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Nickel (Ni) is the most important environmental pollution in the world. Ni has been confirmed to have multi-organ toxicology and carcinogenicity. Recently, Ni also can impair the male reproductive system, however, its precious mechanism still has not been clarified. The current work found that nickel chloride (NiCl 2) induced histopathological lesions in testis. And, the Johnsen's score, seminiferous tubule diameter, and spermatogenic epithelium thickness were decreased in NiCl 2 -treated mice. The number of spermatogonium, primary spermatocyte, and round spermatid also were significantly reduced after Ni treatment. Next the potential molecular mechanism was measured. NiCl 2 treatment elevated ROS production in the testis. Additionally, NiCl 2 was found to induce apoptosis with features including up-regulation of Bax, cleaved-caspase-3, cleaved-caspase-8, caspase-9, and caspase-12, while down-regulation of Bcl-2 expression. In the meantime, the marker protein of DNA damage γ-H2AX was significantly increased in NiCl 2 -primed mice testis. To clarify effects of reactive oxygen species (ROS) in apoptosis and DNA damage induced by NiCl 2 , NiCl 2 was used to co-treat antioxidant NAC (N-Acetyl-L-cysteine). NAC weakened ROS production induced by NiCl 2 , and played an inhibition role in apoptosis and DNA damage. Moreover, co-treatment using NiCl 2 and NAC group also eliminated spermatogenesis disorders. In summary, research results reveal the relations of spermatogenesis disorder induced by NiCl 2 with apoptosis and DNA damage mediated by ROS and apoptosis in the testis. [Display omitted] • NiCl 2 impairs histological structure in testis and epididymis. • NiCl 2 increases ROS, DNA damage and apoptosis in the testis. • ROS is an important primary inducer in Ni-induced sperm parameters disorder • NiCl 2 -induced spermatogenesis disorder is related to ROS-mediated apoptosis and DNA damage. [ABSTRACT FROM AUTHOR]

Nickel, as a widely polluted metal, has been shown nephrotoxicity. Ferroptosis is a new type of cell death driven by iron-dependent lipid peroxidation. Our study found that nickel chloride (NiCl 2) induced ferroptosis in mouse kidney and TCMK-1 cells. The iron content was significantly increased in the kidney and TCMK-1 cells after NiCl 2 treatment. Lipid peroxidation and MDA content were significantly increased, and GSH content and T-SOD activity were significantly decreased after exposure to NiCl 2. Moreover, NiCl 2 increased COX-2 protein levels, decreased SLC7A11 and GPX4 protein levels, and elevated Ptgs2 mRNA levels. Next, the mechanism of Ni-induced ferroptosis was investigated. The results showed that NiCl 2 induced autophagy in TCMK-1 cells, which promoted ferroptosis induced by NiCl 2. Furthermore, the data of autophagy activation or inhibition experiment showed that autophagy facilitated ferroptosis through the degradation of the iron regulation protein NCOA4 and FTH1. Otherwise, iron chelator DFOM treatment inhibited ferroptosis induced by NiCl 2. Finally, ferroptosis inhibitor Fer-1 treatment significantly alleviated cytotoxicity induced by NiCl 2. To sum up, our above results showed that ferroptosis is involved in NiCl 2 -induced nephrotoxicity, and NiCl 2 induces autophagy-dependent ferritin degradation, releases iron ions, leads to iron overload, and induces ferroptosis. This study supplies a new theoretical foundation for the study of nickel and renal toxicity. [Display omitted] • NiCl 2 induced ferroptosis in mouse kidney and TCMK-1 cells. • NiCl 2 induced autophagy in TCMK-1 cells, which promoted ferroptosis. • Autophagy facilitated ferroptosis through the degradation of ferritin. • Ferroptosis is involved in NiCl 2 -induced nephrotoxicity. [ABSTRACT FROM AUTHOR]

This study was designed to evaluate the toxicological effect of dietary nickel chloride (NiCl2) on the counts of intestinal bacteria and diversity of microorganisms in broilers. Plate counting and polymerase chain reaction-denaturing gradient gel electrophoresis (PCR-DGGE) assays were used. A total of 240 one-day-old avian broilers chicks were divided into four equal groups and kept on corn-soybean basal diet along with supplementation of 0, 300, 600 and 900 mg/kg NiCl2 for 42 days. Samples were taken at 21 and 42 days of age during the experiment. The bacterial count results showed that dietary NiCl2 in the range of 300 to 900 mg/kg decreased the counts of Bifidobacterium spp. and Lactobacillus , increased Escherichia coli (E. coli) and Enterococcus spp. in the ileum and cecum. PCR-DGGE analysis showed that bacterial band numbers, profile similarity, and the Shannon index of the ileum and cecum were all decreased in the 300, 600, and 900 mg/kg groups at 21 and 42 days of age. In conclusion, dietary NiCl2 affected the amount and diversity of intestinal microbiota in the ileum and cecum of broilers. This finding implies that NiCl2 has toxicological effect on the intestinal ecosystem and, possibly functions. [ABSTRACT FROM AUTHOR]

As an extensively environmental pollution, Nickel (Ni) represents a serious hazard to human health. The present study focused on exploring the mechanism of Ni-mediated nephrotoxicity, such as apoptosis, autophagy and oxidative stress. In the current work, NiCl 2 treatment could induce kidney damage. Meanwhile, NiCl 2 treatment elevated ROS production and MDA content and suppressed the antioxidant activity, which was characterized by reducing T-AOC, CAT, SOD activity and GSH content. For investigating the role of oxidative stress on NiCl 2 -mediated nephrotoxicity, N-acetyl cysteine (NAC, effective antioxidant and free radical scavenger) was co-treated with NiCl 2. The results showed that NAC significantly suppressed the NiCl 2 -mediated oxidative stress and mitigated NiCl 2 -induced the kidney damage. Then, whether oxidative stress-induced autophagy and apoptosis were involved in NiCl 2 -induced nephrotoxicity was explored. The findings demonstrated that NAC relieved NiCl 2 -induced autophagy and reversed the activation of Akt/AMPK/mTOR pathway. Concurrently, the results indicated that NAC attenuated NiCl 2 -induced apoptosis, as evidenced by reduction of apoptotic cells and cleaved-caspase-3/− 8/− 9 together with cleaved-PARP protein levels. To sum up, our findings suggested that NiCl 2 -mediated renal injury was associated with oxidative stress-induced apoptosis and autophagy. This study provides new theoretical basis for excess Ni exposure nephrotoxic researches. [Display omitted] • NiCl 2 -treatment could induce oxidative stress, autophagy and apoptosis in the kidney. • Oxidative stress is an essential inducer of NiCl 2 -induced kidney damage. • NiCl 2 induces autophagy through oxidative stress-mediated Akt/AMPK/mTOR pathway. • Oxidative stress play an important role in NiCl 2 -induced apoptosis and autophagy. [ABSTRACT FROM AUTHOR]

Obesity is a risk factor of many diseases, but could be beneficial to the individuals with bacterial infection. The present study was conducted to investigate the relationship between obesity and heart during nonfatal bacterial infection. Male normal (lean) and diet-induced obesity mice (DIO, fed with high-fat diet) were chosen to perform nasal instillation with E. coli to establish a nonfatal acute mouse model. The cardiac histopathology, inflammation and oxidative damage, as well as apoptosis were detected post-infection. The results revealed that the Escherichia coli (E.coli)-infected mice exhibited increased cardiac index, contents of IL-1β, IL-6, IL-8, TNF-α, leptin and resistin, levels of apoptotic proteins (caspase-3 and caspase-9, and bax/bcl-2 ratio), cardiac pathological changes and oxidative stress. Furthermore, these parameters were more serious in the lean mice than those in the DIO mice. In summary, our findings gave a new sight that E.coli infection impaired heart via histopathological lesions, inflammation and oxidative stress and excessive apoptosis of cardiomyocytes. Interestingly, obesity exerted attenuated effects on the heart of mice with non-fatal infection of E.coli through decreased inflammation, oxidative stress and apoptosis of cardiac tissue. • Attenuated Cardiac Injury in Obese Mice with nonfatal infection of Escherichia coli. • Obesity could attenuate Escherichia coli-induced oxidative stress. • Obesity could attenuate Escherichia coli-induced inflammatory responses. • Obesity could attenuate Escherichia coli-induced apoptosis. [ABSTRACT FROM AUTHOR]

As a common environmental pollutant, nickel chloride (NiCl 2) poses serious threat to human and animals health. NiCl 2 has adverse effects on reproductive function in male, however, the underlying mechanisms are not fully illuminated. In this study, 64 male ICR mice were divided into four groups (8 mice per each period/ group), in which mice orally administrated with 0, 7.5, 15 or 30 mg/kg body weight for 14 or 28 consecutive days, respectively. The results showed that the sperm concentration (12.95%, 29.78% and 37.63% -) and sperm motility (19.79%, 34.88% and 43.10%) were dose-dependent significantly reduced, and the total sperm malformation rates (110.15%, 206.84% and 292.27%) were dose-dependent significantly elevated in the 7.5, 15 and 30 mg/kg NiCl 2 treatment groups (vs control at 28 days), respectively (P < 0.05). Meanwhile, NiCl 2 also decreased the relative weights of testis and epididymis and caused histopathological lesions of testis and epididymis. Furthermore, serum testosterone levels were significantly decreased after NiCl 2 treatment. And the findings showed that NiCl 2 down-regulated the expression of LH-R, StAR, P450scc, 3β-HSD, 17β-HSD, ABP and INHβB in the testis, however, the relative genes in the hypothalamus (Kiss-1, GPR54 and GnRH) and pituitary (GnRH-R, LHβ and FSHβ) did not exhibit noticeable change. In summary, NiCl 2 induced spermatogenesis disorder by testicular damage and hypothalamic-pituitary-testis axis disruption in mice, and only impaired the genes on the testis of HPT axis. [Display omitted] • NiCl 2 exposure could induce spermatogenesis disorder in mice. • NiCl 2 caused testicular and epididymal histopathological lesions in mice. • NiCl 2 decreased serum testosterone levels in mice. • NiCl 2 inhibited the expressions of key genes in the testis of hypothalamic-pituitary-testis axis. [ABSTRACT FROM AUTHOR]

Nickel (Ni), a widely distributed metal, is an important pollutant in the environment. Although kidney is a crucial target of Ni toxicity, information on autophagy and the potential mechanisms of Ni-induced renal toxicity are still poorly described. As we discovered, NiCl 2 could induce renal damage including decrease in renal weight, renal histological alterations, and renal function injury. According to the obtained results, NiCl 2 could obviously increase autophagy, which was characterized by increase of LC3 expression and decrease of p62 expression. Meanwhile, the result of ultrastructure observation showed increased autolysosomes numbers in the kidney of NiCl 2 -treated mice. In addition, NiCl 2 increased mRNA and protein levels of autophagy flux proteins including Beclin1, Atg5, Atg12, Atg16L1, Atg7, and Atg3. Furthermore, NiCl 2 induced autophagy through AMPK and PI3K/AKT/mTOR pathways which featured down-regulated expression levels of p-PI3K, p-AKT and p-mTOR and up-regulated expression levels of p-AMPK and p-ULK1. In summary, the above results indicate involvement of autophagy in renal injury induced by NiCl 2 , and NiCl 2 induced autophagy via PI3K/AKT/mTOR and AMPK pathways in mouse kidney. [Display omitted] • High Ni exposure could induce autophagy in kidney of mice. • Ni increases mRNA and protein expressions of autophagy flux proteins. • Ni induces autophagy via AMPK and PI3K/AKT/mTOR signaling pathways. [ABSTRACT FROM AUTHOR]

Copper (Cu), as a common chemical contaminant in environment, is known to be toxic at high concentrations. The current research demonstrates the effects of copper upon hepatocyte cell-cycle progression (CCP) in mice. Institute of cancer research (ICR) mice (n = 240) at an age of four weeks were divided randomly into groups treated with different doses of Cu (0, 4, 8, and 16 mg/kg) for 21 and 42 days. Results showed that high Cu exposure caused hepatocellular G0/G1 cell-cycle arrest (CCA) and reduced cell proportion in the G2/M phase. G0/G1 CCA occurred with down-regulation (p < 0.05) of Ras, p-PI3K (Tyr458), p-Akt (Thr308), p-forkhead box O3 (FOXO3A) (Ser253), p-glycogen synthase kinase 3-β (GSK3-β) (Ser9), murine double minute 2 (MDM2) protein, and mRNA expression levels, and up-regulation (p < 0.05) of PTEN, p-p53 (Ser15), p27, p21 protein, and mRNA expression levels, which subsequently suppressed (p < 0.05) the protein and mRNA expression levels of CDK2/4 and cyclin E/D. These results indicate that Cu exposure suppresses the Ras/PI3K/Akt signaling pathway to reduce the level of CDK2/4 and cyclin E/D, which are essential for the G1-S transition, and finally causes hepatocytes G0/G1 CCA. • High Cu exposure caused hepatocellular G0/G1 cell-cycle arrest. • Cu decreases the G0/G1 cell-cycle phase proteins CDK4/2 and cyclin E/D. • Cu induces G0/G1 cell-cycle arrest through inhibition of the Ras/PI3K/Akt signaling pathway. [ABSTRACT FROM AUTHOR]

Although copper is among the indispensable trace elements in animal physiological processes, it exerts toxicity upon over-exposure. The present study aimed to investigate hepatocyte autophagy induced by CuSO 4 and its potential mechanism. A total of 240 ICR mice (four-week-old, 120 males and 120 females) were randomly divided into four groups, in which mice separately received 0, 4, 8, and 16 mg/kg of Cu (Cu2+-CuSO 4) for 42 d. The results of increased autophagosomes and autophagy marker LC3B brown cell staining showed that excessive intake of Cu enhanced hepatocyte autophagy. Simultaneously, Cu inhibited the activity of mTOR through suppressing mRNA and protein expressions in mTOR, which in turn up-regulated expression levels of ULK1 and initiated autophagy. Also, over-exposure to Cu increased mRNA and protein expressions of Beclin1, Atg12, Atg5, Atg16L1, Atg7, Atg3, and LC3 and decreased mRNA and protein expressions of p62. These results indicate that excess Cu can enhance hepatocyte autophagy via inhibiting the mTOR signaling pathway and regulating mRNA and protein expressions of factors implicated to autophagy in mice. • This study proves that copper can induce hepatic autophagy in mice. • Copper induces hepatocyte autophagy by inhibiting the mTOR signaling pathway • Copper up-regulates the levels of Beclin1, Atg12/5/7/3, Atg16L1 and LC3 in liver. • Copper down-regulates the levels of p62 in liver. [ABSTRACT FROM AUTHOR]

Hepatic oxidative stress, as one important mechanism of cadmium (Cd)-induced hepatic toxicity, could, as known, be ameliorated by vitamin E (VE). However, the underlying mechanism remains to be elucidated. To investigate whether the antioxidant vitamin E can protect against Cd-induced sub-chronic liver injury associated with oxidative stress and nuclear factor erythrocyte 2-related factor 2 (Nrf2) pathway, male Sprague-Dawley rats (nine-week-old) were randomly divided into four groups (eight rats/group), namely, control, VE (100 mg/kg VE), Cd (5 mg/kg CdCl 2) and VE+Cd (100 mg/kg VE+5 mg/kg CdCl 2), and received intragastric administration of Cd and/or VE for four weeks. Cd-exposure alone resulted in reduced liver weight, liver histological alteration and oxidative stress, accumulation of Cd in the liver, elevated ALT and AST concentrations in serum together with decreased mRNA and protein expressions of Nrf2 pathway related molecules (Nrf2, HO-1, NQO-1, GCLC, GCLM and GST). However, the co-treatment of Cd and VE significantly ameliorated the changes mentioned above, and promoted the expression of genes and proteins of Nrf2 pathway related molecules in comparison to the Cd-exposure alone. Our results indicate that the protective effect of VE against Cd-induced sub-chronic hepatic damage in rats is associated with the inhibition of oxidative stress and activation of Nrf2 pathway. • This study explored the possible protective mechanism of VE against Cd-induced hepatotoxicity. • Cd caused sub-chronic liver damage and oxidative stress resulting in hepatic dysfunction, which was ameliorated by VE. • VE augments Nrf2 pathway to alleviate the hepatic damages caused by Cd. • Thus, this study may offer therapeutic potential in humans exposed to Cd. [ABSTRACT FROM AUTHOR]

Nickel (Ni) is a widely distributed metal in the environment and an important pollutant because of its many industrial applications. With increasing incidences of Ni contamination, Ni toxicity has become a global public health concern and recent evidence suggests that Ni adversely affects the immune system. Hence, this paper reviews the literature on immune-related effects of Ni exposure, the immunotoxicological effects of Ni, and the underlying mechanism of Ni immunotoxicity. The main focus was on the effect of Ni on the development of organs of immune system, lymphocyte subpopulations, cytokines, immunoglobulins, natural killer (NK) cells, and macrophages. Moreover, Ni toxicity also induces inflammation and several studies demonstrated that Ni could induce immunotoxicity. Excessive Ni exposure can inhibit the development of immune organs by excessively inducing apoptosis and inhibiting proliferation. Furthermore, Ni can decrease T and B lymphocytes, the specific mechanism of which requires further research. The effects of Ni on immunoglobulin A (IgA), IgG, and IgM remain unknown and while Ni inhibited IgA, IgG, and IgM levels in an animal experiment, the opposite result was found in research on humans. Ni inhibits the production of cytokines in non-inflammatory responses. Cytokine levels increased in Ni-induced inflammation responses, and Ni activates inflammation through toll like (TL)4-mediated nuclear factor-κB (NF-κB) and signal transduction cascades mitogen-activated protein kinase (MAPK) pathways. Ni has been indicated to inactivate NK cells and macrophages both in vitro and in vivo. Identifying the mechanisms underlying the Ni-induced immunotoxicity may help to explain the growing risk of infections and cancers in human populations that have been exposed to Ni for a long time. Such knowledge may also help to prevent and treat Ni-related carcinogenicity and toxicology. Image 1 • Ni inhibits immune organ development. • Ni inhibits cytokines and immunoglobulins production. • Ni impair NK cells and macrophages activity. • Ni induces allergic contact dermatitis. [ABSTRACT FROM AUTHOR]

The present study investigated the expressions of signalling molecules and inflammatory cytokines involved in copper-induced inflammatory responses of the mouse liver. A total of 240 institute of cancer research (ICR) mice (half male and half female) aged four weeks were randomly allocated to four groups treated with 0, 4, 8, and 16 mg/kg of [Cu] (Cu2+-CuSO 4) for 42 days, respectively. [Cu] exceeding 4 mg/kg was found to induce inflammatory responses of the liver. Results showed significant up-regulation of mRNA and protein levels of apoptosis signal-regulating kinase 1 (ASK1), mitogen-activated protein kinase kinases 3/6 (MEK3/6), c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (p38 MAPK), mitogen-activated protein kinase kinases 4/7 (MEK4/7), mitogen-activated protein kinase kinases 1/2 (MEK1/2), and extracellular signal-regulated protein kinases 1/2 (Erk1/2) due to Cu. By doing so, copper could activate the mitogen-activated protein kinases (MAPKs) signalling pathway. Concurrently, the nuclear factor-kappa B (NF-κB) signalling pathway was also activated in the Cu-treatment, as demonstrated by higher expressions of NF-κB and cyclooxygenase-2 (COX-2), activities of inducible nitric oxide synthase (iNOS), contents of nitric oxide (NO) and prostaglandin E2 (PGE2), and reducing levels of expression of inhibitory kappa B (IκB). High Cu intake also up-regulated expression levels of some pro-inflammatory mediators such as interleukin-2 (IL-2), interleukin-1β (IL-1β), and interleukin-8 (IL-8), and down-regulated the levels of expression of transforming growth factor beta (TGF-β), an anti-inflammatory mediator. Additionally, our results indicated that Cu caused hepatic dysfunction, with evidence of occurrence of histopathological lesions and higher serum activities of alkaline phosphatase (AKP), aspartic acid transferase (AST), alanine amino transferase (ALT), and gamma-glutamyl transpeptidase (GGT), contents of albumin (ALB) and total bilirubin (TBIL). Altogether, the aforementioned results indicate that [Cu], at more than 4 mg/kg, induces the inflammatory responses in the liver via NF-κB and MAPKs signalling pathways, subsequently inducing hepatic dysfunction. Image 1 • This study proves that copper induce hepatic inflammatory responses in mice, damage hepatocytes and hepatic functions. • Copper induces inflammatory responses by activating NF-κB and MAPKs pathways. • Activated NF-κB and MAPKs pathways represent mechanisms underlying Cu-induced inflammatory responses. [ABSTRACT FROM AUTHOR]

Copper (Cu), a transition metal, is an essential trace element in human and animal nutrition at low concentration, but Cu has toxic effects on tissues and organs at high concentration. Endoplasmic reticulum (ER) is a toxicological target in Cu poison. Thus far, no studies have focused on the relationship among copper, endoplasmic reticulum (ER) stress and apoptosis in animal and human livers. In the present study, mice treated with copper sulfate (CuSO 4) were used to assess the impacts of copper on ER stress and hepatic apoptosis. A total of 240 mice were orally administered with 0 (control), 10, 20 and 40 mg/kg of CuSO 4 for 42 days. The results indicated that CuSO 4 at 10 mg/kg markedly induced hepatocyte apoptosis and ER stress. In addition, ER stress was characterized by the increased mRNA and protein levels of glucose-regulated protein 78 (GRP78) and 94 (GRP94). Furthermore, ER stress-triggered 3 apoptotic pathways were also activated by the increased intracellular calcium and up-regulated expression levels of genes involved in growth arrest- and DNA damage-inducible gene 153 (Gadd153/CHOP), c-Jun N-terminal kinase (JNK) and cysteine aspartate-specific protease 12 (caspase-12) signaling pathways in CuSO 4 -treated mice. In conclusion, CuSO 4 -induced ER stress can promote hepatic apoptosis in mice by activating CHOP, JNK and caspase-12 signaling pathways. Image 1 • Copper sulfate (CuSO 4) can induce endoplasmic reticulum (ER) stress and apoptosis in the mouse liver. • CuSO 4 -caused ER stress can promote hepatic apoptosis. • The CHOP, JNK and caspase-12 apoptotic signaling pathwaysactivated by Cu-induced ER stress are systematically expounded. [ABSTRACT FROM AUTHOR]