# Dibutyl phthalate exposure induces thyroid toxicity through follicular cell pyroptosis via the NRF2/KEAP1/NF-κB pathway

## TL;DR

Exposure to dibutyl phthalate harms the thyroid by causing cell death and inflammation through specific molecular pathways.

## Contribution

This study reveals a novel mechanism of thyroid toxicity caused by dibutyl phthalate via NRF2/KEAP1/NF-κB pathway-mediated pyroptosis.

## Key findings

- DBP exposure caused systemic toxicity, reduced body weight, and increased oxidative stress markers.
- Thyroid dysfunction was observed with disrupted endocrine function and follicular morphology.
- DBP suppressed NRF2/KEAP1 and activated NF-κB, leading to pyroptosis in thyroid cells.

## Abstract

Dibutyl phthalate (DBP) is a plasticizer that bioaccumulates in organisms through multiple exposure routes. Although previous studies have documented DBP’s detrimental effects on the reproductive tract, liver, and neurodevelopment, the mechanisms underlying DBP-induced thyrotoxicity are inadequately understood.

To determine whether subchronic DBP exposure induces thyrotoxicity progression via thyroid follicular cell pyroptosis mediated by the NRF2/KEAP1/NF-κB pathway.

Four-week-old male C57BL/6 mice were exposed to 50 or 250 mg/kg DBP by gavage five times weekly for 8 weeks. Systemic toxicity was assessed through body weight measurements and serum oxidative stress markers. Thyroid endocrine function and follicular morphology were evaluated via histopathological analysis. The molecular pathways regarding thyrotoxicity were determined using immunofluorescence analysis.

DBP exposure induced systemic toxicity, as evidenced by reduced body weight and elevated serum oxidative stress markers. Thyroid dysfunction was observed, including disrupted endocrine function and altered follicular morphology, accompanied by increased apoptosis, macrophage infiltration, and excessive inflammatory cytokine production. Notably, DBP promoted pyroptosis in thyroid follicular cells, as indicated by upregulated expression of NLRP3, ASC, CASPASE-1, and GSDMD. Mechanistically, DBP suppressed the NRF2/KEAP1 antioxidative pathway while activating NF-κB signalling.

DBP induces thyrotoxicity through oxidative stress, inflammation, and pyroptosis, mediated by NRF2/KEAP1 suppression and NF-κB activation. These results provide novel insights into the mechanisms of DBP-induced thyroid damage and highlight potential health risks associated with prolonged exposure.