Micro- and nanoplastics (MNPs) are increasingly recognized as reproductive toxicants in aquatic organisms. Although numerous in vivo and in vitro studies have documented MNPs-induced reproductive damage, the underlying molecular mechanisms remain poorly understood. The SIRT protein family, a group of NAD+-dependent histone deacetylases, plays important roles in regulation of reproductive function. This study aims to systematically elucidate the role of the SIRT proteins in mediating responses to polystyrene nanoplastics (PS-NPs) in female zebrafish. Adult female zebrafish were exposed to a range of PS-NPs concentrations. Exposure resulted in a dose-dependent reduction in the gonadosomatic index (GSI), fecundity, spawning capacity, fertilization rate and hatching rate of offspring. Significant changes in SIRT family gene expression were also observed. Molecular docking analysis indicated that PS-NPs can bind to and potentially inhibit all SIRT isoforms. To further investigate the role of SIRT proteins, zebrafish were co-exposed to 1.5 mg/L PS-NPs with the SIRT activator resveratrol (RSV) or the SIRT inhibitor nicotinamide (NAM). RSV significantly upregulated ovarian SIRTs expression, attenuated PS-NPs-induced increase in reactive oxygen species, and loss of mitochondrial membrane potential in ovarian follicles. In contrast, NAM suppressed SIRTs expression and exacerbated these mitochondrial and oxidative defects. qPCR revealed that RSV increased transcription of antioxidant genes (NRF, SOD, CAT, GPX) and mitochondrial fusion/biogenesis genes (OPA1, MFN1/2, TFAM), while decreasing the fission gene (DRP1), whereas NAM produced the opposite effects pattern. Together, these results implicate SIRT proteins in protecting ovarian function against PS-NPs toxicity and suggest SIRT modulation as a potential mechanism underlying MNP-induced female reproductive dysfunction.
