Search

Heavy metals interact with each other in a coexisting manner to produce complex combined toxicity to organisms. At present, the toxic effects of chronic co-exposure to heavy metals hexavalent chromium [Cr(VI)] and divalent nickel [Ni(II)] on organisms are seldom studied and the related mechanisms are poorly understood. In this study, we explored the mechanism of the colon injury in mice caused by chronic exposure to Cr or/and Ni. The results showed that, compared with the control group, Cr or/and Ni chronic exposure affected the body weight of mice, and led to infiltration of inflammatory cells in the colon, decreased the number of goblet cells, fusion of intracellular mucus particles and damaged cell structure of intestinal epithelial. In the Cr or/and Ni exposure group, the activity of nitric oxide synthase (iNOS) increased, the expression levels of MUC2 were significantly down-regulated, and those of ZO-1 and Occludin were significantly up-regulated. Interestingly, factorial analysis revealed an interaction between Cr and Ni, which was manifested as antagonistic effects on iNOS activity, ZO-1 and MUC2 mRNA expression levels. Transcriptome sequencing further revealed that the expression of genes-related to inflammation, intestinal mucus and tight junctions changed obviously. Moreover, the relative contents of Cr(VI) and Ni(II) in the Cr, Ni and Cr+Ni groups all changed with in-vitro gastrointestinal （IVG）digestion, especially in the Cr+Ni group. Our results indicated that the chronic exposure to Cr or/and Ni can lead to damage to the mice colon, and the relative content changes of Cr(VI) and Ni(II) might be the main reason for the antagonistic effect of Cr+Ni exposure on the colon damage. [Display omitted] • Cr or/and Ni can cause colon damage in mouse. • Cr or/and Ni interfere gene expression in colon of mouse. • Cr and Ni showed antagonistic effects on iNOS activity, ZO-1 and MUC2 mRNA expression levels. • Cr(IV) and Ni (II) underwent valence changes in vitro gastrointestinal digestion phase. [ABSTRACT FROM AUTHOR]

Di-(2-ethylhexyl) phthalate (DEHP) is a widely used plasticizer known for its environmental endocrine-disrupting properties, posing potential risks to various organs. However, the precise impact of DEHP on intestinal health and its contribution to the initiation of intestinal inflammation remains elucidated. This study aims to investigate the underlying mechanisms of DEHP-induced intestinal inflammation in mice, specifically focusing on the complex interplay between the gut microbiota-metabolite axis and associated pathophysiological alterations. Our findings showed that DEHP-induced damage of multiple organs systemically, as indicated by abnormal liver and kidney biochemical markers, along with a disrupted ileum morphology. Additionally, DEHP exposure disrupted gut barrier function, causing intestinal inflammation characterized by bacterial translocation and alterations in defense and inflammation-related gene expressions. Moreover, 16S rRNA analysis suggested that DEHP-induced gut microbial remodeling is characterized by an upregulation of detrimental bacteria (Erysipelotrichaceae) and a downregulation of beneficial bacteria (Muribaculaceae, Ruminococcaceae, and Lachnospiraceae). Metabolomics analysis revealed DEHP perturbed gut metabolic homeostasis, particularly affecting the degradation of aromatic compounds, which generated an aberrant activation of the AhR and NF-κB, subsequently causing intestinal inflammation. Consequently, our results elucidate the mechanistic link between disrupted gut microbiota and metabolome and the initiation of DEHP-induced intestinal inflammation, mediated through the AhR/NF-κB signaling pathway. [Display omitted] • DEHP induces systemic multiple organ damage in mice. • DEHP causes the imbalance of intestinal homeostasis and bacterial migration. • DEHP induces the imbalance of gut microbiota homeostasis and the change of metabolites. • DEHP induces intestinal inflammation by activating the AhR/NF-κB pathway. [ABSTRACT FROM AUTHOR]

Copper (Cu) and mercury (Hg) are major pollutants worldwide, but the gastrointestinal damage caused by copper and mercury exposure is unclear. We are committed to scientific research on the harm and transformation of copper and mercury exposure to the rectal microbial population of female mice. Kunming mice (n = 24) were randomly divided into four equal groups, i.e., 1) Rectal Colon Control (RCK) group, 0 mg/kg of Cu and Hg), 2) Rectal Copper (RCu group), 5 mg/kg weight of Cu), 3) Rectal Mercury (RHg) group, 2 mg/kg weight of Hg) and 4) Rectal copper-mercury (RCH) group, 2.5 and 1 mg/kg weight of Cu and Hg. On the 90th day, the rectal and intestinal tissues were analyzed for pathophysiology, and quantitative analysis by PCR, then a library was prepared, and sequencing was carried out. The rectal tissue of the RCu and RCH group had histopathological and physiological damage, including low weight, low pH value, increased thickness of the outer muscle layer, smooth muscle tissue, widening of the submucosal layer, reduction of goblet cells, blunt intestinal villi and severe aging of the central mammary duct. In addition, Sequencing results of 16S rRNA genes compared with RCK showed that the abundance of the Treponema, Coprococcus, and Dehalobacterium in RCu was more significant than the RCK. Still, the bacillus, Jeotgalicoccus, Salinicoccus, Staphylococcus, and Ignatzschineria was just the opposite. The abundance of Butyricimonas, Streptococcus, Dehalobacterium, Coprococcus, Oscillospira, and Helicobacter in RHg was more significant than in the RCK. Still, Corynebacterium, Bacillus, Jeotgalicoccus, Salinicoccus, Staphylococcus, Lactococcus, and Ignatzschineria were the opposite. We found some similar exciting things. The abundance of the Dehalobacterium, Coprococcus, and Oscillospira was significantly more significant than the RCK. Still, the Corynebacterium, Salinicoccus, Jeotgalicoccus, Staphylococcus, Lactococcus, Sutterella, and Ignatzschineria were the opposite. In addition, the Staphylococcus in RCu was increased than in the RCH, and the Streptococcus in RCu was increased than in the RCH. The results of the present study furnish a source for a more precise validation of the risk of digestive tract diseases driven by Cu and Hg. [ABSTRACT FROM AUTHOR]

Aflatoxin B1 (AFB1) is a stable mycotoxin that contaminates animal feed on a large scale and causes severe damage to intestinal cells, induces inflammation and stimulates autophagy. Transient receptor potential mucolipin subfamily 1 (TRPML1) is a regulatory factor of autophagy, but the underlying mechanisms of TRPML1-mediated autophagy in AFB1 intestine toxicity remain elucidated. In the present study, AFB1 (0, 5, 10 μg/mL) was shown to reduce cell viability, increase reactive oxygen species (ROS) accumulation and apoptosis rate. Additionally, AFB1 caused structural damage to mitochondria and lysosomes and increased autophagosomes numbers. Furthermore, AFB1 promoted Ca2+ release by activating the TRPML1 channel, stimulated the expression of autophagy-related proteins, and induced autophagic flux blockade. Moreover, pharmacological inhibition of autophagosome formation by 3-methyladenine attenuated AFB1-induced apoptosis by downregulating the levels of TRPML1 and ROS, whereas blockade of autophagosome-lysosomal fusion by chloroquine alleviated AFB1-induced apoptosis by upregulating TRPML1 expression and exacerbating ROS accumulation. Intriguingly, blocking AFB1-induced autophagic flux generated ROS- and TRPML1-dependent cell death, as shown by the decreased apoptosis in the presence the free radical scavenger N-Acetyl- L -cysteine and the TRPML1 inhibitor ML-SI1. Overall, these results showed that AFB1 promoted apoptosis of IPEC-J2 cells by disrupting autophagic flux through activation of the ROS/TRPML1 pathway. [Display omitted] • AFB1 induces ROS accumulation and apoptosis in porcine intestinal epithelial cells. • AFB1 causes the blockage in autophagic flux in porcine intestinal epithelial cells. • Inhibition of autophagosome formation by 3-MA attenuate AFB1-induced apoptosis. • Blocking autophagosome-lysosome fusion by CQ exacerbates AFB1-induced apoptosis. • Inhibition of TRPML1 activates autophagic flux to relieve AFB1-induced apoptosis. [ABSTRACT FROM AUTHOR]

The aims of this study were determining the co-induced effects of dietary Cadmium (Cd) and high intake of Molybdenum (Mo) on renal toxicity in ducks. 240 healthy 11-day-old ducks were randomly divided into 6 groups, which were treated with Mo or/and Cd at different doses added to the basal diet for 120 days. Ducks of control group were fed with basal diet, LMo and HMo groups were fed with 15 mg/kg Mo and 100 mg/kg Mo respectively; ducks of Cd group were provided with 4 mg/kg Cd which was added into basal diet. Two combination groups were treated with 15 mg/kg Mo+4 mg/kg Cd and 100 mg/kg Mo+4 mg/kg Cd respectively. On days 30, 60, 90 and 120, the mRNA expression levels of inflammatory cytokines and contents of trace elements were detected. In addition, transmission electron microscopic examination was used for ultrastructural studies. The results indicated that the mRNA expression levels of tumor necrosis factor-α (TNF-α), nuclear factor-kappa B (NF-κB), and cyclooxygenase-2 (COX-2) showed an upward tendency in treatment groups in comparison with control group, and in the later period of the experiment it showed a significant rise in joint groups compared with the Mo and Cd group ( P< 0.01); the contents of copper (Cu) and iron (Fe) decreased in joint groups in the later period ( P< 0.05) while the contents of Mo and Cd significantly increased ( P< 0.01); zinc (Zn) and selenium (Se) concentration had a slight downtrend in treated groups, but showed no significant difference ( P> 0.05). The ultrastructural analysis showed that kidney tissues were severely injured in joint groups on day 120. These results suggested that the combination of Mo and Cd could aggravate damages to the kidney. In addition, dietary of Mo or/and Cd caused the decrease of Cu, Fe, Zn, and Se contents, inflammatory response and pathological lesions whose mechanism is somehow linked with Mo and Cd deposition in kidney. [ABSTRACT FROM AUTHOR]

ApxIA and ApxIVA are the main virulence factors of Actinobacillus pleuropneumoniae (A. pleuropneumoniae). The preparation of their antibodies is of great significance for diagnosing and treating porcine pleuropneumonia. This study used chemically synthesized ApxIA and ApxIVA peptides as immunogens to prepare polyclonal antibodies against ApxIA and ApxIVA. Their titers were determined by ELISA and Dot blotting. Histopathology of apparently infected organs was carried out. Finally, the immunofluorescence method detected the distribution of antigens in the visceral tissues of mice infected with ApxIA and ApxIVA toxins. The results showed that ApxIA and ApxIVA polyclonal antibodies with titer as high as 1: 200000 and 1: 50000, respectively, were successfully obtained. The immunofluorescence results showed that these polyclonal antibodies could accurately detect ApxIA and ApxIVA antigens in mouse lungs with strong specificity. Histopathologically, there were perialveolar hemorrhages, pulmonary emphysema, and sloughing of bronchiolar epithelium. There was vacuolation and infiltration of chronic inflammatory cells in the liver parenchymal tissue. Atrophy of intestinal villi and glands and sloughing of villus epithelium, and congestion. There was increased urinary space and congestion in the proximal convoluted tubules. Lymphoid follicles increased in size in the spleen, the germinal center enlarged, and congestion in surrounding lymphoid tissue were observed. This study laid a foundation for the research and development of a rapid detection kit for A. pleuropneumoniae and provided conditions for diagnosing and treating porcine contagious pleuropneumonia. [ABSTRACT FROM AUTHOR]

Copper (Cu) as a transition metal can be toxic to public and ecosystem health at high level, but the specific mechanism of Cu-evoked nephrotoxicity remains elusive. Here, we first revealed the crosstalk between mitofusin2 (Mfn2)-dependent mitochondria-associated endoplasmic reticulum membrane (MAM) dynamics and autophagy in duck renal tubular epithelial cells under Cu exposure. Primary duck renal tubular epithelial cells were treated with 100 and 200 μM Cu sulfate for 12 h and exposed to lentivirus to deliver mitofusin2 (Mfn2). We found that excessive Cu disrupted MAM integrity, decreased the mitochondrial calcium level, co-localization of IP3R and VDAC1, the mRNA levels of PACS2, Mfn2, IP3R and MCU, and Mfn2 and VDAC1 protein levels, causing MAM dysfunction. Furthermore, Mfn2 overexpression ameliorated Cu-induced MAM dysfunction, and increased Cu-evoked autophagy in duck renal tubular epithelial cells accompanied with the elevation of autophagosomes number, ROS level, LC3 puncta, Atg5 and LC3B mRNA levels, and Beclin1, Atg14, LC3BII/LC3BI protein levels. Accordingly, our data proved that excessive Cu could trigger MAM dysfunction and autophagy in duck renal tubular epithelial cells, and Cu-induced autophagy could be activated through Mfn2-dependent MAM, providing evidence on the toxicological exploration mechanisms of Cu. [Display omitted] • Copper (Cu) could yield toxic effects on duck renal tubular epithelial cells. • Cu caused mitochondria-associated endoplasmic reticulum membrane (MAM) dysfunction. • Cu-induced MAM dysfunction could be relieved via Mfn2 overexpression. • MAM dysfunction might increase Cu-evoked autophagy. [ABSTRACT FROM AUTHOR]

Cadmium (Cd) is an occupational and environmental pollutant, which mainly causes nephrotoxicity by damaging renal proximal tubular cells. To evaluate the effects of Cd on pyroptosis and the relationship between pyroptosis and apoptosis in duck renal tubular epithelial cells, the cells were cultured with 3CdSO 4 ·8H 2 O (0, 2.5, 5.0, or 10.0 μM Cd), N-acetyl-L-cysteine (NAC) (100.0 μM), Z-YVAD-FMK (10.0 μM) or the combination of Cd and NAC or Z-YVAD-FMK for 12 h, and then cytotoxicity was assessed. The results evidenced that Cd significantly increased the releases of interleukin-18 (IL-18) and interleukin-1β (IL-1β), lactate dehydrogenase (LDH) and nitric oxide (NO), relative conductivity and cellular reactive oxygen species (ROS) level. Simultaneously, Cd also markedly upregulated NLRP3, Caspase-1, ASC, NEK7, IL-1β and IL-18 mRNA levels and NLRP3, Caspase-1 p20, GSDMD and ASC protein levels. Additionally, NAC notably improved the changes of above indicators induced by Cd. Combined treatment with Cd and Z-YVAD-FMK remarkably elevated Bcl-2 mRNA and protein levels, inhibited p53, Bax, Bak-1, Cyt C, Caspase-9 and Caspase-3 mRNA levels and p53, Bax, Bak-1, Caspase-9/cleaved Caspase-9 and Caspase-3/cleaved Caspase-3 protein levels, increased mitochondrial membrane potential (MMP), decreased apoptosis ratio and cell damage compared to treatment with Cd alone. Taken together, Cd exposure induces duck renal tubular epithelial cell pyroptosis through ROS/NLRP3/Caspase-1 signaling pathway, and inhibiting Caspase-1 dependent pyroptosis attenuates Cd-induced apoptosis. Image 1 • Cadmium (Cd) toxicity was evaluated in duck renal tubular epithelial cells. • Cd could induce pyroptosis via ROS/NLRP3/Caspase-1 pathway. • N-acetyl-L-cysteine (NAC) could inhibit pyroptosis induced by Cd. • Inhibiting Caspase-1-dependent pyroptosis might weaken Cd induced-apoptosis. [ABSTRACT FROM AUTHOR]

Copper (Cu) is a vital micronutrient required for numerous fundamental biological processes, but excessive Cu poses potential detrimental effects on public and ecosystem health. However, the molecular details linking endoplasmic reticulum (ER) stress and apoptosis in duck renal tubular epithelial cells have not been fully elucidated. In this study, duck renal tubular epithelial cells exposed to Cu sulfate (CuSO 4) (0, 100 and 200 μM) and a PERK inhibitor (GSK2606414, GSK, 1 μM) for 12 h were used to investigate the crosstalk between ER stress and apoptosis under Cu exposure. Cell and ER morphological and functional characteristics, intracellular calcium (Ca2+) levels, apoptotic rates, ER stress and apoptosis-related mRNA and protein levels were examined. The results showed that excessive Cu could cause ER expansion and swelling, increase the expression levels of ER stress-associated genes (PERK, eIF2α, ATF4 and CHOP) and proteins (p-PERK and CHOP), induce intracellular Ca2+ overload, upregulate the expression levels of apoptosis-associated genes (Bax, Bak1, Caspase9 and Caspase3) and the cleaved-Caspase3 protein, downregulate Bcl-xl and Bcl2 mRNA levels and trigger apoptosis. PERK inhibitor treatment could ameliorate the above changed factors caused by Cu. In conclusion, these findings indicate that excessive Cu could trigger ER stress via activation of the PERK/ATF4/CHOP signaling pathway and that ER stress might aggravate Cu-induced apoptosis in duck renal tubular epithelial cells. Image 1 • Copper (Cu) has toxic effect on duck renal tubular epithelial cells. • Cu could trigger endoplasmic reticulum (ER) stress via PERK/ATF4/CHOP pathway. • Cu could induce apoptosis in duck renal tubular epithelial cells. • ER stress might aggravate Cu-induced apoptosis via PERK/ATF4/CHOP pathway. [ABSTRACT FROM AUTHOR]

Dichlorvos is a common crop insecticide widely used by people which causes extensive and serious environmental pollution. However, it has been shown that organophosphorus poisoning causes energy metabolism and neural disorders. The overall purpose of this study was to investigate the damage to brain tissue and the changes in AMPK signaling pathway-related gene expression after dichlorvos poisoning in chickens. White-feathered broiler chickens, as the research subjects of this experiment, were divided into three groups: control group, low-dose group (77.5% dichlorvos at 1.13 mg/kg dose) and high-dose group (77.5% dichlorvos at 10.2 mg/kg dose). Clinical symptoms were observed after modeling, and an integrative analysis was conducted using HE staining microscopy, immune-histochemical microscopy, electron microscopy and PCR arrays. The results showed that the high-dose group had more obvious dyspnea, salivation, convulsion and other neurological phenomena. Pathological sections showed that nuclear disintegration of neurons was most obvious in the low-dose group, and apoptosis of brain cells was most obvious in the high-dose group, and the mitochondrial structure was destroyed in the two poisoned group, i.e. low-dose group and high-dose group. PCR arrays showed that AMPK signaling pathway was inhibited and the expressions of genes involved in energy metabolism (ACACA and PRKAA1) were significantly changed. Furthermore, genes associated with protein synthesis (EIF4EBP1) were significantly upregulated. FASN and HMGCR expressions were significantly increased. There were significant changes in the expressions of cell cycle-related genes (STK11, TP53 and FOXO3). Organophosphate poisoning can cause a lot of nuclear disintegration of brain neurons, increases cell apoptosis, disrupts the energy metabolism of mitochondrial structure, and inhibits the AMPK signaling pathway. These results provide a certain idea and basis for studying the mechanism of AMPK signaling after organophosphorus poisoning and provide a research basis for the prevention and treatment of organophosphorus poisoning. Image 1 • Severe pathological damage of chicken brain caused by dichlorvos poisoning. • The gene expression of AMPK signaling pathway in the brain of the poisoned chicken changed significantly. • After dichlorvos poisoning, the AMPK signal pathway of brain tissue can be inhibited. • Dichlorvos poisoning affects fat metabolism, protein metabolism and other related genes. [ABSTRACT FROM AUTHOR]