Human-relevant exposure to mixtures of rare earth elements disrupts T3 homeostasis through impaired synthesis and conversion in human Thyrocytes.

Abstract

Despite epidemiological links between rare earth elements (REEs) exposure and thyroid dysfunction, health risks of chronic, low-dose mixture exposure in populations remain unknown. We exposed human thyroid follicular epithelial cells Nthy-ori 3-1 to a biomimetic 14-REE mixture, encompassing light (La, Ce, Pr, Nd, Sm, and Eu) and heavy (Gd, Tb, Dy, Ho, Yb, Lu, Sc, and Y) elements, at concentrations reflecting human internal exposure from 1× to 1000× serum background concentration (SBC). REEs significantly inhibited triiodothyronine (T3) secretion without affecting thyroxine (T4). This disruption was associated with dysregulation of the dual oxidase 1 (DUOX1)/catalase (CAT)-mediated H₂O₂ redox system involved in thyroid hormone synthesis, together with impaired deiodinase-mediated T4-to-T3 conversion. Upregulation of DUOX1 and thyroid peroxidase (TPO), alongside NRF2-mediated defense activation, was significantly initiated at the 1× SBC level, indicating high sensitivity to background environmental concentrations. REE-induced oxidative stress triggered mitochondrial damage and ATP depletion, which may be mechanistically linked to the impaired deiodinase-mediated T4-to-T3 conversion. Antioxidant intervention effectively restored mitochondrial integrity, ATP levels, and deiodinase activities, thereby rescuing T3 secretion. This study revealed a thyrotoxic mechanism of REEs under realistic exposure scenarios, providing critical evidence for assessing their environmental health risks.

Key Findings

• Exposure to a biomimetic mixture of rare earth elements (REEs) at human-relevant concentrations disrupted T3 secretion without affecting T4 in human thyroid cells.
• REEs induced dysregulation of the DUOX1/CAT-mediated H2O2 redox system and impaired deiodinase-mediated T4-to-T3 conversion.
• REE exposure triggered NRF2-mediated antioxidant defense activation, mitochondrial damage, ATP depletion, and oxidative stress, which were reversible with antioxidant intervention.

Clinical Significance

Citation

Chen Yu, Teng Mengying, Chen Yinuoet al.. Human-relevant exposure to mixtures of rare earth elements disrupts T3 homeostasis through impaired synthesis and conversion in human Thyrocytes. Toxicology and applied pharmacology. 2026-Jun-27.