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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 [-]PPARγ/LXRα axis mediated phenotypic plasticity of lung fibroblasts in silica-induced experimental silicosis
2022
Qi, Yuanmeng | Zhang, Haichen | Fan, Hui | Wang, Xinyu | Zhao, Ahui | Tian, Yangyang | Yang, Guo | Li, Chao | Wei, Jingjing | Yao, Wu | Hao, Changfu
Silicosis is a disease mainly caused by pulmonary interstitial fibrosis caused by long-term inhalation of dust with excessively high content of free SiO₂. Transdifferentiation of lung fibroblasts into myofibroblasts is an important cellular basis for silicosis, but the key transcription factors (TFs) involved in this process are still unclear. In order to explore the biological regulation of transcription factor PPARγ/LXRα in silica-induced pulmonary fibrosis, this study explored the molecular mechanism of PPARγ/LXRα involved in regulating transcription factors related to SiO₂-induced lung injury at the cellular level and in animal models. ChIP-qPCR detected that PPARγ directly regulated the transcriptional activity of the LXRα gene promoter, while the PPARγ agonist RSG increased the expression of LXRα. In addition, we demonstrated in the cell model that upregulation of LXRα can inhibit silica-mediated fibroblast transdifferentiation, accompanied by an increase in the expression of SREBF1, PLTP and ABCA1. The results of LXRα silencing experiment matched those of overexpression experiment. These studies explored the role of LXRα in plasticity and phenotypic transformation between lung fibroblasts and myofibroblasts. Therefore, inhibiting or reversing the transdifferentiation of lung fibroblasts to myofibroblasts by intervening PPARγ/LXRα may provide a new therapeutic target for the treatment of silicosis.
显示更多 [+] 显示较少 [-]Endocrine disrupting potential of veterinary drugs by in vitro stably transfected human androgen receptor transcriptional activation assays
2021
Park, Yooheon | Park, Juhee | Lee, Hee-Seok
We describe the androgen receptor (AR) agonistic/antagonistic effects of 140 veterinary drugs regulated in Republic of Korea, by setting maximum residue limits. It was conducted using two in vitro test guidelines of the Organization for Economic Cooperation and Development (OECD)—the AR-EcoScreen AR transactivation (TA) assay and the 22Rv1/MMTV_GR-KO AR TA assay. These were performed alongside the AR binding affinity assay to confirm whether their AR agonistic/antagonistic effects are based on the binding affinity to AR. Prior to conducting the AR TA assay, the proficiency test was passed the proficiency performance criterion for the AR agonist and AR antagonist assays. Among the veterinary drugs tested, four veterinary drugs (dexamethasone, trenbolone, altrenogest, and nandrolone) and six veterinary drugs (cymiazole, dexamethasone, zeranol, phenothiazine, bromopropylate, and isoeugenol) were determined as AR agonist and AR antagonist, respectively in both in vitro AR TA assays. Zeranol exhibited weak AR agonistic effects with a PC₁₀ value only in the 22Rv1/MMTV_GR-KO AR TA assay. Regarding changing the AR agonistic/antagonistic effects through metabolism, the AR antagonistic activities of zeranol, phenothiazine, and isoeugenol decreased significantly in the presence of phase I + II enzymes.These data indicate that various veterinary drugs could have the potential to disrupt AR-mediated human endocrine system. Furthermore, this is the first report providing information on AR agonistic/antagonistic effects of veterinary drugs using in vitro OECD AR TA assays.
显示更多 [+] 显示较少 [-]Hypoxia modifies the response to flutamide and linuron in male three-spined stickleback (Gasterosteus aculeatus)
2020
Fitzgerald, Jennifer A. | Trznadel, Maciej | Katsiadaki, Ioanna | Santos, Eduarda M.
Hypoxia is a major stressor in aquatic environments and it is frequently linked with excess nutrients resulting from sewage effluent discharges and agricultural runoff, which often also contain complex mixtures of chemicals. Despite this, interactions between hypoxia and chemical toxicity are poorly understood. We exposed male three-spined stickleback during the onset of sexual maturation to a model anti-androgen (flutamide; 250 μg/L) and a pesticide with anti-androgenic activity (linuron; 250 μg/L), under either 97% or 56% air saturation (AS). We assessed the effects of each chemical, alone and in combination with reduced oxygen concentration, by measuring the transcription of spiggin in the kidney, as a marker of androgen signalling, and 11 genes in the liver involved in some of the molecular pathways hypothesised to be affected by the exposures. Spiggin transcription was strongly inhibited by flutamide under both AS conditions. In contrast, for linuron, a strong inhibition of spiggin was observed under 97% AS, but this effect was supressed under reduced air saturation, likely due to interactions between the hypoxia inducible factor and the aryl hydrocarbon receptor (AhR) pathways. In the liver, hypoxia inducible factor 1α was induced following exposure to both flutamide and linuron, however this was independent of the level of air saturation. This work illustrates the potential for interactions between hypoxia and pollutants with endocrine or AhR agonist activity to occur, with implications for risk assessment and management.
显示更多 [+] 显示较少 [-]Activation of aryl hydrocarbon receptor by dioxin directly shifts gut microbiota in zebrafish
2019
Sun, Yumiao | Tang, Lizhu | Liu, Yang | Hu, Chenyan | Zhou, Bingsheng | Lam, Paul K.S. | Lam, James C.W. | Chen, Lianguo
Gut microbiota is of critical importance to host health. Aryl hydrocarbon receptor (AhR) is found to be closely involved in the regulation of gut microbial dynamics. However, it is still not clear how AhR signaling shapes the gut microbiota. In the present study, adult zebrafish were acutely exposed to an AhR antagonist (CH223191), an AhR agonist (polychlorinated biphenyl 126; PCB126) or their combination for 7 d. Overall intestinal health and gut microbial community were temporally monitored (1 d, 3 d and 7 d) and inter-compared among different groups. The results showed that single exposure to PCB126 significantly disrupted the overall health of intestines (i.e., neural signaling, inflammation, epithelial barrier integrity, oxidative stress). However, CH223191 failed to inhibit but enhanced the physiological toxicities of PCB126, implying the involvement of extra mechanisms rather than AhR in the regulation of intestinal physiological activities. Dysbiosis of gut microbiota was also caused by PCB126 over time as a function of sex. It is intriguing that CH223191 successfully abolished the holistic effects of dioxin on gut microbiota, which inferred that growth of gut microbes was directly controlled by AhR activation without the involvement of host feedback modulation. When coming to detailed alterations at certain taxon, both antagonistic and synergistic interactions existed between CH223191 and dioxin, depending on fish sex, exposure duration and bacterial species. Correlation analysis found that gut inflammation was positively associated with pathogenic Legionella bacteria, but was negatively associated with epithelial barrier integrity, suggesting that integral intestinal epithelial barrier can prevent the influx of pathogenic bacteria to induce inflammatory response. Overall, this study has deciphered, for the first time, the direct regulative effects of AhR activity on gut microbiota. Future research is warranted to elucidate the specific mechanisms of AhR action on certain bacterial population.
显示更多 [+] 显示较少 [-]In vitro profiling of toxic effects of prominent environmental lower-chlorinated PCB congeners linked with endocrine disruption and tumor promotion
2018
Pěnčíková, Kateřina | Svržková, Lucie | Strapáčová, Simona | Neča, Jiří | Bartoňková, Iveta | Dvořák, Zdeněk | Hýžďalová, Martina | Pivnička, Jakub | Pálková, Lenka | Lehmler, Hans-Joachim | Li, Xueshu | Vondráček, Jan | Machala, Miroslav
The mechanisms contributing to toxic effects of airborne lower-chlorinated PCB congeners (LC-PCBs) remain poorly characterized. We evaluated in vitro toxicities of environmental LC-PCBs found in both indoor and outdoor air (PCB 4, 8, 11, 18, 28 and 31), and selected hydroxylated metabolites of PCB 8, 11 and 18, using reporter gene assays, as well as other functional cellular bioassays. We focused on processes linked with endocrine disruption, tumor promotion and/or regulation of transcription factors controlling metabolism of both endogenous compounds and xenobiotics. The tested LC-PCBs were found to be mostly efficient anti-androgenic (within nanomolar – micromolar range) and estrogenic (at micromolar concentrations) compounds, as well as inhibitors of gap junctional intercellular communication (GJIC) at micromolar concentrations. PCB 8, 28 and 31 were found to partially inhibit the aryl hydrocarbon receptor (AhR)-mediated activity. The tested LC-PCBs were also partial constitutive androstane receptor (CAR) and pregnane X receptor (PXR) agonists, with PCB 4, 8 and 18 being the most active compounds. They were inactive towards other nuclear receptors, such as vitamin D receptor, thyroid receptor α, glucocorticoid receptor or peroxisome proliferator-activated receptor γ. We found that only PCB 8 contributed to generation of oxidative stress, while all tested LC-PCBs induced arachidonic acid release (albeit without further modulations of arachidonic acid metabolism) in human lung epithelial cells. Importantly, estrogenic effects of hydroxylated (OH-PCB) metabolites of LC-PCBs (4-OH-PCB 8, 4-OH-PCB 11 and 4′-OH-PCB 18) were higher than those of the parent PCBs, while their other toxic effects were only slightly altered or suppressed. This suggested that metabolism may alter toxicity profiles of LC-PCBs in a receptor-specific manner. In summary, anti-androgenic and estrogenic activities, acute inhibition of GJIC and suppression of the AhR-mediated activity were found to be the most relevant modes of action of airborne LC-PCBs, although they partially affected also additional cellular targets.
显示更多 [+] 显示较少 [-]Effect of β-adrenergic receptor agents on cardiac structure and function and whole-body gene expression in Daphnia magna
2018
Jeong, Tae-Yong | Asselman, Jana | De Schamphelaere, Karel A.C. | Van Nieuwerburgh, Filip | Deforce, Dieter | Kim, Sang-don
Propranolol (PRO), a human β-AR (β-adrenergic receptor) antagonist, is considered to result in specific effects in a non-target species, D. magna, based on our previous studies. The present study investigated the effects of β-AR agents, including an antagonist and agonist using pharmacologically relevant endpoints as well as a more holistic gene expression approach to reveal the impacts and potential mode of actions (MOAs) in the model non-target species. Results show that the responses in cardiac endpoints and gene expression in D. magna are partially similar but distinguishable from the observations in different organisms. No effect was observed on heart size growth in PRO and isoprenaline (ISO) exposure. The contraction capacity of the heart was decreased in ISO exposure, and the heart rate was decreased in PRO exposure. Time-series exposures showed different magnitudes of effect on heart rate and gene expression dependent on the type of chemical exposure. Significant enrichment of gene families involved in protein metabolism and biotransformation was observed within the differentially expressed genes, and we also observed differential expression in juvenile hormone-inducible proteins in ISO and PRO exposure, which is suspected of having endocrine disruption potential. Taken together, deviation between the effects of PRO and ISO in D. magna and other organisms suggests dissimilarity in MOAs or attributes of target bio-molecules between species. Additionally, PRO and ISO may act as endocrine disruptors based on the gene expression observation. Results in the present study confirm that it is challenging to predict ecological impact of active pharmaceutical ingredients (APIs) based on the available data acquired through human-focused studies. Furthermore, the present study provided unique data and a case study on the impact of APIs in a non-target organism.
显示更多 [+] 显示较少 [-]SLC6A19 is a novel putative gene, induced by dioxins via AhR in human hepatoma HepG2 cells
2018
Tian, Wenjing | Fu, Hualing | Xu, Tuan | Xu, Sherry Li | Guo, Zhiling | Tian, Jijing | Tao, Wuqun | Xie, Heidi Qunhui | Zhao, Bin
The aryl hydrocarbon receptor (AhR) plays an important role in mediating dioxins toxicity. Currently, genes of P450 families are major research interests in studies on AhR-mediated gene alterations caused by dioxins. Genes related to other metabolic pathways or processes may be also responsive to dioxin exposures. Amino acid transporter B0AT1 (encoded by SLC6A19) plays a decisive role in neutral amino acid transport which is present in kidney, intestine and liver. However, effects of dioxins on its expression are still unknown. In the present study, we focused on the effects of dioxin and dioxin-like compounds on SLC6A19 expression in HepG2 cells. We identified SLC6A19 as a novel putative target gene of AhR activation in HepG2 cells. 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD) increased the expression of SLC6A19 in time- and concentration-dependent manners. Using AhR antagonist CH223191 and/or siRNA assays, we demonstrated that certain AhR agonists upregulated SLC6A19 expression via AhR, including TCDD, 1,2,3,7,8-pentachlorodibenzo-p-dioxin (1,2,3,7,8-PeCDD), 2,3,4,7,8- pentachlorodibenzofuran (2,3,4,7,8-PeCDF) and PCB126. In addition, the expression of B0AT1 was also significantly induced by TCDD in HepG2 cells. Our study suggested that dioxins might affect the transcription and translation of SLC6A19 in HepG2 cells, which might be a novel putative gene to assess dioxins' toxicity in amino acid transport and metabolism in liver.
显示更多 [+] 显示较少 [-]Integrated assessment of persistent toxic substances in sediments from Masan Bay, South Korea: Comparison between 1998 and 2014
2018
Lee, Junghyun | Hong, Seongjin | Kwon, Bong-Oh | Cha, Seung Ah | Jeong, Hee-Dong | Chang, Won Keun | Ryu, Jongseong | Giesy, John P. | Khim, Jong Seong
Complexity of anthropogenic influences on coastal ecosystems necessitates use of an integrated assessment strategy for effective interpretation and subsequent management. In this study a multiple lines of evidence (LOE) approach for sediment assessment, that combined use of chemistry, toxicity, and benthic community structure in the sediment quality triad was used to assess spatiotemporal changes and potential risks of persistent toxic substances (PTSs) in sediments of Masan Bay highlighting “long-term changes” between 1998 and 2014. Specific target objectives encompassed sedimentary PTSs (PAHs, alkylphenols (APs), and styrene oligomers), potential aryl hydrocarbon receptor (AhR; H4IIE-luc assay)- and estrogen receptor (ER; MVLN assay)-mediated activities, and finally several ecological quality (EcoQ) indices of benthic community structure. Concentrations of target PTSs in Masan Bay sediments were generally less by half in 2014 compared to those measured in 1998. Second, AhR-mediated potencies in sediments also decreased during this time interval, whereas ER-mediated potencies increased (+3790%), indicating that there has been substantial ongoing, input of ER agonists over the past 16 years. Potency balance analysis revealed that only 3% and 22% of the AhR- and ER-mediated potencies could be explained by identified known chemicals, such as PAHs and APs, respectively. This result indicated that non-targeted AhR and ER agonists had a considerable presence in the sediments over time. Third, EcoQ indices tended to reflect PTSs contamination in the region. Finally, ratio-to-mean values obtained from the aforementioned three LOEs indicated that quality of sediments from the outer region of the bay had recovery more during the period of 16-years than did the inner region. Overall, the results showed that even with the progress supported by recent efforts from the Korean governmental pollution control, PTSs remain a threat to local ecosystem, especially in the inner region of Masan Bay.
显示更多 [+] 显示较少 [-]Effects of unintentional PCBs in pigments and chemical products on transcriptional activity via aryl hydrocarbon and nuclear hormone receptors
2017
Takeuchi, Shinji | Anezaki, Katsunori | Kojima, Hiroyuki
In recent years, some pigments and chemical products have been reported to contain polychlorinated biphenyl (PCB) congeners as unintentional byproducts, and these have also been detected in residential environments from indoor air and house dust. In this study, using in vitro reporter gene assays, we characterized the agonistic and antagonistic activities of a total of 25 PCB congeners contained in pigments (PCB-1 to -16, -20, -35, -40, -52, -56, -77, -101, -126, and -153) against five nuclear hormone receptors, (estrogen receptor (ER) α/β, glucocorticoid receptor (GR), androgen receptor (AR), thyroid hormone receptor (TR) α1) and aryl hydrocarbon receptor (AhR). In the ERα/β assays, 19 and 13 of the 25 PCBs tested showed ERα/β agonistic and/or antagonistic activities, respectively. Relatively potent agonistic activities against ERα/β were found in PCB congeners possessing chlorides at positions 2 and 3. In the GR and AR assays, five and all of the 25 PCB congeners showed antagonistic activity, respectively. Among the anti-androgenic PCB congeners, the activities were more potent in PCB congeners possessing more than three chlorides including consecutive ortho- and meta- or meta- and para-chlorides. In the AhR assay using a sensitive DR-EcoScreen cell line, five of the 25 PCB congeners showed agonistic activity. We newly found that PCB-1, -35 and -56 can act as AhR agonists. Despite these activities among the PCBs, the effects of PCB-11, mainly detected in pigments and chemical products, against these receptors were found to be weaker than those of other tested PCBs. These results suggest that unintentional PCBs in pigments and chemical products might act as agonists and/or antagonists against ERα/β, AR, GR, and AhR, and some of the PCBs might disrupt endocrine functions via multiple receptors and/or simultaneously induce dioxin-like activity via AhR.
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