Mitochondrial-Endocrine Axis Dysfunction Mediates Diet-Dependent Susceptibility to Nanoplastic Ovarian Toxicity and PCOS Risk

Abstract Nanoplastics (NPs) pollution represents an emerging threat to reproductive health, yet how dietary habits modulate this toxicity remains largely unexplored. Here, mice were assigned to a control (CD), high-fat (HFD), or high-fiber (HFib) diet and received oral doses of deuterated polystyrene nanoparticles at 0, 5, or 25 mg/kg/day over an eight-week period. Ovarian NP accumulation was dose-dependent under CD, reaching 23.33 ± 5.39 μg/g tissue at the highest dose. HFD markedly elevated this burden to 96.87 ± 13.44 μg/g, whereas HFib significantly reduced it to 7.77 ± 1.32 μg/g. Functionally, HFD synergized with NPs to disrupt estrous cyclicity (only 13% regular cycles), suppress anti-Müllerian hormone by 74%, and increase follicular atresia rate, while HFib maintained near-normal ovarian physiology. Transcriptomics identified steroid hormone biosynthesis and oxidative phosphorylation (OXPHOS) as core pathways convergently dysregulated by NPs across all diets. Mechanistically, HFD amplified NP-induced ovarian oxidative stress, inflammation, and mitochondrial OXPHOS impairment, culminating in hyperandrogenism and profound estradiol deficiency. Conversely, HFib preserved aromatase expression and mitochondrial respiratory capacity, thereby restoring steroidogenic homeostasis. Mendelian randomization further linked human orthologues of these dysregulated genes, including UQCR10 and COX4I1 encoding mitochondrial complex III and IV subunits, to elevated polycystic ovary syndrome (PCOS) risk, highlighting the central role of OXPHOS disruption. These findings establish a diet-NP interaction pattern with implications for reproductive health guidance in populations.