Plastic poisoning the next generation: omics-anchored partial-adverse outcome pathway affords a glimpse into how gestational polystyrene nano-plastics exposure compromises adult male offspring reproduction

Ubiquitous environmental nano-plastics (NPs) can enter organisms via multiple pathways, posing potential health risks; however, the adverse effects of gestational polystyrene NPs (PS-NPs) exposure on adult offspring reproductive function and underlying mechanisms remain unclear. The adverse outcome pathway (AOP) framework models toxic events from molecular to organismal levels. This study employed multi-omics analysis to construct a putative partial-AOP network, revealing insights into the mechanism of intergenerational reproductive impairment of PS-NPs in adult offspring. Gestational PS-NPs exposure induced testicular structural damage and abnormal spermatogenesis in adult male offspring. The testicular transcriptomic and serum metabolomic data integration, validation and the omics-anchored AOP network construction highlighted four molecular events in adult male offspring following gestational PS-NPs exposure: increased arachidonic acid release, elevated reactive oxygen species levels, increased palmitic acid levels, and decreased lysophosphatidyl choline levels. These molecular events might be implicated in a series of cellular key events (KEs), ranging from cellular damage and impaired proliferation to cell death. These cellular KEs could contribute to testicular cell reduction and organ-level KEs-testicular injury, reduced androgen secretion, and impaired spermatogenesis-culminating in the adverse outcome of reproductive dysfunction. This putative network characterizes the molecular and histopathological landscape of reproductive impairment in adult male offspring associated with gestational PS-NPs exposure, and provides clues for elucidating the intergenerational toxicity mechanisms of PS-NPs.