The effects of how obesity and elevated androgen levels in women with polycystic ovary syndrome (PCOS) affect their offspring are unclear. We found that daughters of PCOS mothers are more likely to be diagnosed with PCOS in a Swedish nationwide register-based cohort and a clinical case-control study from Chile. Further, female mice (F0) with PCOS-like traits induced by late gestation injection of dihydrotestosterone, with and without obesity, produced female F1–F3 offspring with a PCOS-like reproductive and metabolic phenotypes. Sequencing of single MII oocytes from F1–F3 offspring revealed common and unique altered gene expression across all generations. Notably, four genes were also differentially expressed in serum samples from daughters in the case-control study and unrelated women with PCOS. Our findings provide evidence of transgenerational effects in female offspring of PCOS mothers and identify possible candidate genes for the prediction of a PCOS phenotype in future generations.

Data availability. Raw data of F1-F3 females and of clinical characteristics of daughters are available through https://datadryad.org/stash. All raw and analysed single cell RNA-sequencing data of mouse MII oocytes from F1-F3 females is available at GEO database via accession number GSE133100. Both will be released on publication.

For the Swedish register-based cohort, original data is held by Swedish National Board of Health and Welfare and Statistics Sweden and because of Swedish data privacy laws we cannot make the data publicly available. Any researcher can access the data by obtaining an ethical approval from a regional ethical review board and thereafter asking the Swedish National Board of Health and Welfare and Statistics Sweden for the original data. However, aggregated data used in the analysis of this study are available from the authors upon a reasonable request and with approved data sharing and data processing agreements in line with the General Data Protection Regulation (GDPR). Further use of this data must be authorized by the local ethics committee regarding the merit of the project involved. A detailed description of the unrelated case-control study including global gene expression analyzes is subcutaneous adipose tissue has previously been published²⁸.