Involvement of the heat shock response (HSR) regulatory pathway in cadmium-elicited cerebral damage.

The heat shock response (HSR) is a cellular protective mechanism that is characterized by the induction of heat shock transcription factors (HSFs) and heat shock proteins (HSPs) in response to diverse cellular and environmental stressors, including cadmium (Cd). However, little is known about the relationship between the damaging effects of Cd and the HSR pathway in the chicken cerebrum following Cd exposure. To explore whether Cd exposure elicits cerebral damage and triggers the HSR pathway, chicks were exposed to Cd in the daily diet at different concentrations (35, 70, or 140 mg/kg feed) for 90 days, while a control group was fed the standard diet without Cd. Histopathological examination of cerebral tissue from Cd-exposed chickens showed neuronal damage, as evidenced by swelling and degeneration of neurons, loss of neurons, and capillary damage. Cd exposure significantly increased mRNA expression of HSF1, HSF2, and HSF3, and mRNA and protein expression of three major stress-inducible HSPs (HSP60, HSP70, and HSP90). Moreover, Cd exposure differentially modulated mRNA expression of small HSP (sHSPs), most notably reducing expression of HSP27 (HSPB1). Furthermore, Cd exposure increased TUNEL-positive neuronal apoptotic cells and up-regulated protein expression of caspase-1, caspase-8, caspase-3, and p53, leading to apoptosis. Taken together, these data demonstrate that activation of the HSR and apoptotic pathways by Cd exposure is involved in Cd-elicited cerebral damage in the chicken. Synopsis for the graphical abstract Cadmium (Cd)-induced neuronal damage triggers the heat shock response (HSR) by activating heat shock transcription factors (HSFs) and subsequent induction of major heat shock proteins (notably, HSP60, HSP70, and HSP90). Moreover, Cd exposure activates caspase-1, caspase-8, caspase-3, and p53 protein, thereby resulting in neuronal apoptosis in the chicken brain.

Cerebellar injury induced by cadmium via disrupting the heat-shock response.

Cadmium (Cd) is a food contaminant that poses serious threats to animal health, including birds. It is also an air pollutant with well-known neurotoxic effects on humans. However, knowledge on the neurotoxic effects of chronic Cd exposure on chicken is limited. Thus, this study assessed the neurotoxic effects of chronic Cd on chicken cerebellum. Chicks were exposed to 0 (control), 35 (low), and 70 (high) mg/kg of Cd for 90 days, and the expression of genes related to the heat-shock response was investigated. The chickens showed clinical symptoms of ataxia, and histopathology revealed that Cd exposure decreased the number of Purkinje cells and induced degeneration of Purkinje cells with pyknosis, and some dendrites were missing. Moreover, Cd exposure increased the expression of heat-shock factors, HSF1, HSF2, and HSF3, and heat-shock proteins, HSP60, HSP70, HSP90, and HSP110. These changes indicate that HSPs improve the tolerance of the cerebellum to Cd. Conversely, the expressions of HSP10, HSP25, and HSP40 were decreased significantly, which indicated that Cd inhibits the expression of small heat-shock proteins. However, HSP27 and HSP47 were upregulated following low-dose Cd exposure, but downregulated under high-dose Cd exposure. This work sheds light on the toxic effects of Cd on the cerebellum, and it may provide evidence for health risks posed by Cd. Additionally, this work also identified a novel target of Cd exposure in that Cd induces cerebellar injury by disrupting the heat-shock response. Cd can be absorbed into chicken's cerebellum through the food chain, which eventually caused cerebellar injury. This study provided a new insight that chronic Cd-induced neurotoxicity in the cerebellum is associated with alterations in heat-shock response-related genes, which indicated that Cd through disturbing heat-shock response induced cerebellar injury.

Cadmium Through Disturbing MTF1-Mediated Metal Response Induced Cerebellar Injury.

Cadmium (Cd) is a toxic environmental contaminant, which bio-accumulate in animals through the food chain. Cerebellum is one of the primary target organs for Cd exposure. In this study, we established a chronic Cd exposure model; 60 chickens were treated with Cd (0 mg/kg, 35 mg/kg, 70 mg/kg) for 90 days. Clinical manifestations indicated that the chicken was depressed and has unstable gait under Cd exposure. Histopathological results indicated that Cd induced neuronal shrunken and indistinct nucleoli, and the number of Purkinje cells decreased significantly. Cerebellar metal contents were analyzed by ICP-MS. We found that Cd caused Cd and Cu accumulation and decreased the content of Se, Fe, and Zn, suggesting that Cd disturbed metal homeostasis. Besides, Cd treatment group also showed high levels of malondialdehyde (MDA) and hydrogen peroxide (H2O2) content and inhibited selenoprotein transcriptome, suggesting that Cd exposure resulted in oxidative stress. Notably, low-dose Cd exposure activated MTF1 mRNA and protein expression and its target metal-responsive genes, including MT1, MT2, DMT1, ZIP8, ZIP10, TF, and ATP7B which indicate cellular adaptive response against Cd-induced damage. On the other hand, 70 mg/kg Cd downregulated MTF1-mediated metal response, which was involved in Cd-induced cerebellar injury in chicken. In conclusion, our data demonstrated that molecular mechanisms are associated with Cd-induced cerebellar injury due to disturbing MTF1-mediated metal response. This study indicated that the cerebellum is one of the target organs of Cd-induced toxicity. Additionally, Cd exposure induced metal dyshomeostasis in chicken's cerebellum, whereas this study found that lower level of Cd dose triggered the activation of the cytoprotective mechanism through activating the expression of MTF1 which regulate MT1, MT2, DMT1, ZIP8, ZIP10, TF, and ATP7B expressions in cerebellum. However, MTF1-mediated metal response was inhibited under the exposure of high dose of Cd, which ultimately caused cerebellar injury. The present study provides a new insight that Cd through disturbed MTF1-mediated metal response disrupts metal homeostasis that induced cerebellar injury.

Nano-selenium alleviates cadmium-induced cerebellar injury by activating metal regulatory transcription factor 1 mediated metal response.

This study aims to investigate the role of metal regulatory transcription factor 1 (MTF1)-mediated metal response in cadmium (Cd)-induced cerebellar injury, and to evaluate the antagonistic effects of nano-selenium (Nano-Se) against Cd toxicity. A total of 80 chicks (1 d old, male, Hy-Line Variety White) were randomly allocated to 4 treatment groups for 3 months: the control group (fed with a basic diet, n = 20), the Nano-Se group (basic diet with 1 mg/kg nano-Se 1 mg/kg Nano-Se in basic diet, n = 20), the Nano-Se + Cd group (basic diet with 1 mg/kg Nano-Se and 140 mg/kg CdCl2, n = 20) and the Cd group (basic diet with 140 mg/kg CdCl2 , n = 20). The results of the experiment showed that the Purkinje cells were significantly decreased with their degradation and indistinct nucleoli after Cd exposure. Moreover, exposure to Cd caused a significant accumulation of Cd and cupper. However, the contents of Se, iron, and zinc were decreased, thereby disturbing the metal homeostasis in the cerebellum. The Cd exposure also resulted in high levels of malondialdehyde (MDA) and down regulation of selenoprotein transcriptome. Furthermore, the expressions of MTF1, metallothionein 1 (MT1), MT2, zinc transporter 3 (ZNT3), ZNT5, ZNT10, zrt, irt-like protein 8 (ZIP8), ZIP10, transferrin (TF), ferroportin 1 (FPN1), ATPase copper transporting beta (ATP7B), and copper uptake protein 1 (CTR1) were inhibited by Cd exposure. However, all these changes were significantly alleviated by the supplementation of Nano-Se. This study proved that Cd could disorder metal homeostasis and induce oxidative stress, whereas Nano-Se could relieve all these negative effects caused by Cd via activating the MTF1-mediated metal response in the cerebellum of chicken.

The protective effect of nnano-selenium against cadmium-induced cerebellar injury via the heat shock protein pathway in chicken.

Cadmium (Cd) is one of the toxic environmental heavy metals that poses health hazard to animals due to its toxicity. Nano-Selenium (Nano-Se) is a Nano-composite form of Se, which has emerged as a promising therapeutic agent for its protective roles against heavy metals-induced toxicity. Heat shock proteins (HSPs) play a critical role in cellular homeostasis. However, the potential protective effects of Nano-Se against Cd-induced cerebellar toxicity remain to be illustrated. To investigate the toxic effects of Cd on chicken's cerebellum, and the protective effects of Nano-Se against Cd-induced cerebellar toxicity, a total of 80 male chicks were divided into four groups and treated as follows: (A) 0 mg/kg Cd, (B) 1 mg/kg Nano-Se (C) 140 mg/kg Cd + 1 mg/kg Nano-Se (D) 140 mg/kg Cd for 90 days. We tested heat shock protein pathway-related factors including heat shock factors (HSFs) HSF1, HSF2, HSF3 and heat shock proteins (HSPs) HSP10, HSP25, HSP27, HSP40, HSP60, HSP70 and HSP90 expressions. Histopathological results showed that Cd treatment caused degradation of Purkinje cells. In addition, HSFs and HSPs expression decreased significantly in the Cd group. Nano-Se co-treatment with Cd enhanced the expression of HSFs and HSPs. In summary, our findings explicated a potential protective effect of Nano-Se against Cd-induced cerebellar injury in chicken, suggesting that Nano-Se is a promising therapeutic agent for the treatment of Cd toxicity.

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.

Selenium sources differ in their potential to alleviate the cadmium-induced testicular dysfunction.

Cadmium (Cd), a major environmental contaminant, is closely associated with male reproductive health. Selenium (Se) has been recognized as an effective chemo-protectant against Cd toxicity, but the underlying mechanisms remain unclear. The objective of present study was to illustrate the toxic effect of Cd on testis, and then compare the antagonistic effect among different Se sources on growth performance, testicular damage, ion homeostasis, antioxidative potential, and the expression of selenotranscriptome and biosynthetic related factors in Cd-treated chicken. Male chickens were fed with (Ⅰ) Control group: basal diet; (Ⅱ) Cd group: basal diet with 140 mg/kg CdCl2; (Ⅲ) YSe + Cd group: basal diet with 140 mg/kg CdCl2 and 3 mg/kg Yeast-Se; (Ⅳ) NSe + Cd group: basal diet with 140 mg/kg CdCl2 and 1 mg/kg Nano-Se; (Ⅴ) SSe + Cd group: basal diet with 140 mg/kg CdCl2 and 3 mg/kg Na2SeO3. It was observed that different Se treatments dramatically alleviated Cd-induced testicular developmental disorder, ion homeostasis disorder, hormone secretion disorder and oxidative stress. Simultaneously, Se mitigated Cd-induced testicular toxicity by regulating selenoprotein biosynthetic related factors to promote selenoprotein transcription. Finally, this study indicated that dietary supplementation of Yeast-Se produced an acceptable Se form to protect testis from Cd exposure.