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AMPK/PPAR-γ/NF-κB axis participates in ROS-mediated apoptosis and autophagy caused by cadmium in pig liver
2022
Wang, Huan | Wang, Anqi | Wang, Xinqiao | Zeng, Xiangyin | Xing, Houjuan
The experiment was conducted to investigate the effects of Cadmium (Cd) on growth performance, blood biochemical parameters, oxidative stress, hepatocyte apoptosis and autophagy of weaned piglets. A total of 12 healthy weaned piglets were randomly assigned to the control and the Cd group, which were fed with a basal diet and the basal diet supplemented with 15 ± 0.242 mg/kg CdCl₂ for 30 d, respectively. Our results demonstrated that Cd significantly decreased final body weight, average daily feed intake (ADFI), average daily gain (ADG) and increased feed-to-gain (F/G) ratio (P < 0.05). For blood biochemical parameters, Cd treatment significantly decreased the red blood cell (RBC), hemoglobin (HGB), hematocrit (HCT), total protein, albumin, copper content and iron content (P < 0.05). In addition, liver injury was observed in the Cd-exposed group. Our results also demonstrated that Cd exposure contributed to the production of ROS, activated the AMPK/PPAR-γ/NF-κB pathway (increasing the expressions of P-AMPK/AMPK, NF-κB, I-κB-β, COX-2, and iNOS, decreasing the expressions of PPAR-γ and I-κB-α), finally induced autophagy (increasing the expressions of Beclin-1, the ratio of LC3-II/LC3-I and p62), and apoptosis (increasing the expressions of Bax, Bak, Caspase-9, and Caspase-3, decreasing the expression of Bcl-2). Overall, these findings revealed the vital role of AMPK/PPAR-γ/NF-κB pathway in Cd-induced liver apoptosis and autophagy, which provided deeper insights into a better understanding of Cd-induced hepatotoxicity.
Show more [+] Less [-]Gestational PCB52 exposure induces hepatotoxicity and intestinal injury by activating inflammation in dam and offspring mice: A maternal and progeny study
2022
Xu, Ling-Ling | Zhang, Qin-Yao | Chen, Yu-Kui | Chen, Li-Jian | Zhang, Kai-Kai | Wang, Qi | Xie, Xiao-Li
Although Polychlorinated biphenyl (PCB) levels are decreased in the environment, the adverse effects of gestational exposure on the mother and offspring cannot be ignored due to the vulnerability of the fetus. In the present study, pregnant Balb/c mice were administered PCB52 (1 mg/kg BW/day) or corn oil vehicle by gavage until parturition. In the dams, PCB52 caused histopathological changes in the liver, higher serum levels of aminotransferase and alanine aminotransferase, and activated apoptosis and autophagy, suggesting hepatotoxicity. Overexpressed indicators of TLR4 pathway were observed in the liver of PCB52-exposed dams, indicated hepatic inflammation. Moreover, PCB52 exposure weakened the intestinal barrier and triggered inflammatory response, which might contribute to the hepatic inflammation by gut-liver axis. In the pups, prenatal PCB52 exposure affected the sex ratio at birth and reduced birth length and weights. Similar to the dams, prenatal PCB52 exposure induced hepatotoxicity in the pups without gender difference. Consistent with the alteration of gut microbiota, intestinal inflammation was confirmed, accompanying the disruption in the intestinal barrier and the activation of apoptosis and autophagy in the PCB52-exposed pups. Intestinal injury might be responsible for hepatotoxicity at least in part. Taken together, these findings suggested that gestational PCB52 exposure induced hepatic and intestinal injury in both maternal and offspring mice by arousing inflammation.
Show more [+] Less [-]Glycine ameliorates MBP-induced meiotic abnormalities and apoptosis by regulating mitochondrial-endoplasmic reticulum interactions in porcine oocytes
2022
Gao, Lepeng | Zhang, Chang | Yu, Sicong | Liu, Shuang | Wang, Guoxia | Lan, Hainan | Zheng, Xin | Li, Suo
Monobutyl phthalate (MBP) is the main metabolite of dibutyl phthalate (DBP) in vivo. MBP has a stable structure, can continuously accumulate in living organisms, and has the potentially to harm animal and human reproductive function. In the ovarian follicle microenvironment, MBP may lead to defects in follicular development and steroid production, abnormal meiotic maturation, impaired ovarian function and other reproductive deficits. In this study, SMART-seq was used to investigate the effects of MBP exposure on the in vitro maturation (IVM) and development of porcine oocytes. The results showed that differentially expressed genes after MBP exposure were enriched in the biological processes cytoskeleton, cell apoptosis, endoplasmic reticulum (ER) and mitochondria. Glycine (Gly) improved the developmental potential of porcine oocytes by regulating mitochondrial and ER function. The effect of Gly in protecting oocytes against MBP-induced damage was studied. The results showed that the addition of Gly significantly decreased the rate of MBP-induced spindle abnormalities, decreased the frequency of MBP-induced mitochondria-associated ER membrane (MAM) interactions, and downregulated the protein and gene expression of the linkage molecules Mitofusin 1 (MFN1) and Mitofusin 2 (MFN2) in the MAM. Additionally, treatment with Gly restored the distribution of the 1,4,5-triphosphate receptor 1 (IP₃R1) and voltage-dependent anion channel 1 (VDAC1), further decreasing the intracellular free calcium concentration ([Ca²⁺]ᵢ) levels and mitochondrial Ca²⁺ ([Ca²⁺]ₘ) , increasing the ER Ca²⁺ ([Ca²⁺]ER) levels, and thus significantly increasing the ER levels and mitochondrial membrane potential (ΔΨ m). Gly also decreased the levels of reactive oxygen species (ROS) and increased the levels of Glutathione (GSH), oocyte apoptosis-related indicators (Caspase-3 activity and Annexin V) and oocyte apoptosis-related genes (BAX, Caspase 3 and AIFM1). Our results suggest that Gly can ameliorate microtubule cytoskeleton abnormalities and improve oocyte maturation by reducing the defective mitochondrial–ER interactions caused by MBP exposure in vitro.
Show more [+] Less [-]TBBPA and its alternative TCBPA induced ROS-dependent mitochondria-mediated apoptosis in the liver of Rana nigromaculata
2022
Jia, Xiuying | Yan, Ruopeng | Lin, Huikang | Liu, Zhiquan | Shen, Lilai | Yang, Hongmei | Wu, Haoying | Shan, Xiaodong | Zhang, Hangjun
Tetrabromobisphenol A (TBBPA), which is the most widely employed brominated flame retardant, and its alternative tetrachlorobisphenol A (TCBPA) are widely distributed in aquatic environments. In the present study, the hepatotoxicity induced by TBBPA and TCBPA was investigated in Rana nigromaculata, and the potential mechanisms were investigated with a particular focus on ROS (reactive oxygen species) -dependent mitochondria-mediated apoptosis. Healthy adult frogs were exposed to 0, 0.001, 0.01, 0.1, and 1 mg/L waterborne TBBPA and TCBPA for 14 days. The results showed that liver weight was significantly increased by 51.52%–98.99% in the 0.01, 0.1, and 1 mg/L TBBPA and TCBPA groups relative to the control. Histological examination revealed that the structure of the liver, to some extent, was influenced by TBBPA and TCBPA with nuclear shrinkage and mitochondrial swelling. Meanwhile, TBBPA and TCBPA have significantly increased the alanine transaminase level in serum and the content of ROS, while inhibiting the activity of superoxide dismutase in the liver. In addition, DNA fragments were observed in the TBBPA and TCBPA groups relative to the control. Expression of Cytochrome C was significantly increased by 1.13-, 1.38-, 1.60-, and 2.46-fold in 0.001, 0.01, 0.1, and 1 mg/L TBBPA, and by 1.26-, 1.51-, 2.14-, and 2.98- fold in 0.001, 0.01, 0.1, and 1 mg/L TCBPA, respectively, which indicated that TCBPA may be more toxic than TBBPA. Similarly, the ratio of Bax/Bcl-2 was increased in a dose-dependent manner. These results indicated that apoptosis in the ROS-dependent mitochondrial pathway mediates hepatotoxicity caused by TBBPA and TCBPA. The present study will facilitate an understanding of the toxicity mechanism of flame retardants.
Show more [+] Less [-]Effects of environmental concentrations of the fragrance amyl salicylate on the mediterranean mussel Mytilus galloprovincialis
2022
Bernardini, I. | Fabrello, J. | Vecchiato, M. | Ferraresso, S. | Babbucci, M. | Peruzza, L. | Rovere, G Dalla | Masiero, L. | Marin, M.G. | Bargelloni, L. | Gambaro, A. | Patarnello, T. | Matozzo, V. | Milan, M.
Amyl salicylate (AS) is a fragrance massively used as a personal care product and following the discharged in wastewaters may end up in the aquatic environment representing a potential threat for the ecosystem and living organisms. AS was recently detected in water of the Venice Lagoon, a vulnerable area continuously subjected to the income of anthropogenic chemicals. The lagoon is a relevant area for mollusc farming, including the Mediterranean mussels (Mytilus galloprovincialis) having an important economic and ecological role. Despite high levels of AS occurred in water of the Lagoon of Venice, no studies investigated the possible consequences of AS exposures on species inhabiting this ecosystem to date. For the first time, we applied a multidisciplinary approach to investigate the potential effects of the fragrance AS on Mediterranean mussels. To reach such a goal, bioaccumulation, cellular, biochemical, and molecular analyses (RNA-seq and microbiota characterization) were measured in mussels treated for 7 and 14 days with different AS Venice lagoon environmental levels (0.1 and 0.5 μg L⁻¹). Despite chemical investigations suggested low AS bioaccumulation capability, cellular and molecular analyses highlighted the disruption of several key cellular processes after the prolonged exposures to the high AS concentration. Among them, potential immunotoxicity and changes in transcriptional regulation of pathways involved in energy metabolism, stress response, apoptosis and cell death regulations have been observed. Conversely, exposure to the low AS concentration demonstrated weak transcriptional changes and transient increased representation of opportunistic pathogens, as Arcobacter genus and Vibrio aestuarianus. Summarizing, this study provides the first overview on the effects of AS on one of the most widely farmed mollusk species.
Show more [+] Less [-]Immunotoxicity of radiofrequency radiation
2022
Yadav, Himanshi | Sharma, Radhey Shyam | Singh, Rajeev
Growing evidence recommends that radiofrequency radiations might be a new type of environmental pollutant. The consequences of RFR on the human immune system have gained considerable interest in recent years, not only to examine probable negative effects on health but also to understand if RFR can modulate the immune response positively. Although several studies have been published on the immune effects of RFR but no satisfactory agreement has been reached. Hence this review aims to evaluate the RFR modulating impacts on particular immune cells contributing to various innate or adaptive immune responses. In view of existing pieces of evidence, we have suggested an intracellular signaling cascade responsible for RFR action. The bio-effects of RFR on immune cell morphology, viability, proliferation, genome integrity, and immune functions such as ROS, cytokine secretion, phagocytosis, apoptosis, etc. are discussed. The majority of existing evidence point toward the possible shifts in the activity, number, and/or function of immunocompetent cells, but the outcome of several studies is still contradictory and needs further studies to reach a conclusion. Also, the direct association of experimental studies to human risks might not be helpful as exposure parameters vary in real life. On the basis of recent available literature, we suggest that special experiments should be designed to test each particular signal utilized in communication technologies to rule out the hypothesis that longer exposure to RFR emitting devices would affect the immunity by inducing genotoxic effects in human immune cells.
Show more [+] Less [-]Bisphenol AF blocks Leydig cell regeneration from stem cells in male rats
2022
Yu, Yige | Xin, Xiu | Ma, Feifei | Li, Xiaoheng | Wang, Yiyan | Zhu, Qiqi | Chen, Haiqiong | Li, Huitao | Ge, Ren-shan
Bisphenol A (BPA) is a ubiquitous environmental pollutant, mainly from the manufacture and use of plastics. The use of BPA is restricted, and its new analogs (including bisphenol AF, BPAF) are being produced to replace it. However, the effect of BPAF on the male reproductive system remains unclear. Here, we report the effect of BPAF on Leydig cell regeneration in rats. Leydig cells were eliminated by ethane dimethane sulfonate (EDS, i.p., 75 mg/kg) and the regeneration began 14 days after its treatment. We gavaged 0, 10, 100, and 200 mg/kg BPAF to rats on post-EDS day 7–28. BPAF significantly reduced serum testosterone and progesterone levels at ≧10 mg/kg. It markedly reduced serum levels of estradiol, luteinizing hormone, and follicle-stimulating hormone at 100 and 200 mg/kg. BPAF significantly reduced Leydig cell number at 200 mg/kg. BPAF significantly down-regulated the expression of Cyp17a1 at doses of 10 mg/kg and higher and the expression of Insl3, Star, Hsd17b3, Hsd11b1 in Leydig cells at 100 and 200 mg/kg, while it induced a significant up-regulation of Fshr, Dhh, and Sox9 in Sertoli cells at 200 mg/kg. BPAF induced oxidative stress and reduced the level of SOD2 at 200 mg/kg. It induced apoptosis and autophagy by increasing the levels of BAX, LC3B, and BECLIN1 and lowering the levels of BCL2 and p62 at 100 and 200 mg/kg. It induced autophagy possibly via decreasing the phosphorylation of AKT1 and mTOR. BPAF also significantly induced ROS production and apoptosis at a concentration of 10 μM, and reduced testosterone synthesis in rat R2C Leydig cells at a concentration of 10 μM in vitro, but did not affect cell viability after 24 h of treatment. In conclusion, BPAF is a novel endocrine disruptor, inhibiting the regeneration of Leydig cells.
Show more [+] Less [-]Effect of polystyrene nanoplastics on cell apoptosis, glucose metabolism, and antibacterial immunity of Eriocheir sinensis
2022
Nan, Xingyu | Jin, Xingkun | Song, Yu | Zhou, Kaimin | Qin, Yukai | Wang, Qun | Li, Weiwei
The adverse effects of plastic waste and nanoplastics on the water environment have become a focus of global attention in recent years. In the present study, using adult Chinese mitten crabs (Eriocheir sinensis) as an animal model, the bioaccumulation and the in vivo and in vitro toxicity of polystyrene nanoplastics (PS NPs), alone or in combination with the bacteria, were investigated. This study aimed to investigate the effects of PS NPs on apoptosis and glucose metabolism in Chinese mitten crabs, and whether PS NPs could synergistically affect the antibacterial immunity of crabs. We observed that NPs were endocytosed by hemocytes, which are immune cells in crustaceans and are involved in innate immunity. The RNA sequencing data showed that after hemocytes endocytosed NPs, apoptosis and glucose metabolism-related gene expression was significantly induced, resulting in abnormal cell apoptosis and a glucose metabolism disorder. In addition, exposure to NPs resulted in changes in the antimicrobial immunity of crabs, including changes in antimicrobial peptide expression, survival, and bacterial clearance. In summary, NPs could be endocytosed by crab hemocytes, which adversely affected the cell apoptosis, glucose metabolism, and antibacterial immunity of Eriocheir sinensis. This study revealed the effects of NPs on crab immunity and lays the foundation for further exploration of the synergistic effect of NPs and bacteria.
Show more [+] Less [-]Endoplasmic reticulum stress aggravates copper-induced apoptosis via the PERK/ATF4/CHOP signaling pathway in duck renal tubular epithelial cells
2021
Wang, Xiaoyu | Zhuang, Yu | Fang, Yukun | Cao, Huabin | Zhang, Caiying | Xing, Chenghong | Guo, Xiaoquan | Li, Guyue | Liu, Ping | Hu, Guoliang | Yang, Fan
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 (CuSO₄) (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.
Show more [+] Less [-]Cadmium exposure induces osteoporosis through cellular senescence, associated with activation of NF-κB pathway and mitochondrial dysfunction
2021
Luo, Huigen | Gu, Renjie | Ouyang, Huiya | Wang, Lihong | Shi, Shanwei | Ji, Yuna | Bao, Baicheng | Liao, Guiqing | Xu, Baoshan
Cadmium (Cd) is a heavy metal toxicant as a common pollutant derived from many agricultural and industrial sources. The absorption of Cd takes place primarily through Cd-contaminated food and water and, to a significant extent, via inhalation of Cd-contaminated air and cigarette smoking. Epidemiological data suggest that occupational or environmental exposure to Cd increases the health risk for osteoporosis and spontaneous fracture such as itai-itai disease. However, the direct effects and underlying mechanism(s) of Cd exposure on bone damage are largely unknown. We used primary bone marrow-derived mesenchymal stromal cells (BMMSCs) and found that Cd significantly induced BMMSC cellular senescence through over-activation of NF-κB signaling pathway. Increased cell senescence was determined by production of senescence-associated secretory phenotype (SASP), cell cycle arrest and upregulation of p21/p53/p16ᴵᴺᴷ⁴ᵃ protein expression. Additionally, Cd impaired osteogenic differentiation and increased adipogenesis of BMMSCs, and significantly induced cellular senescence-associated defects such as mitochondrial dysfunction and DNA damage. Sprague-Dawley (SD) rats were chronically exposed to Cd to verify that Cd significantly increased adipocyte number, and decreased mineralization tissues of bone marrow in vivo. Interestingly, we observed that Cd exposure remarkably retarded bone repair and regeneration after operation of skull defect. Notably, pretreatment of melatonin is able to partially prevent Cd-induced some senescence-associated defects of BMMSCs including mitochondrial dysfunction and DNA damage. Although Cd activated mammalian target of rapamycin (mTOR) pathway, rapamycin only partially ameliorated Cd-induced cell apoptosis rather than cellular senescence phenotypes of BMMSCs. In addition, a selective NF-κB inhibitor moderately alleviated Cd-caused the senescence-related defects of the BMMSCs. The study shed light on the action and mechanism of Cd on osteoporosis and bone ageing, and may provide a novel option to ameliorate the harmful effects of Cd exposure.
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