Co-reporter:Qiansheng Huang;Yajie Chen;Qionghua Chen;Huanteng Zhang
Archives of Toxicology 2017 Volume 91( Issue 4) pp:1915-1924
Publication Date(Web):23 September 2016
DOI:10.1007/s00204-016-1854-0
Polychlorinated biphenyls (PCBs) contain 209 congeners with various structure–activities. Exposure to PCBs was related to disorders of female reproduction. Endometriosis (EM) is an estrogen- and inflammation-dependent disease with high prevalence and severe health outcomes. Epidemiological studies have shown the effects of PCBs exposure on EM in regard to various structures of PCBs. However, little evidence is available from the toxicology considering the structure of PCBs. In the study, environmentally relevant concentrations of PCBs were used to treat primary cultured endometrial cells and an EM mouse model. Dioxin-like CB126, but not non-dioxin-like CB153, significantly enhanced 17β-estradiol (E2) biosynthesis in a dose-dependent manner. Among the genes related to estrogen metabolism, the level of 17β-hydroxysteroid dehydrogenase 7 (HSD17B7) showed significant increase following CB126 exposure. We further found that CB126 exposure decreased the methylation of the HSD17B7 promoter. Elevated expression of HSD17B7 was observed in the eutopic endometrium of EM patients. CB126 rather than CB153 triggered the inflammatory response by directly stimulating the secretion of inflammatory factors and indirectly reducing the level of lipoxin A4 (LXA4). Furthermore, the inflammation enhanced the expression of HSD17B7. Antagonism of the aryl hydrocarbon receptor (AhR) diminished the effects induced by CB126. In vivo, the PCB-treated EM mouse model confirmed that CB126 rather than CB153 increased the levels of both E2 and inflammatory factors in peritoneal fluid and promoted the development of endometriotic lesions. In all, CB126, but not CB153, triggered EM development by stimulating estrogen biosynthesis, inflammation and their interactions and that these effects were mediated by the AhR receptor.
Co-reporter:Yi Lin, Dongxiao Ding, Qiansheng Huang, Qiong Liu, Haoyang Lu, Yanyang Lu, Yulang Chi, Xia Sun, Guozhu Ye, Huimin Zhu, Jie Wei, Sijun Dong
Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids 2017 Volume 1862, Issue 9(Issue 9) pp:
Publication Date(Web):1 September 2017
DOI:10.1016/j.bbalip.2017.05.001
•BPA downregulates miR-192 via inhibition of miR-192 maturation.•SREBF1 is a direct target of miR-192.•BPA induced-miR-192 deficiency serves to raise SREBF1, thus promoting the development of NAFLD.Exposure to Bisphenol A (BPA) has been associated with the development of nonalcoholic fatty liver disease (NAFLD) but the underlying mechanism remains unclear. Given that microRNA (miRNA) is recognized as a key regulator of lipid metabolism and a potential mediator of environmental cues, this study was designed to explore whether exposure to BPA-triggered abnormal steatosis and lipid accumulation in the liver could be modulated by miR-192. We showed that male post-weaning C57BL/6 mice exposed to 50 μg/kg/day of BPA by oral gavage for 90 days displayed a NAFLD-like phenotype. In addition, we found in mouse liver and human HepG2 cells that BPA-induced hepatic steatosis and lipid accumulation were associated with decreased expression of miR-192, upregulation of SREBF1 and a series of genes involved in de novo lipogenesis. Downregulation of miR-192 in BPA-exposed hepatocytes could be due to defective pre-miR-192 processing by DROSHA. Using HepG2 cells, we further confirmed that miR-192 directly acted on the 3′UTR of SREBF1, contributing to dysregulation of lipid homeostasis in hepatocytes. MiR-192 mimic and lentivirus-mediated overexpression of miR-192 improved BPA-induced hepatic steatosis by suppressing SREBF1. Lastly, we noted that lipid accumulation was not a strict requirement for developing insulin resistance in mice after BPA treatment. In conclusion, this study demonstrated a novel mechanism in which NAFLD associated with BPA exposure arose from alterations in the miR-192-SREBF1 axis.
Co-reporter:Xia Sun;Yi Lin;Qiansheng Huang;Junpeng Shi;Ling Qiu;Mei Kang;Yajie Chen;Chao Fang;Ting Ye
Journal of Cellular and Molecular Medicine 2015 Volume 19( Issue 3) pp:581-594
Publication Date(Web):
DOI:10.1111/jcmm.12409
Abstract
Di(2-ethylhexyl) phthalate (DEHP) is used as plasticizer and is ubiquitously found in the environment. Exposure to DEHP has been linked to an increased incidence of type 2 diabetes. Pancreatic β-cell dysfunction is a hallmark of type 2 diabetes; however, it is unknown whether DEHP exposure contributes to this risk. Here, we aimed to investigate the cytotoxic effects of DEHP on INS-1 cells and to further explore the related underlying mechanisms. INS-1 cells were exposed to 0, 5, 25, 125 or 625 μM DEHP for 24 hrs. Cell viability, glucose-stimulated insulin secretion, reactive oxygen species (ROS) generation, cellular antioxidant response, Ca2+ homoeostasis and the levels of genes and proteins involved in endoplasmic reticulum (ER) stress were measured. The results showed that DEHP decreased insulin secretion and content and induced apoptosis in INS-1 cells in a dose-dependent manner. Furthermore, ROS generation was increased and Nrf2-dependent antioxidant defence protection was dysregulated in INS-1 cells after DEHP exposure. Most importantly, DEHP effectively depleted ER Ca2+ and triggered the ER stress response as demonstrated by the elevated transcription and translation of the ER chaperone GRP78 and GRP94, the increased phosphorylation of protein kinase R-like endoplasmic reticulum kinase (PERK) and its downstream substrate eukaryotic translation initiation factor 2α (eIF2α), as well as the increased levels of activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP). Taken together, DEHP exerted toxic effects on INS-1 cells by inducing apoptosis, which is dependent on the activation of the PERK–ATF4–CHOP ER stress signalling pathway and the suppression of Nrf2-dependent antioxidant protection.
Co-reporter:Chao Fang;Bo Ning;Ahmed Bilal Waqar;Manabu Niimi;Shen Li;Kaneo Satoh;Masashi Shiomi;Ting Ye;Jianglin Fan
Journal of Applied Toxicology 2015 Volume 35( Issue 9) pp:1058-1070
Publication Date(Web):
DOI:10.1002/jat.3103
ABSTRACT
Bisphenol A (BPA) is an artificial environmental endocrine disrupter. Excess exposure to BPA may induce many disorders in the metabolism and cardiovascular system. However, the underlying toxicological mechanisms remain largely unknown. In this study, we administered genetically hyperlipidemic Watanabe heritable hyperlipidemic (WHHL-MI) rabbits (male, 14 week old), which have more common features with humans than the mouse and rat especially in the metabolism and cardiovascular system, with BPA at 40 mg kg–1 day–1 for 8 weeks by gavage and compared their plasma lipids, glucose and insulin response with those of the vehicle group. All of the rabbits were sacrificed, and their pancreas, liver, adipose tissue, heart and aorta were analyzed using histological and morphometric methods. Furthermore, we treated human hepatoma HepG2 cells and human umbilical cord vein endothelial cells (HUVECs), with different doses of BPA based on the serum BPA levels in the WHHL rabbits for 6 h to investigate the possible molecular mechanisms. Our results showed that BPA-treated rabbits showed insulin resistance, prominent adipose accumulation and hepatic steatosis. Additionally, BPA exposure also caused myocardial injury and enhanced the development of atherosclerosis in the aortic arch with increased macrophage number (86%) and advanced lesion areas (69%). Increased expression of inflammatory genes found in the liver of BPA-treated rabbits along with the up-regulation of ER stress, lipid and glucose homeostasis and inflammatory genes in the cultured HepG2 cells and HUVECs suggest that BPA may induce metabolic disorders and enhance atherosclerosis through regulating above molecular pathways in the liver and endothelium. Copyright © 2015 John Wiley & Sons, Ltd.
Co-reporter:Y Lin, X Sun, L Qiu, J Wei, Q Huang, C Fang, T Ye, M Kang, H Shen and S Dong
Cell Death & Disease 2013 4(1) pp:e460
Publication Date(Web):2013-01-01
DOI:10.1038/cddis.2012.206
Bisphenol A (BPA) is widely used in plastic products, through which humans are exposed to it. Accumulating evidence suggests that BPA exposure is associated with β-cell dysfunction. Mitochondrial defects can cause impairment and failure of β cells, but there is little information about the effects of BPA on the mitochondrial function of β cells. In this study, we assessed the role of mitochondria-mediated mechanisms underlying BPA-induced β-cell dysfunction and resulting β-cell apoptosis. INS-1 cells were cultured with 0, 0.0020, 0.020, 0.20, or 2.0 μM BPA. Cell viability, glucose-stimulated insulin secretion (GSIS), and mitochondrial function were examined. The mitochondrial apoptotic pathway was also analyzed at molecular level. We found that BPA suppressed cell viability and disturbed GSIS in a dose-dependent manner. Positive Annexin- propidium iodide (PI) staining and altered expression of Bcl-2 family members and caspases in INS-1 cells indicated that the cells progressively became apoptotic after BPA exposure. Additionally, BPA-induced apoptosis was associated with mitochondrial defects in β cells, as evidenced by depletion of ATP, release of cytochrome c, loss of mitochondrial mass and membrane potential, and alterations in expression of genes involved in mitochondrial function and metabolism. Taken together, these findings provide strong evidence that BPA triggers INS-1 cells dysfunction and apoptosis may be meditated via the mitochondrial pathway.
Co-reporter:Jie Zhang, Lijuan Yan, Meiping Tian, Qiansheng Huang, Siyuan Peng, Sijun Dong, Heqing Shen
Journal of Pharmaceutical and Biomedical Analysis 2012 Volume 66() pp:287-297
Publication Date(Web):July 2012
DOI:10.1016/j.jpba.2012.03.045
Humans undergo simultaneous daily exposure to a multitude of endocrine-disrupting compounds (EDCs). In present study, after combined exposure to endocrine disruptors DEHP and Aroclor 1254 for 12 days, a liquid chromatography/time-of-flight mass spectrometer method combining both reversed-phase (RP) and hydrophilic interaction chromatography (HILIC) separations was carried out to investigate the metabolic responses in mice. The metabolic profiles of endogenous metabolites could differentiate the dose and control groups in both RPLC and HILIC modes. Moreover, the male mice and female mice in different groups could be obviously clustered in their own regions with combined model. Fourteen lysoPCs, PC(18:4/18:1), lysoPE(18:2/0:0), phenylalanine and tryptophan were identified as potential biomarkers for the combined toxicity of DEHP and Aroclor 1254. Different change trends could be observed for the identified lysoPCs, due to their different levels of uptake and metabolism in mice. Moreover, gender-specific differences in several lysoPCs (e.g. lysoPC(18:0), lysoPC(22:6), lysoPC(20:3), and PC(18:4/18:1)) were observed for treated mice. The metabonomic results indicated the combined exposure led to a disturbance of lipid metabolism. The mRNA expressions of PLA2, ACOX1, CPT1, FAS and SCD1 involved in lipid metabolism were investigated. Among them, significant increases of FAS and SCD1 expressions in the liver induced by the exposure could be observed for both male and female mice, contributing to the hepatic lipid accumulation in mice. Besides lipid metabolism, tryptophan metabolism and phenylalanine metabolism may also be involved with the toxic responses to these EDCs. The present study not only improves the understanding of the combined toxicity of phthalates and PCBs but also shows that the metabonomic approach may prove to be a promising technique for the toxicity research of EDCs.
Co-reporter:Jia Wang
Inflammation 2012 Volume 35( Issue 3) pp:859-870
Publication Date(Web):2012 June
DOI:10.1007/s10753-011-9387-4
The present study aimed to determine whether curcumin isolated from the rhizome of Curcuma longa Linn could inhibit di-(2-ethylhexyl) phthalate (DEHP)-induced allergic inflammatory responses in human umbilical vein endothelial cells (HUVECs). We found that DEHP dose-dependently elevated adhesion molecule-1 (ICAM-1) protein level within 15–30 min, which was independent of de novo protein synthesis. And a late-phase induction of ICAM-1 was observed within 8 h treatment of DEHP via de novo protein synthesis through transcription and translation. DEHP also increased the expression of interleukin (IL)-8 in a time- and dose-dependent manner. Pretreatment with curcumin dose-dependently decreased DEHP-induced expression of ICAM-1 and IL-8 as well as phosphorylation of ERK1/2 and p38. Preincubation with ERK1/2 inhibitor (PD98059) or p38 inhibitor (SB203580) markedly blocked DEHP-stimulated activation of ICAM-1 and IL-8. We suggest that curcumin inhibits DEHP-induced expression of ICAM-1 and IL-8 through ERK and p38 MAPK signaling pathways in HUVECs and may contribute to ameliorate pathologies of DEHP-related allergic disorders.
Co-reporter:Qiansheng Huang;Chao Fang;Yajie Chen
Environmental Science and Pollution Research 2012 Volume 19( Issue 7) pp:2506-2514
Publication Date(Web):2012 August
DOI:10.1007/s11356-012-1034-6
The prevalence of bisphenol A (BPA) in the environment has attracted increasing attention because of the toxicity of this manmade pollutant. However, the toxicity related to cardiac development remains largely unknown. In the present paper, we investigated the cardiac toxicity of BPA using marine medaka (Oryzias melastigma) embryos. At 2 days postfertilization (dpf), the embryos were continuously exposed to a low concentration of BPA (200 μg/L) for the whole embryonic stage. Heart rate and sinus venosus (SV)–bulbus arteriosus (BA) distance were measured under microscopy. The mRNA expression levels of genes were quantified by SYBR real-time RT-PCR, and hematoxylin and eosin (H&E) staining was used to examine the histology of fish larvae hearts. Neither the heart rate nor the SV-BA distance of the embryos was affected by BPA exposure. However, the mRNA expression levels of Na+–K+–ATPase, BMP4, COX-1, FGF8, GATA4, and NKX2.5 were all downregulated at the critical developmental stages (6 and 10 dpf). Interestingly, the mRNA expression levels of COX-2 and LERP were significantly upregulated at 10 dpf. The mRNA expressions of inflammation-related genes (TNFα, IL1β, SOD, and CCL11) were all significantly upregulated after exposure. Moreover, we found that both the body length and the body width decreased in the larvae after embryonic exposure to BPA. The distributed foci of inflammation were observed in the juveniles after 2 weeks’ depuration. Exposure to BPA at embryonic stages could alter the expression of heart development-related genes and inflammation-related genes of O. melastigma. The larvae hatched from exposed embryos showed the foci of inflammation in the heart ventricles and the decrease of the body length and width.
Co-reporter:Ting Ye, Mei Kang, Qiansheng Huang, Chao Fang, Yajie Chen, Heqing Shen, Sijun Dong
Aquatic Toxicology (January 2014) Volume 146() pp:115-126
Publication Date(Web):January 2014
DOI:10.1016/j.aquatox.2013.10.025
Co-reporter:Chao Fang, Xinlong Wu, Qiansheng Huang, Yanyan Liao, Liangpo Liu, Ling Qiu, Heqing Shen, Sijun Dong
Aquatic Toxicology (15 January 2012) Volumes 106–107() pp:9-19
Publication Date(Web):15 January 2012
DOI:10.1016/j.aquatox.2011.10.009
Co-reporter:Qiansheng Huang, Yajie Chen, Lifeng Lin, Yiyao Liu, Yulang Chi, Yi Lin, Guozhu Ye, Huiming Zhu, Sijun Dong
Science of The Total Environment (1 October 2017) Volume 595() pp:752-758
Publication Date(Web):1 October 2017
DOI:10.1016/j.scitotenv.2017.03.263
•Effects of BPA, TBBPA and TCBPA were compared.•TCBPA was the most toxic to hatching, followed by TBBPA and BPA.•Long term BPA exposure affected the reproductive ability rather than H-BPAs.•Developmental stages affected the responses of gene expression to exposure.Bisphenol A (BPA) and its halogenated compounds (H-BPAs) are widely detected in the environmental media and organisms. However, their toxicological effects, especially chronic exposure at low doses, have not been fully compared. In this study, the effects of BPA and H-BPAs on the reproduction and development of Oryzias melastigma were systematically assessed and compared at various developmental stages. BPA and its derivatives tetrabromobisphenol A (TBBPA) and tetrachlorobisphenol A (TCBPA) elicited the acceleration of embryonic heartbeat. BPA did not show any significant impact on the hatching time and rate of embryos. In contrast, both TBBPA and TCBPA led to the delayed hatching and decreased hatching rate. Accordingly, the expressions of hatching enzyme significantly decreased upon exposure and TCBPA was found to be more toxic than TBBPA. The body weight and gonadsomatic index (GSI) of the treated fish were relatively lower than the control fish upon long-term (four months from larvae to adult) exposure to BPA rather than H-BPAs. Slowed oocyte development occurred in the ovary, and the estrogen level decreased after exposure to BPA rather than H-BPAs. In male fish, no significant alteration was observed in the testis for all groups. The concentration of testosterone significantly decreased upon exposure to BPA rather than H-BPAs. The effects of these three chemicals on the estrogen-related gene expressions were different under various developmental stages. Our study indicated the importance of considering both the exposure stages and structure-activity relationship when assessing the eco-toxicological impact of pollutants.Download high-res image (128KB)Download full-size image
Co-reporter:Qiansheng Huang, Yajie Chen, Lifeng Lin, Yiyao Liu, Yulang Chi, Yi Lin, Guozhu Ye, Huiming Zhu, Sijun Dong
Science of The Total Environment (1 October 2017) Volume 595() pp:752-758
Publication Date(Web):1 October 2017
DOI:10.1016/j.scitotenv.2017.03.263
•Effects of BPA, TBBPA and TCBPA were compared.•TCBPA was the most toxic to hatching, followed by TBBPA and BPA.•Long term BPA exposure affected the reproductive ability rather than H-BPAs.•Developmental stages affected the responses of gene expression to exposure.Bisphenol A (BPA) and its halogenated compounds (H-BPAs) are widely detected in the environmental media and organisms. However, their toxicological effects, especially chronic exposure at low doses, have not been fully compared. In this study, the effects of BPA and H-BPAs on the reproduction and development of Oryzias melastigma were systematically assessed and compared at various developmental stages. BPA and its derivatives tetrabromobisphenol A (TBBPA) and tetrachlorobisphenol A (TCBPA) elicited the acceleration of embryonic heartbeat. BPA did not show any significant impact on the hatching time and rate of embryos. In contrast, both TBBPA and TCBPA led to the delayed hatching and decreased hatching rate. Accordingly, the expressions of hatching enzyme significantly decreased upon exposure and TCBPA was found to be more toxic than TBBPA. The body weight and gonadsomatic index (GSI) of the treated fish were relatively lower than the control fish upon long-term (four months from larvae to adult) exposure to BPA rather than H-BPAs. Slowed oocyte development occurred in the ovary, and the estrogen level decreased after exposure to BPA rather than H-BPAs. In male fish, no significant alteration was observed in the testis for all groups. The concentration of testosterone significantly decreased upon exposure to BPA rather than H-BPAs. The effects of these three chemicals on the estrogen-related gene expressions were different under various developmental stages. Our study indicated the importance of considering both the exposure stages and structure-activity relationship when assessing the eco-toxicological impact of pollutants.Download high-res image (128KB)Download full-size image
