Oocyte lipid damage from maternal aging marks neurodevelopment in mouse offspring

Abstract STUDY QUESTION Is advanced maternal age (AMA) associated with lipid dysregulation in oocytes that correlates with the intergenerational persistence of altered lipid homeostasis and neurodevelopmental pathway signatures in downstream offspring? SUMMARY ANSWER Lipid profile alterations characterised in AMA oocytes are associated with distinct lipidomic and spectral variations in the foetal brain and yolk sac, displaying intergenerational persistence that extends up to the fourth generation, independently of the gestational uterine environment. WHAT IS KNOWN ALREADY Advanced maternal age is a recognised prenatal risk factor for neurodevelopmental conditions in offspring. However, whether early-life oocyte lipid variations correlate with altered lipid profiles and molecular signatures in the developing brains of subsequent generations remain uncharacterised. STUDY DESIGN, SIZE, DURATION This controlled animal model study compared oocytes, blastocysts and foetuses from AMA mice (8–16 months old) to those from young maternal age (YMA, 3–4 months old) controls and featured an embryo transfer (ET) of AMA blastocysts into young surrogates and longitudinal, lineage-specific tracking up to the fourth generation (F4). PARTICIPANTS/MATERIALS, SETTING, METHODS Complementary approaches, including LC-MS proteomics and lipidomics, MALDI-TOF/TOF MS, RNA sequencing, atomic force microscopy (AFM), Coherent Anti-Stokes Raman Scattering (CARS) chemical imaging microscopy, Raman and Fourier transform infrared (FTIR) spectroscopies, and histology were conducted on single oocytes, blastocysts and foetal structures (brain and yolk sac) from AMA and YMA mice. ET was utilised to decouple the oocyte derived phenotype from the effects of an ageing maternal uterine environment. MAIN RESULTS AND THE ROLE OF CHANCE AMA oocytes and preimplantation blastocysts exhibited significant lipid droplet and lipid membrane alterations, a higher relative absorbance of intracellular lipid bands, and altered expression of lipid-regulatory transcripts, corresponding to early embryonic pathway shifts. Following the embryo transfer of AMA blastocysts to young surrogates (ET AMA group), distinct lipidomic variations and structural alterations were observed in the F1 yolk sac and foetal brains. Furthermore, these lipid-associated spectral and molecular signatures displayed intergenerational persistence, tracking through the yolk sac, brain and oocytes of the third- (F3) and fourth-generation (F4) descendants derived from the oocyte of AMA progenitors. LARGE SCALE DATA The transcriptomic data have been deposited in the NCBI Gene Expression Omnibus (GEO) under accession number GSE349634. Processed transcriptomic, lipidomic and proteomic datasets, together with the shared transcript–protein analysis, have been deposited in RODBUK under DOI https://doi.org/10.57903/UJ/LVQ7FU. All datasets are publicly available. LIMITATIONS, REASONS FOR CAUTION This study was conducted exclusively in a mouse model. Given species-specific variations in baseline oocyte lipid content and developmental kinetics, these findings require cautious interpretation before extrapolation to human clinical contexts. Additionally, the exact molecular and epigenetic mechanisms underlying the intergenerational persistence of these lipid signatures warrant further characterisation. WIDER IMPLICATIONS OF THE FINDINGS These findings demonstrate an association between early-life oocyte lipid changes and downstream pathway-level molecular signatures of neurodevelopmental alterations. By establishing an intergenerational pathway that persists independently of the maternal uterine environment, this work introduces a novel framework linking metabolic programming at conception to neurodevelopmental outcomes, offering new directions for reproductive medicine and translational neuroscience. FUNDING This research was funded by National Science Centre of Poland Grants 2021/41/B/NZ3/03507 and 2019/35/B/NZ4/03547 (to G.E.P.), 2022/44/C/NZ4/00076 (to M.F.H.) and 2019/35/N/NZ3/03213 (to Ł.G.), and the program “Excellence initiative–research university” for the AGH University of Krakow (ABK). Proteomics was supported by the subsidy no 16.16.160.557 of the Polish Ministry of Science and Higher Education (to PS). Raman analysis at the National Synchrotron Radiation Centre SOLARIS was supported by the Ministry of Science and Higher Education, Poland, under contract no. 1/SOL/2021/2. DISCLOSURES The authors declare no competing interests.