Thiram Disrupts Hepatic and Tibial Calcium Homeostasis via ER Stress-Mediated IP3R1/VDAC1 Hyperactivation

Thiram is an agricultural fungicide known to disrupt cellular calcium homeostasis by inducing endoplasmic reticulum (ER) stress and mitochondrial calcium overload in hepatic and growth plate (GP) tissues. Current study investigated thiram-induced alterations at mitochondria-associated membranes (MAMs) and their impact on inter-organ calcium signaling. Following thiram exposure in chickens, hepatic ER stress markers GRP78 and CHOP, along with key calcium-transfer proteins mediating ER-mitochondrial coupling, including inositol 1,4,5-trisphosphate receptor 1 (IP3R1) and voltage-dependent anion channel 1 (VDAC1), were significantly upregulated. Importantly, hepatic ER stress driven hyperactivation of IP3R1/VDAC1 signaling was accompanied by parallel calcium dysregulation and mitochondrial stress responses in the tibial growth plate, providing direct evidence that liver ER stress acts upstream of skeletal calcium imbalance. These findings establish a previously unrecognized liver-bone axis in which thiram-induced hepatic ER stress propagates calcium signaling disturbances to the growth plate, thereby disrupting chondrocyte calcium homeostasis and bone development. Collectively, this study elucidates a mechanistic framework linking MAM-mediated calcium-transfer, ER stress, and cross-organ communication, offering new insights into how toxicant-induced hepatic stress orchestrates systemic calcium metabolism and skeletal pathology.