Molecular mechanisms underlying altered neurobehavioural development of female offspring of mothers with polycystic ovary syndrome: FOS-mediated regulation of neurotrophins in placenta

Abstract

Background This study explored the mechanisms underlying altered neurobehavioural development of female offspring born to mothers with polycystic ovary syndrome (PCOS). Methods In total, 20 women with PCOS and 32 healthy women who underwent caesarean deliveries with a single female foetus were recruited. Infants were assessed with Dubowitz scoring. Swan71 cell line with stable FOS overexpression was used to verify the regulatory effects of FOS on brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) expression. Learning and memory in female first-generation (F1) and second-generation (F2) offspring in a rat model of PCOS was tested using the Morris water maze at puberty and adulthood. Transcriptome analysis of pubertal hippocampi and hypothalami of female F1 offspring was conducted. Findings Total score and behaviour subscales of Dubowitz scoring were significantly lower in female infants of women with PCOS. FOS and NGF protein levels were downregulated in placental villi of the PCOS group. FOS played a key role in BDNF inhibition and enhancing NGF in Swan71 cells. PCOS female F1 rats exhibited lower target crossing times during puberty when compared to controls. Transcriptome analysis revealed significant changes in hippocampal and hypothalamic neuronal pathways in female F1 rats at puberty. Interpretation FOS regulation of neurotrophins in the placenta negatively affects neurobehavioural development of female offspring of PCOS mothers. Funding This study was funded by the National Key R&D Program of China (2018YFC1004900 to F.Q. and F.W.) and the National Natural Science Foundation of China (81874480 to F.Q.; 81873837 to F.W.).

Aberrant miRNA-mRNA regulatory network in polycystic ovary syndrome is associated with markers of insulin sensitivity and inflammation

“…SPI1 was reported as an ETS transcription factor involved in the androgen-mediated transcriptional regulation of NR4A1 in PCOS (42). FOS was reported to mediate the regulation of neurotrophins in the placenta of female offspring of mothers with PCOS (43). The target gene Arntl was reported to affect PCOS by altering the circadian clock (44).…”

Neurobehavioral alternations of the female offspring born to polycystic ovary syndrome model rats administered by Chinese herbal medicine

“…To further investigate the mechanism of action of BSTJF on female offspring born to PCOS, based on our previous work [ 27 ], immunohistochemistry was used to observe the expression of Gabrb1, Grin2b, and Adra1b in the dentate gyrus of female offspring rats. Anti-Gabrb1 (1:100; Affinity Biosciences, LTD., Jiangsu, China; no.…”

“…In our previous study, FOS protein levels were found to be downregulated in the placental villi of the PCOS group [ 27 ]. We also found that Gabrb1, Grin2b, and Adra1b, which are enriched in the neuroactive ligand-receptor interaction pathway, were expressed differently (compared with the controls) in the hippocampus of female offspring of PCOS model rats by analyzing transcriptomic data and KEGG pathway enrichment [ 27 ].…”

“…In our previous study, FOS protein levels were found to be downregulated in the placental villi of the PCOS group [ 27 ]. We also found that Gabrb1, Grin2b, and Adra1b, which are enriched in the neuroactive ligand-receptor interaction pathway, were expressed differently (compared with the controls) in the hippocampus of female offspring of PCOS model rats by analyzing transcriptomic data and KEGG pathway enrichment [ 27 ]. Many studies have found that PCOS affects the neural development of progeny, such as autism spectrum disorder [ 28 ], attention deficit hyperactivity disorder [ 29 ], anxiety and emotional borderline symptoms [ 30 ].…”

Oxidized high‐density lipoprotein enhances endocrine disorders and ovarian damage in rats

“…However, the effect of miR‐34a on PCOS is scarcely understood. A prior study revealed the presence of decreased levels of FOS protein level in placental villi of the PCOS rats 10 and in ovarian tissues of PCOS patients 11 . An analysis of human genomic sequences from the tentative promoter of miR‐34a gene showed the presence of NF‐κB, c‐FOS and p53 response elements 12 .…”