Thiram-driven XBP1 and CHOP pathways orchestrate ER stress and avian tibial dyschondroplasia via metabolic inflammatory axis.

Thiram, one of the most widely used dithiocarbamate fungicides, has turned out to be a very potent cellular metabolic homeostasis disruptor through the induction of endoplasmic reticulum (ER) stress. The present study examines the mechanistic foundation of thiram-induced tibial dyschondroplasia in birds, emphasizing ER stress and inter-organ crosstalk. According to our findings, thiram caused impairment in the function of hepatocytes, as well as inducing an inflammatory cascade of signals in the tibial growth plate and liver tissues. This dual effect on tissue underlines the systemic disruption of the liver-bone axis characterized by inflammatory cytokine enrichment and metabolic dysregulation. Further, the impairment of pancreatic enzyme activities, as represented by the significant (P < 0.05) decrease in activities of amylase and lipase, suggested more far-reaching pathophysiological influence of thiram. To complement these outcomes, 16S rRNA sequencing uncovered considerable shifts in gut microbiota composition in thiram supplemented groups, leading to a dose-dependent decrease in microbial diversity, specifically at higher doses (G4). Therefore, results implicate thiram as an important etiological agent in tibial dyschondroplasia and other bone metabolic disorders through the induction of ER stress and inter-organ communication. These findings not only elucidate a novel mechanistic association between environmental toxicants and metabolic bone disease but also indicates the gut-liver-bone axis as a therapeutic target in avian metabolic bone diseases.