Associations between maternal occupational exposures and pregnancy outcomes among Chinese nurses: a nationwide study.

BACKGROUND: Several studies have provided evidence about adverse pregnancy outcomes of nurses involved in occupational exposure. However, the pregnancy outcomes among nurses in middle-income countries are not well demonstrated. The main aim of this study is to present the prevalence and influencing factors of pregnancy outcomes among female nurses in China. METHODS: We included 2243 non-nurse health care workers, and 4230 nurses in this national cross-sectional study in China. Information on occupational exposures and pregnancy outcomes was collected using a face-to-face investigation. Odds ratios (ORs) were estimated through logistic regression. RESULTS: The proportion of threatened abortion, spontaneous abortion, and stillbirth of female nurses was 2.6%, 7%, and 2.1%, respectively. We found an increased risk of threatened abortion among nurses with overtime work (OR = 1.719, 95% CI 1.158-2.550). The risk of threatened abortion and spontaneous abortion was elevated among nurses handling disinfectant (OR = 2.293 and 1.63, respectively). We found a nearly twofold increased risk of premature birth (OR = 2.169, 95% CI 1.36-3.459) among nurses handling anti-cancer drugs. CONCLUSIONS: Our findings suggested that maternal occupational exposures might be associated with the risk of adverse pregnancy outcomes among female nurses in China. We recommend that policy-markers and hospital managers work together to reduce exposure to occupational hazards and improve pregnancy outcomes among female nurses.

Effect of arsenic and copper in kidney of mice: Crosstalk between Nrf2/ Keap1 pathway in apoptosis and pyroptosis.

Arsenic (As) and copper (Cu) are two common contaminants in the environment. When organisms are exposed to As or/ and Cu in large quantities or for sustained periods, oxidative stress is induced, adversely affecting kidney function. However, the molecular mechanisms involved in As or/ and Cu-induced nephrotoxicity remain elusive. In this experiment, wild-type C57BL/6 and Nrf2-knockout mice (n = 24 each) were exposed to arsenic trioxide and copper chloride alone or in combination. Our research findings indicate that exposure to As or/ and Cu can activate the Nrf2 antioxidant pathway by upregulating the levels of Nrf2, HO-1, CAT, and downregulating the level of Keap1, thereby reducing As or/ and Cu-induced oxidative stress. Meanwhile, exposure induced kidney cell pyroptosis and apoptosis by promoting the expression of NLRP3 inflammasomes and Caspase-3, which peaked in mice co-treated with As and Cu. Subsequently, we investigated its role in As or/ and Cu-induced kidney injury by knocking out Nrf2. Our results show that after knocking out Nrf2, the expression of antioxidant factors CAT and HO-1 significantly decreased. Based on the low antioxidant capacity after Nrf2 knockout, the levels of NLRP3 inflammasome, GSDMD, and Caspase1 were significantly upregulated after exposure to As and Cu, indicating more severe cellular pyroptosis. In addition, the level of Caspase3-mediated apoptosis was also more severe. Taken together, there is crosstalk between Nrf2-mediated antioxidant capacity and apoptosis/ pyroptosis induced by exposure to As or/ and Cu. Depletion of Nrf2 alters its antioxidant capacity, ultimately leading to more severe apoptosis, pyroptosis, and nephrotoxicity.

Fluorophore-Dapagliflozin Dyad for Detecting Diabetic Liver/Kidney Damages via Fluorescent Imaging and Treating Diabetes via Inhibiting SGLT2.

Type II diabetes is a prevalent disease; if left untreated, it could cause serious complications including liver and kidney damages. Hence, early diagnosis for these damages and effective treatment of diabetes are of high importance. Herein, a fluorophore-dapagliflozin dyad (DX-B-DA) has been developed as a theranostic system that can be triggered by intrahepatic/intrarenal reactive oxygen species (ROS) to concomitantly release a near-infrared (NIR) fluorescent dye (DX) and a SGLT2 inhibitor dapagliflozin (DA). In this dyad (DX-B-DA), the NIR fluorophore (DX) and the drug DA were covalently linked through a boronate ester bond which serves as the fluorescence quencher as well as the ROS-responsive moiety that can be cleaved by pathological levels of ROS in diabetics. The in vitro experiments indicate that, in the absence of hydrogen peroxide, the dyad is weakly emissive and keeps its drug moiety in an inactive state, while upon responding to hydrogen peroxide, the dyad simultaneously releases the NIR dye and the drug DA, suggesting that it can serve as an activatable probe for detecting and imaging diabetic liver/kidney damages as well as a prodrug for diabetes treatment upon being triggered by ROS. The dyad was then injected in mouse model of type II diabetes, and it is found that the dyad can not only offer visualized diagnosis for diabetes-induced liver/kidney damages but also exhibit high efficacy in treating type II diabetes and consequently ameliorating diabetic liver/kidney damages.

Associations of age at natural menopause and occupations in Chinese female workers: A cross-sectional study.

AIMS: To investigate the impact of occupation types on age at natural menopause. METHODS: This is a nation-wide cross-sectional study based on 17,948 female workers aged over 40, who come from different industries or organizations. A face-to-face standardized questionnaire was conducted in all participants with the help of occupational hygienists. Occupational titles were coded according to the International Standard Classification of Occupations (2008) (ISCO08). Cox regression model was used to assess the association between each independent occupation and menopausal timing. Models were adjusted for marriage, education, average annual family income, parity, cigarette smoking, alcohol consumption. RESULTS: Higher risks of earlier age at natural menopause was found among legislators and senior officials (ISCO Minor group:111, HR = 2.328, P < 0.001), among other health associated professionals (ISCO Minor group: 325, HR = 1.477, P = 0.003), the workers involved in mining and mineral processing (ISCO Minor group: 811, HR = 1.515, P = 0.048) and metal processing and finishing (ISCO Minor group: 812, HR = 1.722, P < 0.001). Reduced risks of earlier age at natural menopause, including: finance professionals (ISCO Minor group: 241, HR = 0.751, P = 0.021), manufacturing and construction supervisors (ISCO Minor group: 312, HR = 0.477, P = 0.002), administrative and specialized secretaries (ISCO Minor group: 334, HR = 0.788, P = 0.045), cleaners and helpers (ISCO Minor group: 911, HR = 0.633, P = 0.01). CONCLUSIONS: This is the first study to address the influence of occupation types on reproductive aging, showing some specific occupations could be associated with age at natural menopause. Further investigations are necessary to clarify whether it is chance finding or a true association.

Protective effects of curcumin on ATO-induced nephrotoxicity in ducks in relation to suppressed autophagy, apoptosis and dyslipidemia by regulating oxidative stress.

Arsenic trioxide (ATO) has been known as common environmental pollution, and is deemed to a threat to global public health. Curcumin (Cur) is a phytoconstituent, which has been demonstrated to have antioxidant effects. In the current experiment, we investigated the efficacy of Cur against ATO-induced kidney injury and explored the potential molecular mechanisms that have not yet been fully elucidated in ducks. The results showed that treatment with Cur attenuated ATO-induced body weight loss, reduced the content of ATO in the kidney, and improved ATO-induced kidney pathological damage. Cur also remarkably alleviated the ascent of ATO-induced MDA level and activated the Nrf2 pathway. Using the TEM, we found Cur relieved mitochondrial swelling, autolysosomes generating and nuclear damage. Simultaneously, Cur was found that it not only significantly reduced autophagy-related mRNA and protein levels (mTOR, LC3-Ⅰ, LC3-Ⅱ, Atg-5, Beclin1, Pink1 and Parkin) and but also decreased apoptosis-related mRNA and protein expression levels (cleaved caspase-3, Cytc, p53 and Bax). Furthermore, through nontargeted metabolomics analysis, we observed that lipid metabolism balance was disordered by ATO exposure, while Cur administration alleviated the disturbance of lipid metabolism. These results showed ATO could induce autophagy and apoptosis by overproducing ROS in the kidney of ducks, and Cur might relieve excessive autophagy, apoptosis and disturbance of lipid metabolism by regulating oxidative stress. Collectively, our findings explicate the potential therapeutic value of Cur as a new strategy to a variety of disorders caused by ATO exposure.

Metabolomics and transcriptomics indicated the molecular targets of copper to the pig kidney.

Copper poses huge environmental and public health concerns due to its widespread and persistent use in the past several decades. Although it is well established that at higher levels copper causes nephrotoxicity, the exact mechanisms of its toxicity is not fully understood. Therefore, this experimental study for the first time investigates the potential molecular mechanisms including transcriptomics, metabolomics, serum biochemical, histopathological, cell apoptosis and autophagy in copper-induced renal toxicity in pigs. A total of 14 piglets were randomly assigned to two group (7 piglets per group) and treated with a standard diet (11 mg CuSO4 per kg of feed) and a high copper diet (250 mg CuSO4 per kg of feed). The results of serum biochemical tests and renal histopathology suggested that 250 mg/kg CuSO4 in the diet significantly increased serum creatinine (CREA) and induced renal tubular epithelial cell swelling. Results on transcriptomics and metabolomics showed alteration in 804 genes and 53 metabolites in kidneys of treated pigs, respectively. Combined analysis of transcriptomics and metabolomics indicated that different genes and metabolism pathways in kidneys of treated pigs were involved in glycerophospholipids metabolism and glycosphingolipid metabolism. Furthermore, copper induced mitochondrial apoptosis characterized by increased bax, bak, caspase 3, caspase 8 and caspase 9 expressions while decreased bcl-xl and bcl2/bax expression. Exposure to copper decreased the autophagic flux in terms of increased number of autophagosomes, beclin1 and LC3b/LC3a expression and p62 accumulation. These results indicated that the imbalance of glycosphingolipid metabolism, the impairment of autophagy and increase mitochondrial apoptosis play an important role in copper induced renal damage and are useful mechanisms to understand the mechanisms of copper nephrotoxicity.

Arsenic (III) and/or Antimony (III) induced disruption of calcium homeostasis and endoplasmic reticulum stress resulting in apoptosis in mice heart.

Arsenic (As) and antimony (Sb) are known as an environmental contaminant with cardiotoxicity properties. The endoplasmic reticulum (ER) is the largest calcium reservoir in the cell, and its calcium homeostasis disorder plays a vital role in endoplasmic reticulum stress (ERS) and apoptosis. The objective of this study was to investigate whether As and Sb induced apoptosis via endoplasmic reticulum stress (ERS) linked to calcium homeostasis disturbance. In this study, thirty-two adult mice were gavage-fed daily with As2O3 (4 mg/kg), SbCl3 (15 mg/kg) and co-treat with SbCl3 (15 mg/kg) and As2O3 (4 mg/kg) daily for 60 days. It was observed that As or/and Sb caused histopathological lesions and ER expansion of the heart. Meanwhile, the gene expression of ER Ca2+ release channels (RyR2 and IP3R) and calmodulin-dependent protein kinase II (CaMKII) increased while the levels of mRNA and protein of ER Ca2+ uptake channel (SERCA2) downregulated significantly compared to the controls. Then, As or/and Sb induced ERS and triggered the ER apoptotic pathway by activating unfolded protein response (UPR)-associated genes ((PERK, ATF6, IRE1, XBP1, JNK, GRP78), and apoptosis-related genes (Caspase12, Caspase3, p53, CHOP). Above indicators in As + Sb group became more severe than that of As group and Sb group. Overall, our results proved that the cardiotoxicity caused by As or/and Sb might be concerning disturbing calcium homeostasis, which induced apoptosis through the ERS pathway.

Chronic tribasic copper chloride exposure induces rat liver damage by disrupting the mitophagy and apoptosis pathways.

Despite the fact that copper (Cu) is a vital micronutrient to maintain body function, high doses of Cu through environmental exposure damage various organs, especially the liver, which is the main metabolic organ. To investigate the influence of long-term Cu-induced toxicity on mitophagy and apoptosis in rat liver, 96 seven-month-old male Sprague-Dawley rats were fed TBCC for 24 weeks. The results revealed that exposure to high Cu concentrations could promote oxidative stress liver injury by increasing the hepatic function index (ALT, AST and ALP) and MDA content, while reducing the activity of antioxidant enzymes (T-SOD, GSH-Px and CAT) related to oxidative stress. Consistent with histopathological observations, proper dietary Cu (15-60 mg/kg) could improve antioxidant stress levels and induce a dose-dependent increase in the mRNA expression of mitophagy-related genes, whereas a high Cu concentration (120 mg/kg) could cause severe liver impairment and ultrastructural changes and a reduction in mitophagosomes, accompanied by downregulation of Atg5, Beclin1, Pink1, Parkin, NIX, P62 and LC3B. The expression of apoptosis-related genes (Bax, Bax/Bcl-2, Caspase3, Cytc and p53) and proteins (Caspase3 and p53) was upregulated with the addition of dietary Cu. The results demonstrated that an appropriate dose of TBCC could improve liver function by promoting mitophagy and Cu enzymes that play antioxidative roles, while the accumulation of excess Cu could induce liver lesions by enhancing apoptosis and inhibiting mitophagy pathways.

Copper induces oxidative stress with triggered NF-κB pathway leading to inflammatory responses in immune organs of chicken.

Copper (Cu) is a necessary trace mineral due to its biological activity. Excessive Cu can induce inflammatory response in humans and animals, but the underlying mechanism is still unknown. Here, 240 broilers were used to study the effects of excessive Cu on oxidative stress and NF-κB-mediated inflammatory responses in immune organs. Chickens were fed with diet containing different concentrations of Cu (11, 110, 220, and 330 mg of Cu/kg dry matter). The experiment lasted for 49 days. Spleen, thymus, and bursa of Fabricius (BF) on day 49 were collected for histopathological observation and assessment of oxidative stress status. Additionally, the mRNA and protein levels of NF-κB and inflammatory cytokines were also analyzed. The results indicated that excess Cu could increase the number and area of splenic corpuscle as well as the ratio of cortex and medulla in thymus and BF. Furthermore, excessive Cu intake could decrease activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px); but increase contents of malondialdehyde (MDA), TNF-α, IL-1, IL-1ß; up-regulate mRNA levels of TNF-α, IFN-γ, IL-1, IL-1ß, IL-2, iNOS, COX-2, NF-κB and protein levels of TNF-α, IFN-γ, NF-κB, p-NF-κB in immune organs. In conclusion, excessive Cu could cause pathologic changes and induce oxidative stress with triggered NF-κB pathway, and might further regulate the inflammatory response in immune organs of chicken.

Long-term exposure to copper induces autophagy and apoptosis through oxidative stress in rat kidneys.

Copper (Cu) is an essential trace element for most organisms. However, excessive Cu can be highly toxic. The purpose of this study was to elucidate the mechanism underlying Cu toxicity in the kidneys of rats after treatment with CuCl2 (15 [control], 30, 60, or 120 mg/kg in the diet) for 180 days. Histological and ultrastructural changes, antioxidant enzyme activity, and the mRNA and protein levels of apoptosis and autophagy-related genes were measured. The results showed that Cu exposure led to significant accumulation of copper in kidneys and disorganized kidney morphology. The activities of total anti-oxidation capacity (T-AOC) and superoxide dismutase (SOD) in the kidneys decreased significantly, while the malondialdehyde (MDA) content increased. Furthermore, excessive Cu markedly upregulated the expression of autophagy and apoptosis-related genes (LC3A, LC3B, ATG-5, Beclin-1, Caspase3, CytC, P53, Bax), but downregulated the expression of P62, mTOR and BCL-2. Moreover, the LC3B/LC3A, ATG-5, Beclin-1, P53, Caspase3 proteins were up-regulated while P62 was down-regulated in the kidney tissues of the treatment groups. Overall, these findings provide strong evidence that excess Cu can trigger autophagy and apoptosis via the mitochondrial pathway by inducing oxidative stress in rat kidneys.

Copper induces energy metabolic dysfunction and AMPK-mTOR pathway-mediated autophagy in kidney of broiler chickens.

To explore the effects of copper (Cu) on energy metabolism and AMPK-mTOR pathway-mediated autophagy in kidney, a total of 240 one-day-old broiler chickens were randomized into four equal groups and fed on the diets with different levels of Cu (11, 110, 220, and 330 mg/kg) for 49 d. Results showed that excess Cu could induce vacuolar degeneration and increase the number of autophagosomes in kidney, and the adenosine triphosphate (ATP) level and mRNA levels of energy metabolism-related genes were decreased with the increasing dietary Cu level. Moreover, immunohistochemistry and immunofluorescence showed that the positive expressions of Beclin1 and LC3-II were mainly located in cytoplasm of renal tubular epithelial cells and increased significantly with the increasing levels of Cu. The mRNA levels of Beclin1, Atg5, LC3-I, LC3-II, Dynein and the protein levels of Beclin1, Atg5, LC3-II/LC3-I and p-AMPKα1/AMPKα1 were markedly elevated in treated groups compared with control group (11 mg/kg Cu). However, the mRNA and protein levels of p62 and p-mTOR/mTOR were significantly decreased with the increasing levels of Cu. These results suggest that impaired energy metabolism induced by Cu may lead to autophagy via AMPK-mTOR pathway in kidney of broiler chickens.

Effects of copper on oxidative stress and autophagy in hypothalamus of broilers.

The purpose of this research was to discuss the effects of copper (Cu)-induced toxicity on oxidative stress and autophagy in hypothalamus of broilers. In this study, 240 one-day-old broilers were randomly divided into 4 groups and the contents of dietary Cu in 4 groups were 11 mg/kg (control group), 110 mg/kg (group I), 220 mg/kg (group II), and 330 mg/kg (group III). The experiment lasted for 49 days and the hypothalamus tissues were collected for histological observation and detection of Cu content. Additionally, the indicators related to oxidative stress in hypothalamus were determined. Moreover, the mRNA expression levels of autophagy-related genes and the protein expression levels of Beclin1, LC3-II/LC3-I, and p62 in hypothalamus were measured. Results showed that the treated groups were observed vacuolar degeneration in hypothalamus compared to control group, and the Cu content in hypothalamus was increased with the increase of dietary Cu. Furthermore, the activities of SOD, CAT, T-AOC were increased in group I and group II and then decreased in group III, and the content of MDA and the mRNA levels of Nrf2, HO-1, SOD-1, CAT, GCLC, GCLM, and GST in treated groups were elevated compared to control group. Moreover, the mRNA expression levels of Beclin1, Atg5, LC3-I, LC3-II and the protein expression levels of Beclin1 and LC3-II/LC3-I up-regulated significantly with the increasing levels of Cu. However, the mRNA expression levels of p62 and mTOR and the protein expression level of p62 down-regulated remarkably. Taken together, our present study evidenced that excessive intake of Cu could induce oxidative stress and autophagy in hypothalamus of broilers.

Inhibition of Caspase-1-dependent pyroptosis attenuates copper-induced apoptosis in chicken hepatocytes.

The purpose of this study was to investigate the effects of copper (Cu) on hepatocyte pyroptosis and the relationship between pyroptosis and apoptosis in the mechanisms of Cu toxicity. Primary chicken hepatocytes were cultured in different concentrations of Cu sulfate (CuSO4) (0, 10, 50, and 100 µM), N-acetylcysteine (NAC) (1 mM), and Z-YVAD-fluoromethylketone (Z-YVAD-FMK) (10 µM) for 24 h, and the combination of Cu and NAC or Z-YVAD-FMK for 24 h. Cellular morphology and function, cell viability, mitochondria membrane potential (MMP), apoptosis rate, mRNA expression of pyroptosis-related and apoptosis-related genes, and Caspase-1, Caspase-3 proteins expression were determined. These results indicated that Cu markedly induced the mRNA expression of pyroptosis-related genes (Caspase-1, IL-1ß, IL-18, and NLRP3) and Caspase-1 protein expression. Furthermore, contents of Caspase-1, IL-1ß, and IL-18 in the supernatant fluid of culture hepatocytes were significantly increased in hepatocytes. NAC relieved excess Cu-caused the changes of above genes and proteins. Additionally, Z-YVAD-FMK, caspase-1 inhibitor, which attenuated Cu-induced the increased lactic dehydrogenase (LDH), aspartate amino transferase (AST), alanine aminotransferase (ALT) activities. Furthermore, treatment with Cu and Z-YVAD-FMK could down-regulate the mRNA levels of Caspase-3, Bak1, Bax, and CytC and Caspase-3 protein expression, up-regulate the mRNA expression of Bcl2, increase the MMP and reduce cell apoptosis compared to treatment with Cu in hepatocytes. Collectively, these finding evidenced that excess Cu induced pyroptosis by generating ROS in hepatocytes, and the inhibition of Caspase-1-dependent pyroptosis might attenuate Cu-induced apoptosis.

[An investigation of prevalence of malignant tumors in 1204 nurses].

OBJECTIVE: To investigate the prevalence of malignant tumors in nurses and its influencing factors and to provide a reference for protecting the health of nurses. METHODS: Cluster sampling was used to randomly survey 1204 married nurses working in one tumor hospital and two tertiary general hospital in Beijing, China, from June to August in 2014. Using the homemade health questionnaire and medical examination reports, the prevalence of malignant tumors in nurses was analyzed. RESULTS: The prevalence of malignant tumors in nurses was 18.3‰, and the prevalence of malignant tumors in the tumor hospital was the highest, reaching 40.1‰. The prevalence of malignant tumors varied significantly between nurses in different hospitals (P<0.05) and in different departments (P<0.05). The malignant tumors in nurses mainly included breast cancer, thyroid cancer, and cervical cancer. The mean age of nurses suffering from malignant tumors was 41 years, and the mean length of service was 20 years. The hospital and department where nurses worked, as well as their age and length of service, were significantly associated with malignant tumors (P<0.05). CONCLUSION: The prevalence of breast cancer, thyroid cancer, and cervical cancer is high in nurses surveyed, particularly those working in the tumor hospital. Further in-depth analysis of the reasons is needed to take preventive interventions for protecting the health of nurses.

Mitochondrial miR-12294-5p-Regulated Copper Exposure-Caused Mitochondrial-Dependent Ferroptosis by Targeted Inhibition of CISD1 in Chicken Hepatocytes.

Copper (Cu) is a common trace element additive in animal and human foods, and excessive intake of Cu has been shown to cause hepatotoxicity, but the underlying mechanism remains unclear. Our previous research found that Cu exposure dramatically upregulated mitochondrial miR-12294-5p expression and confirmed its targeted inhibition of CISD1 expression in chicken hepatocytes. Thus, we aimed to explore the potential role of mitomiR-12294-5p/CISD1 axis in Cu exposure-resulted hepatotoxicity. Here, we observed that Cu exposure resulted in Cu accumulation and pathological injury in chicken livers. Moreover, we found that Cu exposure caused mitochondrial-dependent ferroptosis in chicken hepatocytes, which were prominent on the increased mitochondrial Fe2+ and mitochondrial lipid peroxidation, inhibited levels of CISD1, GPX4, DHODH, and IDH2, and also enhanced level of PTGS2. Notably, we identified that inhibition of mitomiR-2954 level effectively mitigated Cu-exposure-resulted mitochondrial Fe2+ accumulation and mitochondrial lipid peroxidation and prevented the development of mitochondrial-dependent ferroptosis. However, increasing the mitomiR-12294-5p expression considerably aggravated the influence of Cu on these indicators. Meanwhile, the overexpression of CISD1 effectively alleviated Cu-caused mitochondrial-dependent ferroptosis, while silent CISD1 eliminated the therapeutic role of mitomiR-12294-5p inhibitor. Overall, our findings indicated that mitomiR-12294-5p/CISD1 axis played a critical function in Cu-caused hepatotoxicity in chickens by regulating mitochondrial-dependent ferroptosis.

Mitochondrial derived vesicle-carrying protein MIGA2 promotes copper-induced autophagosomes-lysosomes fusion by regulating ATG14.

As an environmental pollution metal, copper (Cu) exposure-induced toxicity is closely related to mitochondrial damage. Mitochondrial-derived vesicles (MDVs) plays an essential role in mitochondrial quality control and cellular metabolism. However, the mechanism by which MDVs are involved in cellular metabolism under Cu exposure remains unclear. Here, the MDV-carrying protein MIGA2 was identified as a crucial molecule involved in the Cu-induced autophagosomes-lysosomes fusion. Furthermore, Cu exposure significantly promoted MDVs secretion, accompanied by a markedly increased MIGA2 expression in MDVs, as well as accelerated the autophagosomes-lysosomes fusion. However, small RNA interference of SNX9 (the MDVs secretion inductor) and MIGA2 blocked autophagic flux induced by Cu, leading to failure of autophagosomes degradation. Co-immunoprecipitation assay further demonstrated that ATG14 was a regulation target protein of MIGA2. Overexpression and knockdown of ATG14 significantly affected the autophagosomes-lysosomes fusion induced by Cu. Meanwhile, knockdown of ATG14 dramatically reversed the effect of MIGA2-overexpression in promoting autophagosomes-lysosomes fusion, while overexpression of ATG14 shows the opposite effect. These results demonstrated that MDVs-carrying MIGA2 protein promoted autophagosomes-lysosomes fusion induced by Cu. This study demonstrated that MDVs is involved in regulating organelles-to-organelles communication, providing a new insight into the toxicity mechanism of Cu exposure on hepatocytes.

Hesperidin alleviates terbuthylazine-induced ferroptosis via maintenance of mitochondria-associated endoplasmic reticulum membrane integrity in chicken hepatocytes.

Terbuthylazine (TBA) is a common triazine herbicide used in agricultural production, which causes toxic damage in multiple tissues. Hesperidin (HSP) is a flavonoid derivative that has anti-inflammatory, antioxidant and cytoprotective effects, but its role in reducing toxic damage caused by pesticides is still unclear. In this study, we aimed to investigate the toxic effect of TBA exposure on chicken hepatocytes and the therapeutic effect of HSP on the TBA-induced hepatotoxicity. Our results demonstrated that HSP could alleviate TBA exposure-induced endoplasmic reticulum (ER) stress. Interestingly, TBA significantly disrupted the integrity of mitochondria-associated endoplasmic reticulum membrane (MAM), while HSP treatment showed the opposite tendency. In addition, TBA could significantly trigger ferroptosis in liver, and HSP treatment reversed ferroptosis under TBA exposure. These results suggested that HSP could inhibit ER stress and alleviate ferroptosis under TBA exposure via maintaining MAM integrity, which provided a novel strategy to take precautions against TBA toxicity.

Drp1 Aggravates Copper Nanoparticle-Induced ER-Phagy by Disturbing Mitochondria-Associated Membranes in Chicken Hepatocytes.

As an efficient alternative copper (Cu) source, copper nanoparticles (nano-Cu) have been widely supplemented into animal-producing food. Therefore, it is necessary to assess the effect of nano-Cu exposure on the biological health risk. Recently, the toxic effects of nano-Cu have been confirmed but the underlying mechanism remains unclear. This study reveals the impact of nano-Cu on endoplasmic reticulum autophagy (ER-phagy) in chicken hepatocytes and further identifies Drp1 and its downstream gene FAM134B as crucial regulators of nano-Cu-induced hepatotoxicity. Nano-Cu exposure can induce Cu ion overaccumulation and pathological injury in the liver, trigger excessive mitochondrial fission and mitochondria-associated membrane (MAM) integrity damage, and activate ER-phagy in vivo and in vitro. Interestingly, the knockdown of Drp1 markedly decreases the expression of FAM134B induced by nano-Cu. Furthermore, the expression levels of ATL3, CCPG1, SEC62, TEX264, and LC3II/LC3I induced by nano-Cu exposure are decreased by inhibiting the expression of Drp1. Simultaneously, the inhibition of FAM134B effectively alleviates nano-Cu-induced ER-phagy by downregulating the expression of ATL3, CCPG1, SEC62, TEX264, and LC3II/LC3I. Overall, these results suggest that Drp1-mediated impairment of MAM integrity leads to ER-phagy as a novel molecular mechanism involved in the regulation of nano-Cu-induced hepatotoxicity. These findings provide new ideas for future research on the mechanism of nano-Cu-induced hepatotoxicity.

Copper toxicity in the liver of broiler chicken: insights from metabolomics and AMPK-mTOR mediated autophagy perspective.

Exposure to copper (Cu) has been associated with metabolic disorders in animals and humans, but the underlying mechanism remains unclear. One-day-old broiler chickens, numbering a total of 192, were nourished with dietary intakes that contained varying concentrations of Cu, specifically 11, 110, 220, and 330 mg/kg of Cu, for a period extending over a duration of 7 wk. As a result of the study, Cu exposure resulted in vacuolization, fragmentation of mitochondria cristae, and the increase of autophagosomes in hepatocytes. Metabolomics analysis illustrated that Cu caused a total of 59 different metabolites in liver, predominantly associated with the glycerophospholipid metabolic pathway, leading to metabolic disruption. Moreover, high-Cu diet markedly reduced the levels of AMPKα1, p-AMPKα1, mTOR, and p-mTOR and enhanced the expression levels of the autophagy-related factors (Atg5, Dynein, Beclin1, and LC3-II). Overall, Cu exposure caused chicken liver injury and resulted in disturbed metabolic processes and mediated autophagy primarily through the AMPK-mTOR axis.

Gut microbiota disorders aggravate terbuthylazine-induced mitochondrial quality control disturbance and PANoptosis in chicken hepatocyte through gut-liver axis.

Terbuthylazine (TBA) is a widely prevalent pesticide pollutant, which is a global concern due to its environmental residual. However, the toxic mechanism of TBA have not been fully solved. Here, we explored that TBA exposure disrupts the intestinal flora and aggravated disturbance of mitochondrial quality control and PANapoptosis in hepatocytes via gut-liver axis. Our findings demonstrated that TBA exposure induced significant damage to the jejunum barrier, evidenced by a marked decrease in the expression of Occludin and ZO-1. Moreover. TBA led to intestinal microflora disorder, manifested as the decreased abundance of Firmicutes, and increased abundance of the Nitrospirota, Chloroflexi, Desulfobacterota, Crenarchaeota, Myxococcota, and Planctomycetota. Meanwhile, intestinal microflora disorder affected the biological processes of lipid metabolism and cell growth and death of hepatocytes by RNA-Seq analysis. Furthermore, TBA could induced mitochondrial quality control imbalance, including mitochondrial redox disorders, lower activity of mitochondrial fusion and biogenesis decrease, and increasing level of mitophagy. Subsequently, TBA significantly increased expression levels of pyroptosis, apoptosis and necroptosis-related proteins. In general, these results demonstrated the underlying mechanisms of TBA-induced hepatotoxicity induced via the gut-liver axis, which provides a theoretical basis for further research of ecotoxicology of TBA.