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

  • Toxicology. 2026 Jun:523:154449. doi: 10.1016/j.tox.2026.154449.
Haitao Yang  1 ,  Liqing Wu  1 ,  Shuyan Niu  1 ,  Menghao Guo  1 ,  Chenyu Liu  1 ,  Tianshu Wu  1 ,  Mengjing Cui  1 ,  Yuying Xue  2
Affiliations
  • 1. Key Laboratory of Environmental Medicine and Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing 210009, China.
  • 2. Key Laboratory of Environmental Medicine and Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing 210009, China. Electronic address: [email protected].
PMID: 41833704 DOI: 10.1016/j.tox.2026.154449
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/CA2 + /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.
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