Hereditary PCOS and the environmental toxicant F-53B converge on lipid metabolic reprogramming to impair fetal brain development

Polycystic ovary syndrome (PCOS) is associated with an increased risk of neurodevelopmental disorders in offspring, yet how maternal PCOS interacts with environmental toxicants to influence fetal brain development remains unclear.We hypothesized that an AMH-programmed PCOS-like background increases neurodevelopmental vulnerability, which is worsened by gestational F-53B exposure through lipid metabolic reprogramming. Our study reveals how endocrine-metabolic dysfunction and environmental toxicants interact to impact fetal brain development. F0 dams were exposed to anti Müllerian hormone in late gestation to generate PCOS like F1 females and simultaneously received F-53B or vehicle, yielding four groups: Con, AMH, F-53B, and AF. F1 females from AMH lineages exhibited reproductive abnormalities characteristic of PCOS, which were most pronounced in the AF group. Bulk RNA sequencing of E14.5 F2 embryonic brains revealed progressive transcriptomic divergence across groups, with AF embryos showing the greatest shift from controls. Genes differentially expressed in both the F-53B vs Con and AF vs AMH comparisons were enriched in lipid metabolism and PPAR-related pathways, accompanied by graded upregulation of Cidec , Plin1 , Fabp4 , and Pparg and reciprocal downregulation of Aqp7 , which was confirmed at the protein level for CIDEC, PLIN1, and AQP7. At the cellular level, AF embryos exhibited the most severe neurodevelopmental defects, including loss of TBR2⁺ positive intermediate progenitors, reduced TBR1⁺ and SATB2⁺ cortical neurons, diminished Neurod1⁺ and Tuj1⁺ expression, and decreased Olig2⁺ positive oligodendroglial cells. We hypothesized that an AMH-programmed PCOS-like background would prime offspring for subtle neurodevelopmental vulnerability, F-53B exposure during pregnancy would induce lipid metabolic reprogramming in the offspring fetal brain, and the combination of AMH-induced PCOS-like programming and F-53B exposure would exert ‘two-hit’ effects, leading to the greatest disruption of neurogenesis and gliogenesis. By linking an emerging PFAS alternative to mechanistically grounded alterations in fetal brain lipid metabolism and neural lineage development on a PCOS-like background, our work provides an integrated framework for understanding how endocrine–metabolic disorders and environmental contaminants converge to shape neurodevelopmental risk.