Key Laboratory of Molecular Animal Nutrition, Ministry of Education, College of Animal Sciences, Zhejiang University, Hangzhou 310058, China.
Agrobiology and Environmental Sciences Center, Zhejiang University, Hangzhou 310058, China.
ACS Nano. 2024 Oct 22;18(42):28849-28865. doi: 10.1021/acsnano.4c08737. Epub 2024 Oct 11.
Contaminant-bearing polystyrene microplastics (PSMPs) may exert significantly different toxicity profiles from their contaminant-free counterparts, with the role of PSMPs in promoting contaminant uptake being recognized. However, studies investigating the environmentally relevant exposure and toxic mechanisms of aged PSMPs binding to Cr are limited. Here, we show that loading of chromium (Cr) markedly alters the physicochemical properties and toxicological profiles of aged PSMPs. Specifically, Cr-bearing aged PSMPs induced severe body weight loss, oxidative stress (OS), autophagy, intestinal barrier injury, inflammation-pyroptosis response, and enteropathogen invasion in mice. Mechanistic investigations revealed that PSMPs@Cr exacerbated the OS, resulting in intestinal barrier damage and inflammation-pyroptosis response via overactivated Notch signaling and autophagy/cathepsin B/IL-1β pathway, respectively, which ultimately elevated mortality related to bacterial pathogen infection. In vitro experiments confirmed that autophagy-mediated reactive oxygen species (ROS) overproduction resulted in severe pyroptosis and impaired intestinal stem cells differentiation alongside the overactivation of Notch signaling in PSMPs@Cr-exposed organoids. Overall, our findings provide an insight into autophagy-modulated ROS overproduction within the acidic environment of autophagosomes, accelerating the release of free Cr from PSMPs@Cr and inducing secondary OS, revealing that PSMPs@Cr is a stable hazard material that induces intestinal injury. These findings provided a potential therapeutic target for environmental MPs pollution caused intestinal disease in patients.
含污染物的聚苯乙烯微塑料 (PSMPs) 可能表现出与不含污染物的 PSMPs 显著不同的毒性特征，PSMPs 促进污染物吸收的作用已得到认可。然而，研究 PSMPs 与 Cr 结合的环境相关暴露和毒性机制的研究有限。在这里，我们表明 Cr 的负载显著改变了老化 PSMPs 的物理化学性质和毒理学特征。具体来说，含 Cr 的老化 PSMPs 可诱导小鼠体重明显减轻、氧化应激 (OS)、自噬、肠道屏障损伤、炎症-焦亡反应和肠道病原体入侵。机制研究表明，PSMPs@Cr 通过过度激活 Notch 信号和自噬/组织蛋白酶 B/IL-1β途径，分别加剧 OS，导致肠道屏障损伤和炎症-焦亡反应，从而增加与细菌病原体感染相关的死亡率。体外实验证实，自噬介导的活性氧 (ROS) 过度产生导致严重的焦亡和肠道干细胞分化受损，同时 PSMPs@Cr 暴露的类器官中的 Notch 信号过度激活。总体而言，我们的研究结果提供了一个深入了解自噬调节的 ROS 过度产生的机制，即在自噬体的酸性环境中，加速了从 PSMPs@Cr 中释放游离 Cr，并引发二次 OS，表明 PSMPs@Cr 是一种稳定的危险物质，可导致肠道损伤。这些发现为环境 MPs 污染引起的患者肠道疾病提供了一个潜在的治疗靶点。
