Sight of Aged Microplastics\nAdsorbing Heavy Metal\nExacerbated Intestinal Injury: A Mechanistic Study of Autophagy-Mediated\nToxicity Response

Contaminant-bearing polystyrene microplastics (PSMPs)\nmay exert\nsignificantly different toxicity profiles from their contaminant-free\ncounterparts, with the role of PSMPs in promoting contaminant uptake\nbeing recognized. However, studies investigating the environmentally\nrelevant exposure and toxic mechanisms of aged PSMPs binding to Cr\nare limited. Here, we show that loading of chromium (Cr) markedly\nalters the physicochemical properties and toxicological profiles of\naged PSMPs. Specifically, Cr-bearing aged PSMPs induced severe body\nweight loss, oxidative stress (OS), autophagy, intestinal barrier\ninjury, inflammation–pyroptosis response, and enteropathogen\ninvasion in mice. Mechanistic investigations revealed that PSMPs@Cr\nexacerbated the OS, resulting in intestinal barrier damage and inflammation–pyroptosis\nresponse via overactivated Notch signaling and autophagy/cathepsin\nB/IL-1β pathway, respectively, which ultimately elevated mortality\nrelated to bacterial pathogen infection. In vitro experiments confirmed\nthat autophagy-mediated reactive oxygen species (ROS) overproduction\nresulted in severe pyroptosis and impaired intestinal stem cells differentiation\nalongside the overactivation of Notch signaling in PSMPs@Cr-exposed\norganoids. Overall, our findings provide an insight into autophagy-modulated\nROS overproduction within the acidic environment of autophagosomes,\naccelerating the release of free Cr from PSMPs@Cr and inducing secondary\nOS, revealing that PSMPs@Cr is a stable hazard material that induces\nintestinal injury. These findings provided a potential therapeutic\ntarget for environmental MPs pollution caused intestinal disease in\npatients.