Co-exposure to polystyrene nanoplastics and cadmium induces apoptosis in intestinal cells: Role of the IP3R/Ca²⁺/STAT3 signaling pathway

Abstract

The widespread use of plastic products has elevated nanoplastics (NPs) pollution to a critical global concern, with polystyrene nanoplastics (PS-NPs) and cadmium (Cd) emerging as common environmental contaminants whose co-occurrence and combined toxicity increasingly alarm the scientific community. The intestine, as the main xenobiotic exposure site, is a primary target for PS-NPs and Cd exposure-individually or combined. While PS-NPs and Cd's individual intestinal toxicity mechanisms are well-studied, their combined effects remain poorly understood, especially at the molecular level. This study investigated the combined effects of environmentally relevant concentrations of PS-NPs and Cd on intestinal apoptosis and the regulatory role involving the IP3R/Ca^{2 +} /STAT3 pathway using both C. elegans and Caco-2 cell models. In C. elegans, 72-hour PS-NPs (10 μg/L) and Cd (5 μg/L) co-exposure induced developmental retardation, intestinal structural abnormalities, and dysregulated expression of apoptosis-related genes along with key components of the IP3R/Ca²⁺/STAT3 pathway. Parallel experiments in Caco-2 cells demonstrated that 24-hour co-treatment with PS-NPs (20 μg/mL) and Cd (0.25 μg/mL) significantly elevated apoptosis rates and triggered endoplasmic reticulum stress. Molecular analyses revealed these effects were mediated through increased IP3R phosphorylation, elevated cytosolic Ca²⁺ concentrations, and enhanced phosphorylation of the downstream effector STAT3. Notably, pharmacological inhibition of IP3R (2-APB, 10 μM), Ca²⁺ chelation (BAPTA, 10 μM), or STAT3 phosphorylation (stattic, 5 μM) significantly attenuated PS-NPs and Cd-induced apoptosis. These results establish the IP3R/Ca²⁺/STAT3 axis as a pivotal regulatory switch governing intestinal apoptosis under NP-heavy metal co-exposure, providing mechanistic foundations for environmental risk assessment of combined pollutant exposure.

Keywords: Apoptosis; Calcium ions; Cd; Co-exposure; Intestinal toxicity; PS-NPs.