KEY POINTS
- Female C57BL/6J mice were assigned to irradiated and non-irradiated groups receiving either regular water or tetrathiomolybdate. The copper chelator was administered at 0.1 mg/mL from seven days before until seven days after irradiation, corresponding to approximately 230 µg per mouse per day.
- The neck region received a single 15-Gy X-ray dose. Salivary-gland collagen, epithelial morphology, tight-junction expression, copper availability, and pilocarpine-stimulated saliva secretion were assessed up to 30 days after irradiation.
- Systemic treatment reduced the copper-to-molybdenum ratio by 97% in serum (p<0.001) and 48% in submandibular glands (p<0.01). Plasma ceruloplasmin activity became nearly undetectable during treatment but returned to baseline within seven days after tetrathiomolybdate was stopped.
- Irradiated glands from mice receiving regular water showed a significant increase in collagen-positive area at days 14 and 30 (p<0.0001 versus non-irradiated controls). Collagen coverage in irradiated mice receiving tetrathiomolybdate did not differ significantly from non-irradiated controls.
- Irradiation reduced expression of the apical tight-junction protein ZO-1. By day 30, ZO-1 expression was significantly higher after tetrathiomolybdate than after irradiation alone (p<0.05), while E-cadherin expression remained unchanged across groups.
- At day 30, saliva flow was significantly higher in irradiated mice receiving tetrathiomolybdate than in irradiated controls (p=0.0412). Saliva flow did not differ significantly from that of non-irradiated controls (p=0.0839).
- The study did not quantify inflammatory cytokines, myofibroblast persistence, or lysyl-oxidase activity and did not formally monitor drug toxicity. Water consumption—and therefore systemic exposure—also varied between animals.
CLINICAL TAKEAWAY
Systemic copper chelation may interrupt early fibrotic remodelling and preserve salivary function after irradiation, offering a less invasive alternative to local drug delivery. The findings remain preclinical and require dose optimization, longer follow-up, safety assessment, and confirmation in clinically relevant fractionated-radiotherapy models.