Cadmium causes spleen toxicity in chickens by regulating mitochondrial unfolded protein response and nuclear receptors response

Cadmium (Cd) is a heavy metal that pollutes the environment and threatens human and animal health via the food chain. The spleen is one of the target organs affected by Cd toxicity. However, the mechanism of Cd toxicity is not fully understood. In this study, 80 chicks were allocated into 4 groups (n = 20) and exposed to different doses of CdCl2 (0 mg/kg, 35 mg/kg, 70 mg/kg and 140 mg/kg) for 90 days. The pathological changes in the spleen, mitochondrial dynamics-related factors, cytochrome P450 (CYP450) enzyme system contents, activities, transcription levels, nuclear receptors (NRs) response molecule levels, and mitochondrial unfolded protein-related factors were detected. The findings indicate that exposure to Cd significantly leads to spleen injury. In Cd groups, the total contents of CYP450 and cytochrome b5 (Cyt b5) increased, and the activities of the CYP450 enzyme system (APND, ERND, AH, and NCR) changed. The NRs response was induced, and the gene levels of AHR/CAR and corresponding CYP450 isoforms (CYP1B1, CYP1A5, CYP1A1, CYP2C18, CYP2D6 and CYP3A4) were found altered. The study found that Cd exposure altered the mRNA expression levels of mitochondrial dynamics-related factors, such as OPA1, Fis1, MFF, Mfn1, and Mfn2, breaking mitochondrial fusion and cleavage and ultimately leading to mitochondrial dysfunction. Changes were detected in the gene levels of several mitochondrial unfolded protein response (mtUPR)-related factors, namely (SIRT1, PGC-1α, NRF1, TFAM, SOD2, and HtrA2). Cd also altered the gene levels of mitochondrial function-related factors (VDAC1, Cyt-C, COA6, PRDX3, RAF and SIRT3). It is showed that Cd can initiate the NRs response, influence the homeostasis of the CPY450 enzyme system, trigger the mtUPR, impair mitochondrial function, and ultimately lead to Cd toxicity in the spleen of chickens.