 , Lindsay E Wu 1
  1. School of Medical Sciences, UNSW Sydney, Sydney, New South Wales, Australia
  2. School of Women's and Children's Health, UNSW Sydney, Sydney, New South Wales, Australia
  3. Garvan Institute of Medical Research, Sydney, New South Wales, Australia
  4. Prince of Wales Clinical School, UNSW Sydney, Sydney, New South Wales, Australia
  5. Department of Genetics, Harvard Medical School, Boston, MA, USA

 

Cancer survivors can face infertility from cytotoxic chemotherapy drugs, which exhaust the follicular reserve, leading to endocrine disruption. This can cause infertility with premature menopause and declining bone health. We assessed the effects of the NAD+ precursor nicotinamide mononucleotide (NMN) on ovarian function, fertility, hormone levels, and late-life bone health. Seven-day old female mice were treated +/-cisplatin (2 mg/kg) and two weeks later received NMN (2 g/L) in drinking water, persisting throughout life. A breeding trial was conducted at 6 weeks, and animals were sacrificed at 24 months to assess late-life effects on bone structure. This experiment was then replicated with collection at 3, 6, and 10 weeks of age to assess early life impacts on bone. Cisplatin caused a dramatic decline in all fertility endpoints. NMN supplementation rescued the cumulative number of pups born per female in cisplatin treated animals by 5-fold (p=0.015). Given the link between estrogen and osteoporosis and the improvement in breeding, we tested whether these interventions impacted late-life bone health at the age of 24 months. Bones from these animals were subject to mechanical and structural analysis to assess osteoporosis onset differences. In cisplatin treated animals, NMN rescued cortical bone thickness, bone volume, and bone density to control levels, and increased mechanical strength. Cisplatin caused striking differences in cortical porosity and matrix organization with consistent rescue by NMN. Surprisingly, in the young animal cohort, in 3-week old mice, cisplatin improved bone trabecular volume, thickness and BV/TV, and cortical volume, density, and wall thickness. Estrogen levels were undetectable at 3 weeks, but progesterone was increased with NMN+/-chemo, with preliminary histology suggesting a higher number of corpora lutea.  Together, long-term NMN treatment delivered following chemotherapy protected against ovarian failure and infertility, and notably improved late-life bone health, possibly due to the prevention of premature ovarian failure.