Cadmium induced cerebral toxicity via modulating MTF1-MTs regulatory axis

Metal-responsive transcription factor 1 (MTF1) participates in redox homeostasis and heavy metals detoxification via regulating the expression of metal responsive genes. However, the exact role of MTF1 in Cd-induced cerebral toxicity remains unclear. Herein, we explored the mechanism of Cd-elicited cerebral toxicity through modulating MTF1/MTs pathway in chicken cerebrum exposed to different concentrations of Cd (35 mg, 70 mg, and 140 mg/kg CdCl2) via diet. Notably, cerebral tissues showed varying degrees of microstructural changes under Cd exposure. Cd exposure significantly up-regulated the expression of metal transporters (DMT1, ZIP8, and ZIP10) with concomitant elevated Cd level, as determined by ICP-MS. Cd significantly altered other cerebral biometals concentrations (particularly, Zn, Fe, Se, Cr, Mo, and Pb) and redox balance, resulting in increased cerebral oxidative stress. More importantly, Cd exposure suppressed MTF1 mRNA and nuclear protein levels and its target metal-responsive genes, notably metallothioneins (MT1 and MT2), and Fe and Cu transporter genes (FPN1, ATOX1, and XIAP). Moreover, Cd disrupted the regulation of expression of selenoproteome (particularly, GPxs and SelW), and cerebral Se level. Overall, our data revealed that molecular mechanisms associated with Cd-induced cerebral damage might include over-expression of DMT1, ZIP8 and ZIP10, and suppression of MTF1 and its main target metal-responsive genes as well as several selenoproteins. Environmentally relevant hazardous neurotoxic metal Cd uptake in neurons/nerve cells is mediated by over-expression of membrane metal transporters (DMT1, ZIP8, and ZIP10). Once inside the cerebral cells, Cd perturbed cerebral ionic homeostasis as well as redox balance and thereby induced oxidative stress. Meanwhile, Cd and/or Cd-mediated oxidative stress triggered the transcription factor MTF1 to translocate into the nucleus and thereby suppressing MTF1 and its major target metal-responsive genes (MT1, MT2, ATOX1, and FPN1), leading to neuronal damage. Moreover, Cd disrupted the regulation of the expression of cerebral selenoproteins. Above these pathways simultaneously induced dose-dependent cerebral toxicity. [Display omitted] •The MTF1 is the potential molecular target of Cd-induced cerebral toxicity.•Cd-induced overexpression of DMT1, ZIP8 and ZIP10 mediated cerebral Cd influx.•Cd induced oxidative stress by affecting bio-metals and redox homeostasis.•Cd induced cerebral toxicity via suppressing