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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.
显示更多 [+] 显示较少 [-]Potentials of orally supplemented selenium-enriched Lacticaseibacillus rhamnosus to mitigate the lead induced liver and intestinal tract injury
2022
Jin, Han | Riaz Rajoka, Muhammad Shahid | Xu, Xiaoguang | Liao, Ning | Pang, Bing | Yan, Lu | Liu, Guanwen | Sun, Hui | Jiang, Chunmei | Shao, Dongyan | Barba, Francisco J. | Shi, Junling
Lead is a metal that exists naturally in the Earth's crust and is a ubiquitous environmental contaminant. The alleviation of lead toxicity is important to keep human health under lead exposure. Biosynthesized selenium nanoparticle (SeNPs) and selenium-enriched Lactobacillus rhamnosus SHA113 (Se-LRS) were developed in this study, and their potentials in alleviating lead-induced injury to the liver and intestinal tract were evaluated in mice by oral administration for 4 weeks. As results, oral intake of lead acetate (150 mg/kg body weight per day) caused more than 50 times and 100 times lead accumulation in blood and the liver, respectively. Liver function was seriously damaged by the lead exposure, which is indicated as the significantly increased lipid accumulation in the liver, enhanced markers of liver function injury in serum, and occurrence of oxidative stress in liver tissues. Serious injury in intestinal tract was also found under lead exposure, as shown by the decrease of intestinal microbiota diversity and occurrence of oxidative stress. Except the lead content in blood and the liver were lowered by 52% and 58%, respectively, oral administration of Se-LRS protected all the other lead-induced injury markers to the normal level. By the comparison with the effects of normal L. rhamnosus SHA113 and the SeNPs isolated from Se-LRS, high protective effects of Se-LRS can be explained as the extremely high efficiency to promote lead excretion via feces by forming insoluble mixture. These findings illustrate the developed selenium-enriched L. rhamnosus can efficiently protect the liver and intestinal tract from injury by lead.
显示更多 [+] 显示较少 [-]Presence of nano-sized mercury-containing particles in seafoods, and an estimate of dietary exposure
2022
Suzuki, Yoshinari | Kondo, Midori | Akiyama, Hiroshi | Ogra, Yasumitsu
The toxicity of nano-sized particles of mercury (NP–Hg), which are thought to be generated during the detoxification of methyl mercury (MeHg), may differ from that of MeHg, elemental Hg (Hg⁰), and inorganic Hg (I–Hg). From a human health perspective, it is important to evaluate the presence of NP-Hg in seafoods. We investigated the in vivo formation of NP-Hg in fish and shellfish, which are the main sources of Hg exposure in humans. NP-Hg was measured in 90 fish samples with single-particle inductively coupled plasma mass spectrometry (spICP-MS) after enzyme degradation with pancreatin and lipase. In addition to NP-Hg, total Hg (T-Hg), MeHg, and selenium (Se) concentrations were evaluated. Transient Hg signals were detected as nanoparticles from almost all samples by using spICP-MS. Higher particle number concentrations (CPN) were observed in the tuna–swordfish group than in the shellfish group (17.7 × 10⁷ vs. 1.2 × 10⁶ particles/g, respectively). Although the CPN and maximum particle mass increased significantly with increasing T-Hg concentration, the increase in CPN was greater than those in maximum particle mass. Assuming that the NP-Hg detected was HgSe (tiemannite) and spherical based on previous reports, the maximum particle diameter was estimated to be 89 nm. The mean dietary exposures to NP-Hg, T-Hg, and MeHg were estimated to be 0.067, 5.75, and 5.32 μg/person per day, respectively. Generation of NP-Hg was inferred to be widespread in marine animals, with a preferential increase in the number of particles rather than an increase in particle size. The mean dietary exposure to NP-Hg in Japanese people was estimated to be 1.2 ng/kg body weight (BW) per day. Compared to PTWI of 4 μg/kg BW per week (0.57 μg/kg BW per day) derived by JECFA (2011), the health risk from redissolved I–Hg from NP-Hg is small.
显示更多 [+] 显示较少 [-]Development of physiologically-based toxicokinetic-toxicodynamic (PBTK-TD) model for 4-nonylphenol (4-NP) reflecting physiological changes according to age in males: Application as a new risk assessment tool with a focus on toxicodynamics
2022
Jeong, Seung-Hyun | Jang, Ji-Hun | Lee, Yong-Bok
Environmental exposure to 4-nonylphenol (4-NP) is extensive, and studies related to human risk assessment must continue. Especially, prediction of toxicodynamics (TDs) related to reproductive toxicity in males is very important in risk-level assessment and management of 4-NP. This study aimed to develop a physiologically-based-toxicokinetic-toxicodynamic (PBTK-TD) model that added a TD prostate model to the previously reported 4-n-nonylphenol (4-n-NP) physiologically-based-pharmacokinetic (PBPK) model. Modeling was performed under the assumption of similar TKs between 4-n-NP and 4-NP because TK experiments on 4-NP, a random-mixture, are practically difficult. This study was very important to quantitatively predict the TKs and TDs of 4-NP by age at exposure using an advanced PBTK-TD model that reflected physiological-changes according to age. TD-modeling was performed based on the reported toxic effects of 4-NP on RWPE-1 cells, a human-prostate-epithelial-cell-line. Through a meta-analysis of reported human physiological data, body weight, tissue volume, and blood flow rate patterns according to age were mathematically modeled. These relationships were reflected in the PBTK-TD model for 4-NP so that the 4-NP TK and TD changes according to age and their differences could be confirmed. Differences in TK and TD parameters of 4-NP at various ages were not large, within 3.61-fold. Point-of-departure (POD) and reference-doses for each age estimated using the model varied as 426.37–795.24 and 42.64–79.52 μg/kg/day, but the differences (in POD or reference doses between ages) were not large, at less than 1.87-times. The PBTK-TD model simulation predicted that even a 100-fold 4-NP PODₘₐₙ dose would not have large toxicity to the prostate. With a focus on TDs, the predicted maximum possible exposure of 4-NP was as high as 6.06–23.60 mg/kg/day. Several toxicity-related values estimated by the dose-response curve were higher than those calculated, depending upon the PK or TK, which would be useful as a new exposure limit for prostate toxicity of 4-NP.
显示更多 [+] 显示较少 [-]Ractopamine at legal residue dosage accelerates atherosclerosis by inducing endothelial dysfunction and promoting macrophage foam cell formation
2022
Chen, Chia-Hui | Guo, Bei-Chia | Hu, Po-An | Lee, Hsueh-Te | Hu, Hsuan-Yun | Hsu, Man-Chen | Chen, Wen-Hua | Lee, Tzong-Shyuan
Ractopamine, a synthetic β-adrenoreceptor agonist, is used as an animal feed additive to increase food conversion efficiency and accelerate lean mass accretion in farmed animals. The U.S. Food and Drug Administration claimed that ingesting products containing ractopamine residues at legal dosages might not cause short-term harm to human health. However, the effect of ractopamine on chronic inflammatory diseases and atherosclerosis is unclear. Therefore, we investigated the effects of ractopamine on atherosclerosis and its action mechanism in apolipoprotein E-null (apoe⁻/⁻) mice and human endothelial cells (ECs) and macrophages. Daily treatment with ractopamine for four weeks increased the body weight and the weight of brown adipose tissues and gastrocnemius muscles. However, it decreased the weight of white adipose tissues in apoe⁻/⁻ mice. Additionally, ractopamine exacerbated hyperlipidemia and systemic inflammation, deregulated aortic cholesterol metabolism and inflammation, and accelerated atherosclerosis. In ECs, ractopamine treatment induced endothelial dysfunction and increased monocyte adhesion and transmigration across ECs. In macrophages, ractopamine dysregulated cholesterol metabolism by increasing oxidized low-density lipoprotein (oxLDL) internalization and decreasing reverse cholesterol transporters, increasing oxLDL-induced lipid accumulation. Collectively, our findings revealed that ractopamine induces EC dysfunction and deregulated cholesterol metabolism of macrophages, which ultimately accelerates atherosclerosis progression.
显示更多 [+] 显示较少 [-]Early life PCB138 exposure induces kidney injury secondary to hyperuricemia in male mice
2022
Ruan, Fengkai | Liu, Changqian | Hu, Weiping | Ruan, Jinpeng | Ding, Xiaoyan | Zhang, Lu | Yang, Chunyan | Zuo, Zhenghong | He, Chengyong | Huang, Jiyi
Polychlorinated biphenyls (PCBs) are a class of persistent organic pollutants (POPs) that have adverse effects on human health. However, the long-term health effects and potential mechanism of neonatal exposure to PCBs are still unclear. In this study, nursing male mice exposed to PCB138 at 0.5, 5, and 50 μg/kg body weight (bw) from postnatal day (PND) 3 to PND 21 exhibited increased serum uric acid levels and liver uric acid synthase activity at 210 days of age. We also found an increased kidney somatic index in the 50 μg/kg group and kidney fibrosis in the 5 and 50 μg/kg groups. Mechanistically, PCB138 induced mitochondrial dysfunction and endoplasmic reticulum (ER) stress, which might have led to inflammatory responses, such as activation of the NF-κB (nuclear factor kappa-B) and NLRP3 (NOD-like receptor protein 3) pathways. The inflammatory response might regulate renal fibrosis and hypertrophy. In summary, this study reports a long-term effect of neonatal PCB exposure on uric acid metabolism and secondary nephrotoxicity and clarifies the underlying mechanism. Our work also indicates that early life pollutant exposure may be an important cause of diseases later in life.
显示更多 [+] 显示较少 [-]Urban fine particulate matter causes cardiac hypertrophy through calcium-mediated mitochondrial bioenergetics dysfunction in mice hearts and human cardiomyocytes
2022
Zou, Lingyue | Li, Binjing | Xiong, Lilin | Wang, Yan | Xie, Wenjing | Huang, Xiaoquan | Liang, Ying | Wei, Tingting | Liu, Na | Chang, Xiaoru | Bai, Changcun | Wu, Tianshu | Xue, Yuying | Zhang, Ting | Tang, Meng
In recent years, the cardiovascular toxicity of urban fine particulate matter (PM₂.₅) has sparked significant alarm. Mitochondria produce 90% of ATP and make up 30% of the volume of cardiomyocytes. Thus knowledge of myocardial mitochondrial dysfunction due to PM₂.₅ exposure is essential for further cardiotoxic effects. Here, the mechanism of PM₂.₅-induced cardiac hypertrophy through calcium overload and mitochondrial dysfunction was investigated in vivo and in vitro. Male and female BALB/c mice were given 1.28, 5.5, and 11 mg PM₂.₅/kg bodyweight weekly through oropharyngeal inhalation for four weeks and were assigned to low, medium, and high dose groups, respectively. PM₂.₅-induced myocardial edema and cardiac hypertrophy were detected in the high-dose group. Mitochondria were scattered and ruptured with abnormal ultrastructural morphology. In vitro experiments on human cardiomyocyte AC16 showed that exposure to PM₂.₅ for 24 h caused opened mitochondrial permeability transition pore --leading to excessive calcium production, decreased mitochondrial membrane potential, weakened mitochondrial respiratory metabolism capacity, and decreased ATP production. Nevertheless, the administration of calcium chelator ameliorated the mitochondrial damage in the PM₂.₅-treated group. Our in vivo and in vitro results confirmed that calcium overload under PM₂.₅ exposure triggered mTOR/AKT/GSK-3β activation, leading to mitochondrial bioenergetics dysfunction and cardiac hypertrophy.
显示更多 [+] 显示较少 [-]Exposure to dechlorane 602 induces perturbation of gut immunity and microbiota in female mice
2022
Li, Yunping | Guo, Tai L. | Xie, Heidi Qunhui | Xu, Li | Liu, Yin | Zheng, Liping | Yu, Shuyuan | Chen, Guomin | Ji, Jiajia | Jiang, Shuai | Xu, Dan | Hang, Xiaoming | Zhao, Bin
The homeostasis of gut immunity and microbiota are associated with the health of the gut. Dechlorane 602 (Dec 602) with food web magnification potential has been detected in daily food. People who were orally exposed to Dec 602 may encounter increased risk of health problems in the gut. In order to reveal the influence of short-term exposure of Dec 602 on gut immunity and microbiota, adult female C57BL/6 mice were administered orally with Dec 602 (low/high doses: 1.0/10.0 μg/kg body weight per day) for 7 days. Lymphocytes were examined by flow cytometry. Gut microbiota was measured by 16S rRNA gene sequencing. Results showed that fecal IgA was upregulated after exposure to the high dose of Dec 602, suggesting that there might be inflammation in the gut. Then, changes of immune cells in mesenteric lymph nodes and colonic lamina propria were examined. We found that exposure to the high dose of Dec 602 decreased the percentages of the anti-inflammatory T regulatory cells in mesenteric lymph nodes. In colonic lamina propria, the production of gut protective cytokine interleukin-22 by CD4⁺ T cells was decreased, and a decreased trend of interleukin-22 production was also observed in type 3 innate lymphoid cells in the high dose group. Furthermore, an altered microbiota composition toward inflammation in the gut was observed after exposure to Dec 602. Additionally, the altered microbiota correlated with changes of immune parameters, suggesting that there were interactions between influenced microbiota and immune parameters after exposure to Dec 602. Taken together, short-term exposure to Dec 602 induced gut immunity and microbiota perturbations, and this might be the mechanisms for Dec 602 to elicit inflammation in the gut.
显示更多 [+] 显示较少 [-]Long-term exposure to particulate matter and roadway proximity with age at natural menopause in the Nurses’ Health Study II Cohort
2021
Li, Huichu | Hart, Jaime E. | Mahalingaiah, Shruthi | Nethery, Rachel C. | Bertone-Johnson, Elizabeth | Laden, Francine
Evidence has shown associations between air pollution and traffic-related exposure with accelerated aging, but no study to date has linked the exposure with age at natural menopause, an important indicator of reproductive aging. In this study, we sought to examine the associations of residential exposure to ambient particulate matter (PM) and distance to major roadways with age at natural menopause in the Nurses’ Health Study II (NHS II), a large, prospective female cohort in US. A total of 105,996 premenopausal participants in NHS II were included at age 40 and followed through 2015. Time-varying residential exposures to PM₁₀, PM₂.₅₋₁₀, and PM₂.₅ and distance to roads was estimated. We calculated hazard ratios (HR) and 95% confidence intervals (CIs) for natural menopause using Cox proportional hazard models adjusting for potential confounders and predictors of age at menopause. We also examined effect modification by region, smoking, body mass, physical activity, menstrual cycle length, and population density. There were 64,340 reports of natural menopause throughout 1,059,229 person-years of follow-up. In fully adjusted models, a 10 μg/m³ increase in the cumulative average exposure to PM₁₀ (HR: 1.02, 95% CI: 1.00, 1.04), PM₂.₅₋₁₀ (HR: 1.03, 95% CI: 1.00, 1.05), and PM₂.₅ (HR: 1.03, 95% CI: 1.00, 1.06) and living within 50 m to a major road at age 40 (HR: 1.03, 95%CI: 1.00, 1.06) were associated with slightly earlier menopause. No statistically significant effect modification was found, although the associations of PM were slightly stronger for women who lived in the West and for never smokers. To conclude, we found exposure to ambient PM and traffic in midlife was associated with slightly earlier onset of natural menopause. Our results support previous evidence that exposure to air pollution and traffic may accelerate reproductive aging.
显示更多 [+] 显示较少 [-]Farmed tilapia as an exposure route to microcystins in Zaria-Nigeria: A seasonal investigation
2021
Chia, Mathias Ahii | Abdulwahab, Rabiu | Ameh, Ilu | Balogun, J Kolawole | Auta, Jehu
Several studies have reported the contamination of farmed fish by microcystins, however, alternations in levels of contamination resulting from seasonal changes are infrequently described. This investigation is focused on the seasonal accumulation of microcystins in farmed Nile Tilapia muscle tissue across three farms located in Zaria, Nigeria, as a means of assessing the health risks associated with the consumption of contaminated fish. Total microcystins and cyanobacteria content, respectively, in muscle tissue and gut of tilapia varied, seasonally in the farms. Microcystin levels were higher in fish tissues analyzed in the dry season than the rainy season at Nagoyi and Danlami ponds. Correlating with the levels of microcystins found in fish tissues, the highest dissolved microcystins levels in all the fish farms occurred in the dry season, where the Bal and Kol fish farm had the highest concentration (0.265 ± 0.038 μgL⁻¹). Gut analysis of fish obtained from the ponds, revealed a predominance of Microcystis spp. among other cyanobacteria. Estimation of total daily intake of consumed contaminated Nile tilapia muscles reveal values exceeding WHO recommended (0.04 μg kg⁻¹ body weight) total daily intake of MC-LR. Consumption of tilapia from Danlami pond presented the greatest risk with a value of 0.093 μg kg⁻¹ total daily intake. Results of the present study necessitate the implementation of legislation and monitoring programs for microcystins and other cyanobacteria contaminants of fish obtained from farms and other sources in Zaria and indeed several other African countries.
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