Publications by authors named "Yushan Cui"

26 Publications

  • Page 1 of 1

Intratumor Heterogeneity of MIF Expression Correlates With Extramedullary Involvement of Multiple Myeloma.

Front Oncol 2021 29;11:694331. Epub 2021 Jun 29.

Department of Hematology, Institute of Hematology, West China Hospital, Sichuan University, Chengdu, China.

Macrophage migration inhibitory factor (MIF) has been shown to promote disease progression in many malignancies, including multiple myeloma (MM). We previously reported that MIF regulates MM bone marrow homing and knockdown of MIF favors the extramedullary myeloma formation in mice. Here, based on MIF immunostaining of myeloma cells in paired intramedullary and extramedullary biopsies from 17 patients, we found lower MIF intensity in extramedullary MM (EMM) versus intramedullary MM (IMM). Flow cytometry and histology analysis in xenograft models showed a portion of inoculated human MM cells lost their MIF expression (MIF) . Of note, IMM had dominantly MIF cells, while EMM showed a significantly increased ratio of MIF cells. Furthermore, we harvested the extramedullary human MM cells from a mouse and generated single-cell transcriptomic data. The developmental trajectories of MM cells from the MIF to MIF state were indicated. The MIF cells featured higher proliferation. The MIF ones were more quiescent and harbored abundant ribosomal protein genes. Our findings identified differential regulation of MIF expression in MM and suggested a potential pathogenic role of MIF in the extramedullary spread of disease.
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http://dx.doi.org/10.3389/fonc.2021.694331DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8276700PMC
June 2021

Fluoride exposure and children's intelligence: Gene-environment interaction based on SNP-set, gene and pathway analysis, using a case-control design based on a cross-sectional study.

Environ Int 2021 Oct 4;155:106681. Epub 2021 Jun 4.

Department of Epidemiology and Biostatistics, Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China. Electronic address:

Background: Excessive fluoride exposure has been associated with intelligence loss, but little is known about gene-fluoride interactions on intelligence at SNP-set, gene and pathway level.

Objectives: Here we conducted a population-based study in Chinese school-aged children to estimate the associations of fluoride from internal and external exposures with intelligence as well as to explore the gene-fluoride interactions on intelligence at SNP-set, gene and neurodevelopmental pathway level.

Methods: A total of 952 resident children aged 7 to 13 were included in the current study. The fluoride contents in drinking water, urine, hair and nail were measured using the ion-selective electrode method. LASSO Binomial regression was conducted to screen the intelligence-related SNP-set. The gene-fluoride interactions at gene and pathway levels were detected by the Adaptive Rank Truncated Product method.

Results: The probability of high intelligence was inversely correlated with fluoride contents in water, urine, hair and nail (all P < 0.001). The SNP-set based on rs3788319, rs1879417, rs57377675, rs11556505 and rs7187776 was related to high intelligence (P = 0.001) alone and by interaction with water, urinary and hair fluoride (P = 0.030, 0.040, 0.010), separately. In gene level, CLU and TOMM40 interacted with hair fluoride (both P = 0.017) on intelligence. In pathway level, Alzheimer disease pathway, metabolic pathway, signal transduction pathway, sphingolipid signaling pathway and PI3K-AKT signaling pathway interacted with fluoride on intelligence in men.

Conclusions: Our study suggests that fluoride is inversely associated with intelligence. Moreover, the interactions of fluoride with mitochondrial function-related SNP-set, genes and pathways may also be involved in high intelligence loss.
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http://dx.doi.org/10.1016/j.envint.2021.106681DOI Listing
October 2021

Moderating Role of TSHR and PTPN22 Gene Polymorphisms in Effects of Excessive Fluoride on Thyroid: a School-Based Cross-Sectional Study.

Biol Trace Elem Res 2021 May 28. Epub 2021 May 28.

Dazhangzhuang Community Health Service Center, 31 Yongkang Road, Beichen District, Tianjin, 300400, People's Republic of China.

We aimed to investigate the relationship between the effects excessive of fluoride on thyroid health in children and the moderating role of thyroid stimulating hormone receptor (TSHR) or protein tyrosine phosphatase nonreceptor-22 (PTPN22) gene polymorphisms. Four hundred thirteen children (141 with dental fluorosis and 198 boys) were enrolled from both historical endemic and non-endemic areas of fluorosis in Tianjin, China. The fluoride exposure levels, thyroid health indicators, and TSHR (rs2268458) and PTPN22 (rs3765598) polymorphisms were examined. Multiple logistic models were applied to evaluate the relationship between dental fluorosis and thyroid abnormalities. Children over 9 year old with dental fluorosis have lower FT and TGAb levels and thyroid volume and higher TPOAb levels (all P < 0.05). In overall participants, children with dental fluorosis were more likely to have thyroid antibody single positive issues (adjusted P = 0.039) and less likely to have a goiter according to age or body surface area (age or BSA) (adjusted P = 0.003); In the TSHR (rs2268458) SNP = CC/CT or PTPN22 (rs3765598) SNP = CC subgroup, dental fluorosis may cause thyroid antibody single positive (adjusted P = 0.036; adjusted P = 0.002); in the TSHR (rs2268458) SNP = TT or PTPN22 (rs3765598) SNP = CC subgroup, dental fluorosis may protect children from goiter (age or BSA) (adjusted P = 0.018; adjusted P = 0.013). Excessive fluoride may induce thyroid antibody single positive and reduce goiter in children. Heterogeneity exists in the relationship between excessive fluoride and thyroid antibody single positive or goiter issues across children carrying different TSHR (rs2268458) or PTPN22 (rs3765598) genotypes.
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http://dx.doi.org/10.1007/s12011-021-02753-8DOI Listing
May 2021

BMI1 regulates multiple myeloma-associated macrophage's pro-myeloma functions.

Cell Death Dis 2021 May 15;12(5):495. Epub 2021 May 15.

Department of Hematology, West China Hospital, Sichuan University, Chengdu, China.

Multiple myeloma (MM) is an aggressive malignancy characterized by terminally differentiated plasma cells accumulation in the bone marrow (BM). MM BM exhibits elevated MΦs (macrophages) numbers relative to healthy BM. Current evidence indicates that MM-MΦs (MM-associated macrophages) have pro-myeloma functions, and BM MM-MΦs numbers negatively correlate with patient survival. Here, we found that BMI1, a polycomb-group protein, modulates the pro-myeloma functions of MM-MΦs, which expressed higher BMI1 levels relative to normal MΦs. In the MM tumor microenvironment, hedgehog signaling in MΦs was activated by MM-derived sonic hedgehog, and BMI1 transcription subsequently activated by c-Myc. Relative to wild-type MM-MΦs, BMI1-KO (BMI1 knockout) MM-MΦs from BM cells of BMI1-KO mice exhibited reduced proliferation and suppressed expression of angiogenic factors. Additionally, BMI1-KO MM-MΦs lost their ability to protect MM cells from chemotherapy-induced cell death. In vivo analysis showed that relative to wild-type MM-MΦs, BMI1-KO MM-MΦs lost their pro-myeloma effects. Together, our data show that BMI1 mediates the pro-myeloma functions of MM-MΦs.
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http://dx.doi.org/10.1038/s41419-021-03748-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8124065PMC
May 2021

Homoharringtonine synergizes with quizartinib in FLT3-ITD acute myeloid leukemia by targeting FLT3-AKT-c-Myc pathway.

Biochem Pharmacol 2021 Jun 6;188:114538. Epub 2021 Apr 6.

Hematology Research Laboratory, Department of Hematology, West China Hospital of Sichuan University, Chengdu, China. Electronic address:

Acute myeloid leukemia (AML) with FLT3 internal tandem duplication (FLT3-ITD) has a dismal prognosis. FLT3 inhibitors have been developed to treat patients with FLT3-ITD AML; however, when used alone, their efficacy is insufficient. FLT3 inhibitors combined with chemotherapy may be a promising treatment for FLT3-ITD AML. Homoharringtonine (HHT) is a classical anti-leukaemia drug with high sensitivity to FLT3-ITD AML cells. Here, we showed that HHT synergizes with a selective next-generation FLT3 inhibitor, quizartinib, to inhibit cell growth/viability and induce cell-cycle arrest and apoptosis in FLT3-ITD AML cells in vitro, significantly inhibit acute myeloid leukemia progression in vivo, and substantially prolong survival of mice-bearing human FLT3-ITD AML. Mechanistically, HHT and quizartinib cooperatively inhibit FLT3-AKT and its downstream targets GSK3β, c-Myc, and cyclin D1, cooperatively up-regulate the pro-apoptosis proteins Bim and Bax, and down-regulate the anti-apoptosis protein Mcl1. Most strikingly, HHT and quizartinib cooperatively reduce the numbers of side-population (SP) and aldehyde dehydrogenase (ALDH)-positive cells, which reportedly are rich in LSCs. In conclusion, HHT combined with quizartinib may be a promising treatment strategy for patients with FLT3-ITD AML.
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http://dx.doi.org/10.1016/j.bcp.2021.114538DOI Listing
June 2021

Optimal empiric treatment for KPC-2-producing Klebsiella pneumoniae infections in critically ill patients with normal or decreased renal function using Monte Carlo simulation.

BMC Infect Dis 2021 Mar 26;21(1):307. Epub 2021 Mar 26.

State Key Laboratory for Diagnosis and Treatment of Infectious Disease, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, China.

Background: Limited clinical studies describe the pharmacodynamics of fosfomycin (FOS), tigecycline (TGC) and colistin methanesulfonate (CMS) in combination against KPC-producing Klebsiella pneumoniae (KPC-Kp). Population pharmacokinetic models were used in our study. Monte Carlo simulation was conducted to calculate probability of target attainment (PTA) and cumulative fraction of response (CFR) of each agent alone and in combination against KPC-Kp in patients with normal or decreased renal function.

Results: The simulated regimen of FOS 6 g q8h reached ≥90% PTA against a MIC of 64 mg/L in patients with normal renal function. For patients with renal impairment, FOS 4 g q8h could provide sufficient antimicrobial coverage against a MIC of 128 mg/L. And increasing the daily dose could result to the cut-off value to 256 mg/L in decreased renal function. For TGC, conventional dosing regimens failed to reach 90% PTA against a MIC of 2 mg/L. Higher loading and daily doses (TGC 200/400 mg loading doses followed by 100 mg q12h/200 mg q24h) were needed. For CMS, none achieved 90% PTA against a MIC of 2 mg/L in normal renal function. Against KPC-Kp, the regimens of 200/400 mg loading dose followed by 100 q12h /200 mg q24h achieved > 80% CFRs regardless of renal function, followed by CMS 9 million IU loading dose followed by 4.5/3 million IU q12h in combination with FOS 8 g q8h (CFR 75-91%).

Conclusions: The use of a loading dose and high daily dose of TGC and CMS in combination with FOS can provide sufficient antimicrobial coverage against critically ill patients infected with KPC-Kp.
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http://dx.doi.org/10.1186/s12879-021-06000-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8004468PMC
March 2021

Fluoride exposure, dopamine relative gene polymorphism and intelligence: A cross-sectional study in China.

Ecotoxicol Environ Saf 2021 Feb 24;209:111826. Epub 2020 Dec 24.

Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Center, Beijing 100191, PR China. Electronic address:

Background: Excessive fluoride exposure is related to adverse health outcomes, but whether dopamine (DA) relative genes are involved in the health effect of low-moderate fluoride exposure on children's intelligence remain unclear.

Objectives: We conducted a cross-sectional study to explore the role of DA relative genes in the health effect of low-moderate fluoride exposure in drinking water.

Methods: We recruited 567 resident children, aged 6-11 years old, randomly from endemic and non-endemic fluorosis areas in Tianjin, China. Spot urine samples were tested for urinary fluoride concentration, combined Raven`s test was used for intelligence quotient test. Fasting venous blood were collected to analyze ANKK1 Taq1A (rs1800497), COMT Val158Met (rs4680), DAT1 40 bp VNTR and MAOA uVNTR. Multivariable linear regression models were used to assess associations between fluoride exposure and IQ scores. We applied multiplicative and additive models to appraise single gene-environment interaction. Generalized multifactor dimensionality reduction (GMDR) was used to evaluate high-dimensional interactions of gene-gene and gene-environment.

Results: In adjusted model, fluoride exposure was inversely associated with IQ scores (β = -5.957, 95% CI: -9.712, -2.202). The mean IQ scores of children with high-activity MAOA genotype was significantly lower than IQ scores of those with low-activity (P = 0.006) or female heterozygote (P = 0.016) genotype. We detected effect modification by four DA relative genes (ANKK1, COMT, DAT1 and MAOA) on the association between UF and IQ scores. We also found a high-dimensional gene-environment interaction among UF, ANKK1, COMT and MAOA on the effect of IQ (testing balanced accuracy = 0.5302, CV consistency: 10/10, P = 0.0107).

Conclusions: Our study suggests DA relative genes may modify the association between fluoride and intelligence, and a potential interaction among fluoride exposure and DA relative genes on IQ.
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http://dx.doi.org/10.1016/j.ecoenv.2020.111826DOI Listing
February 2021

The relationships between thyroid-stimulating hormone and/or dopamine levels in peripheral blood and IQ in children with different urinary iodine concentrations.

Neurosci Lett 2020 06 25;729:134981. Epub 2020 Apr 25.

School of public health, Tianjin Medical University, 22 Qixiangtai Road, Heping District, Tianjin 300070, PR China; Tianjin Municipal Bureau of Health Inspection, 94 Guizhou Road, Heping District, Tianjin 300070, PR China. Electronic address:

Environmental iodine deficiency or excess can lead to inappropriate iodine nutrition in the population. Little research has been performed to determine whether changes in thyroid-stimulating hormone (TSH) and/or dopamine (DA) concentrations in peripheral blood are involved in intellectual impairment caused by inappropriate iodine nutrition. 498 children aged 7-12 from areas with different water iodine concentrations were included in the study. Children's intelligence and levels of urinary iodine and fluoride, TSH, free triiodothyronine (FT), free thyroxine (FT), and DA were evaluated. The relationship between TSH and/or DA levels and intelligence quotient (IQ) in all participants and in the population with different urinary iodine concentrations (UIC) was evaluated by multivariate regression analysis. The proportion of people with low average and lower intelligence in UIC ≥ 300 μg/L group was significantly higher than that in control group but only a positive correlation was found between DA and IQ in the population with UIC < 100 μg/L (bootstrapped estimation P = 0.032). TSH and/or DA in peripheral blood may be not involved in the progressive decline in intelligence caused by iodine excess but DA had positive correlation with intelligence in iodine deficiency group, and no relationship between TSH concentration and IQ was found in the general population or in different UIC groups.
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http://dx.doi.org/10.1016/j.neulet.2020.134981DOI Listing
June 2020

Stopping the supply of iodized salt alone is not enough to make iodine nutrition suitable for children in higher water iodine areas: A cross-sectional study in northern China.

Ecotoxicol Environ Saf 2020 Jan 11;188:109930. Epub 2019 Nov 11.

Tianjin Centers for Disease Control and Prevention, 6 Huayue Road, Hedong District, Tianjin, 300011, PR China. Electronic address:

Background: For the sake of children's health, iodized salt supply has been stopped in many areas with excessive iodine in the drinking water, but children's iodine nutrition status and thyroid function after terminating the iodized salt supply is unknown. Objective We assessed the iodine nutrition, thyroid function and influencing factors for thyroid abnormalities in children from areas with different concentrations of water iodine; the supply of iodized salt has been stopped in high water iodine areas. This study aimed to evaluate whether the strategy of stopping the supplies of iodized salt alone is enough to avoid thyroid dysfunction in all areas with excess water iodine while still meeting the iodine nutrition needs of children.

Methods: A cross-sectional study was conducted in children from four areas with different drinking water iodine concentrations in Tianjin, China. The drinking water samplings and spot urine samples were collected to estimate the external and internal iodine exposure levels. The thyroid volume was measured, and blood samples were collected to assess thyroid function. Logistic regression analysis was used to analyze risk factors for thyroid abnormalities. A dietary survey was conducted to determine the sources of iodine nutrition among the areas with different iodine concentrations in the drinking water.

Results: In the area with a drinking water iodine concentration ≥300 μg/L, the median urinary iodine concentration (UIC) in children was 476.30 (332.20-639.30) μg/L, which was higher than that in other groups (all P < 0.05), and the prevalence of thyroid nodules and the thyroid goiter rate were higher than those in the <100 μg/L, 100-150 μg/L and 150-300 μg/L areas (all P < 0.01). Binary logistic regression analysis indicated that the risk of thyroid abnormalities was significantly increased in the UIC 200-299 μg/L group (OR: 4.534; 95% CI: 1.565, 13.135; bootstrapped 95% CI: 1.689, 21.206, P = 0.004) and in the UIC ≥ 300 μg/L group (OR: 6.962; 95% CI: 2.490, 19.460; bootstrapped 95% CI: 2.838, 32.570, P = 0.001) compared to the 100-199 μg/L group. The iodine contribution rates from water in areas with water iodine concentrations ≥300 μg/L are up to 63.04%.

Conclusions: After termination of the iodized salt supply, the level of iodine nutrition of children in the area with drinking water iodine concentrations ≥300 μg/L is still excessive. The water source needs to be replaced in this area. In the area with a water iodine concentration of 150-300 μg/L, it is proposed that stopping the supply of iodized salt is sufficient to achieve the proper iodine nutrition status in children.
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http://dx.doi.org/10.1016/j.ecoenv.2019.109930DOI Listing
January 2020

A new variant of mcr-1 identified from an extended-spectrum β lactamase-producing Escherichia coli.

J Glob Antimicrob Resist 2019 09 30;18:26-27. Epub 2019 May 30.

Department of Infectious Diseases, College of Medicine, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang, China; Key Laboratory of Microbial Technology and Bioinformatics of Zhejiang Province, Hangzhou, Zhejiang, China. Electronic address:

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http://dx.doi.org/10.1016/j.jgar.2019.04.009DOI Listing
September 2019

3-Methyladenine alleviates excessive iodine-induced cognitive impairment via suppression of autophagy in rat hippocampus.

Environ Toxicol 2019 Aug 9;34(8):912-920. Epub 2019 May 9.

Department of Occupational and Environmental Health, School of Public Health, Tianjin Medical University, Tianjin, China.

Drinking water with high levels of iodine has been identified as the key contributor to iodine excess, but the mechanisms of neurotoxicity induced by excessive iodine remain elusive. The present study aimed to explore the role of autophagy in the neurotoxic effect induced by excessive iodine in vivo. The Morris water maze test results demonstrated that excessive iodine impaired the learning and memory capabilities of rats, which were associated with marked body weight and brain weight abnormalities. In addition, iodine treatment increased malondialdehyde accumulation, decreased superoxide dismutase activity and glutathione (GSH) level, and enhanced levels of autophagy markers in the hippocampus. Notably, inhibition of autophagy with 3-methyladenine (3-MA) could significantly alleviate excessive iodine-induced cognitive impairment. These data imply that autophagy is involved in the cognitive impairment elicited by excessive iodine as a pathway of cell death, and inhibition of autophagy via 3-MA may significantly alleviate the above damage.
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http://dx.doi.org/10.1002/tox.22762DOI Listing
August 2019

Low-to-moderate fluoride exposure, relative mitochondrial DNA levels, and dental fluorosis in Chinese children.

Environ Int 2019 06 22;127:70-77. Epub 2019 Mar 22.

Department of Occupational and Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China; Key Laboratory of Environment and Health, Ministry of Education and Ministry of Environmental Protection, State Key Laboratory of Environmental Health (incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China. Electronic address:

Background: The alteration of mitochondrial DNA (mtDNA) content contributes to many diseases, however, little is known about its effect on the prevalence of dental fluorosis (DF).

Objectives: We conducted a cross-sectional study to investigate the association of low-to-moderate fluoride exposure with relative mtDNA levels in relation to DF in children.

Methods: We recruited 616 resident children, aged 7-13 years, randomly from low-to-moderate fluoride areas in Tianjin, China. We measured the fluoride concentrations in drinking water and urine using the national standardized ion selective electrode method, and determined the relative levels of mtDNA using a quantitative real-time polymerase chain reaction assay. The association among fluoride exposure, relative mtDNA levels, and the prevalence of DF were examined using multivariable linear and logistic regression models. We also performed stratified and mediation analyses.

Results: The relative mtDNA levels of participants in the DF group were significantly lower than in the non-DF group (0.95 ± 0.44 vs. 1.12 ± 0.45, P < 0.001). In the adjusted models, we found that a 1 mg/L increment in water fluoride concentration was associated with a 0.10-unit decrease in circulating relative mtDNA levels (95% CI: -0.14, -0.06) and a 2.85-fold increase (95% CI: 2.01, 3.92) in moderate DF prevalence. A 1 mg/L increment in urinary fluoride level was associated with a 0.12-unit decrease in circulating relative mtDNA levels (95% CI: -0.14, -0.09) and a 1.85-fold increase (95% CI: 1.39, 2.39) in moderate DF prevalence. Stratified analysis indicated a weaker positive association of DF prevalence with fluoride exposure, while a stronger inverse relationship with relative mtDNA levels in boys than in girls. Assuming causality, we estimated that circulating mtDNA levels mediated 13.0% (95% CI: 5.2, 28.7%) and 9.6% (95% CI: 4.7, 18.5%) of the estimated effect of a 1 mg/L increment in water fluoride and urinary fluoride on prevalence of moderate DF, respectively.

Conclusions: Gender potentially modifies the associations of DF prevalence with relative mtDNA levels and low-to-moderate fluoride exposure. The reduced circulating mtDNA levels may partly mediate the elevated prevalence of moderate DF in children under such exposure.
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http://dx.doi.org/10.1016/j.envint.2019.03.033DOI Listing
June 2019

Dopamine receptor D2 gene polymorphism, urine fluoride, and intelligence impairment of children in China: A school-based cross-sectional study.

Ecotoxicol Environ Saf 2018 Dec 8;165:270-277. Epub 2018 Sep 8.

Tianjin Centers for Disease Control and Prevention, 6 Huayue Road, Hedong District,Tianjin 300011, PR China; School of Public Health, Tianjin Medical University, 22 Qixiangtai Road, Heping District, Tianjin 300070, PR China. Electronic address:

Objective: We aimed to study the association of urine fluoride with intelligence quotient (IQ) in children with a careful consideration of up to 30 potential confounding factors as well as possible heterogeneity of the relation between urine fluoride levels and IQ scores across children with different dopamine receptor-2 (DRD2) Taq 1A genotypes (CC, CT, and TT).

Methods: A school-based cross-sectional study design was applied. A total of 323 children (2014-2015, 7-12 years old) were enrolled from four schools in both historical endemic and non-endemic areas of fluorosis in Tianjin of China using a cluster sampling method. Urine fluoride levels and age-specific IQ scores in children were measured at the enrollment. Polymerase chain reaction-restriction fragment length polymorphism methods were used to genotype DRD2 Taq 1A polymorphism with genomic DNA isolated from whole blood collected at the enrollment. Multiple linear regression models were applied to evaluate the relationship between urine fluoride levels and IQ scores overall and within the DRD2 Taq 1A SNP = CC/CT and TT subgroups. Model robustness was tested through bootstrap, sensitivity analysis, and cross-validation techniques. A safety threshold of urine fluoride levels for IQ impairment was determined in the subgroup TT.

Results: In overall participants, the DRD2 Taq 1A polymorphism itself was not related to IQ scores in children who had a high level of urine fluoride. In the CC/CT subgroup, urine fluoride levels and IQ scores in children were unrelated (adjusted β (95% confidence interval (CI)) = - 1.59 (- 4.24, 1.05), p = 0.236). Among the participants carrying the TT genotype, there was a strong and robust negative linear relationship between log-urine fluoride and IQ scores in children (adjusted β (95% CI) = - 12.31 (- 18.69, - 5.94), p < 0.001). Urine fluoride levels had a stronger association with IQ in children carrying the TT genotype (adjusted β = - 12.31, bootstrapped standard error (SE) = 1.28), compared to that in overall participants (adjusted β = - 2.47, bootstrapped SE = 3.75) (Z = 2.483 and bootstrapped p = 0.007). The safety threshold of urine fluoride levels in the subgroup TT was 1.73 mg/L (95% CI = (1.51, 1.97) (mg/L)).

Conclusions: There is heterogeneity in the relation between urine fluoride and IQ across children carrying different DRD2 Taq 1A genotypes. Large-scale epidemiological studies are needed to confirm our findings.
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http://dx.doi.org/10.1016/j.ecoenv.2018.09.018DOI Listing
December 2018

Excessive apoptosis and disordered autophagy flux contribute to the neurotoxicity induced by high iodine in Sprague-Dawley rat.

Toxicol Lett 2018 Nov 29;297:24-33. Epub 2018 Aug 29.

Tianjin Centers for Disease Control and Prevention, 6 Huayue Road, Hedong District, Tianjin 300011, People's Republic of China; School of Public Health, Tianjin Medical University, 22 Qixiangtai Road, Heping District, Tianjin 300070, People's Republic of China; Tianjin Municipal Inspection Bureau for Health and Family Planning, 94 Guizhou Road, Heping District, Tianjin 300070, People's Republic of China. Electronic address:

In recent years, the detrimental effects of high iodine on intelligence are gaining tons of attention, but the relationship between high iodine and neurotoxicity is controversial. This study aimed to explore whether high iodine intake may impair intelligence and the roles of apoptosis and autophagy in high iodine-induced neurotoxicity. The results showed that high iodine exposure reduced brain coefficient and intelligence of rats, and caused histopathological abnormalities in hippocampus. Moreover, high iodine increased hippocampal apoptosis, as confirmed by elevation of apoptotic proteins and TUNEL-positive incidence. Further study showed that high iodine impaired mitochondrial ultrastructure and caused elevation of Bax, cytochrome c and decline of Bcl2, indicating the participation of mitochondrial apoptotic pathway. Simultaneously, high iodine also increased the number of autophagosomes. Intriguingly, the expression of autophagosomes formation protein Atg7, Beclin1 and autophagic substrate p62 were elevated, suggesting that the accumulated autophagosomes is not only due to the enhancement of formation but also the decline of clearance. These, together with the numerous damaged organelles observed in hippocampal ultrastructure, reveal the crucial role of disordered autophagy flux in high iodine-elicited neurotoxicity. Collectively, these findings suggest that excessive apoptosis and disordered autophagy flux contribute to high iodine-elicited neurotoxicity.
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http://dx.doi.org/10.1016/j.toxlet.2018.08.020DOI Listing
November 2018

Oxidative stress-mediated autophagic cell death participates in the neurotoxic effect on SH-SY5Y cells induced by excessive iodide.

Environ Toxicol 2018 Jun 19. Epub 2018 Jun 19.

Department of Environmental Health and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong Universityof Science and Technology, 13 Hangkong Road, Hubei, Wuhan, 430030, People's Republic of China.

Excessive iodide could induce intellectual damage in children, which has attracted broad attention. To investigate the neurotoxic effect of iodide and its mechanism, a human dopaminergic neuroblastoma cell line (SH-SY5Y) was treated with different concentrations of potassium iodide (KI). The results showed that excessive iodide could decrease cell viability, reduce glutathione (GSH) and superoxide dismutase (SOD), and increase the degree of autophagy (by changing the cellular ultrastructure and raising the autophagy-related mRNA and protein expression of LC3, Beclin1, and p62), which were correlated with the immunofluorescence labeling. Furthermore, treatment with the autophagy inhibitor 3-methyladenine (3MA), antioxidant N-acetylcysteine (NAC) and 30 mM KI for 24 h was conducted in the following research. 3MA significantly decreased autophagy-related mRNA and protein expression and improved cell viability, indicating that excess iodide induced autophagic cell death. In addition, oxidative stress regulated autophagy, reflected by the results that NAC decreased the mRNA and protein expression of LC3, Beclin1, and p62. In summary, autophagic cell death mediated by oxidative stress may participate in excessive iodide-induced SH-SY5Y cell death.
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http://dx.doi.org/10.1002/tox.22571DOI Listing
June 2018

Threshold effects of moderately excessive fluoride exposure on children's health: A potential association between dental fluorosis and loss of excellent intelligence.

Environ Int 2018 09 2;118:116-124. Epub 2018 Jun 2.

Department of Occupational and Environmental Health, Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China. Electronic address:

Background: Excessive fluoride exposure is associated with adverse health outcomes, but little is known of the effects of moderately chronic fluoride exposure on children's health.

Objectives: We conducted a cross-sectional study to explore the health impact of moderately excessive fluoride in drinking water.

Methods: We recruited 2886 resident children, aged 7 to 13 years, randomly from endemic and non-endemic fluorosis areas in Tianjin, China. The fluoride levels in drinking water and urine were measured using the national standardized ion selective electrode method. We examined the dose-response effects of low-to-moderate fluoride exposure on dental fluorosis (DF) and intelligence quotient (IQ), and evaluated the potential relationships between DF grades and intelligence levels using piecewise linear regression and multiple logistic regression, respectively.

Results: The adjusted odds ratios (ORs) of DF were 2.24 (95% confidence interval [CI]: 2.02 to 2.48) for every 0.1 mg/L increment in the water fluoride concentration in the range of 0.80 to 1.50 mg/L, and 2.61 (95% CI: 2.32 to 2.93) for every 0.5 mg/L increment in the urinary fluoride level up to 1.80 mg/L. Every 0.5 mg/L increment in the water fluoride level was associated with a reduction of 4.29 in the IQ score (95% CI: -8.09 to -0.48) in the range of 3.40 to 3.90 mg/L, and a decreased probability of developing excellent intelligence (IQ ≥ 130, OR = 0.60, 95% CI: 0.47 to 0.77) in the range of 0.20-1.40 mg/L, respectively. Every 0.5 mg/L increment in the urinary fluoride level was related to a decrease of 2.67 in the IQ scores (95% CI: -4.67 to -0.68) between 1.60 mg/L to 2.50 mg/L. Excellent intelligence decreased by 51% in children with higher urinary fluoride, and by 30% with each degree increment of DF.

Conclusions: Our study suggests threshold and saturation effects of moderately excessive fluoride exposure on DF and intelligence loss in children, and a potential association between DF and the loss of excellent intelligence.
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http://dx.doi.org/10.1016/j.envint.2018.05.042DOI Listing
September 2018

Comparative Analysis of miRNA Expression Profiles of Multiple Myeloma with 1q21 Gains and Normal FISH.

Acta Haematol 2018;139(2):96-100. Epub 2018 Feb 2.

Background: Multiple myeloma (MM) with 1q21 gains invariably has a poor prognosis. Many recent studies have reported the relationship between micro (mi)RNA expression and MM prognosis. However, there is little information on the association between miRNA alterations and 1q21 gains.

Methods: We compared the miRNA expression profiles of MM with 1q21 gains and MM with normal fluorescence in situ hybridisation (FISH) by gene expression array. Differentially expressed miRNAs were identified using Affymetrix TAC software. Thresholds were defined as a false discovery rate <0.05, p value <0.05, and n-fold change >2.

Results: Six miRNAs (let-7f-5p and -7g-5p, and miR-29a-3p, -29b-1-5p, -331-3p, and -223-3p) were downregulated and 4 (miR-30e-5p, -17-3p, -18b-5p, and -19a-3p) were upregulated in MM with 1q21 gains relative to MM with normal FISH.

Conclusions: The identified set of miRNAs can serve as biomarkers for distinguishing MM with 1q21 gains from MM with normal FISH.
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http://dx.doi.org/10.1159/000486662DOI Listing
March 2019

Autophagy regulates high concentrations of iodide-induced apoptosis in SH-SY5Y cells.

Toxicol Lett 2018 Mar 11;284:129-135. Epub 2017 Dec 11.

School of Public Health, Tianjin Medical University, 22 Qixiangtai Road, Heping District, Tianjin 300070, People's Republic of China; Tianjin Centers for Disease Control and Prevention, 6 Huayue Road, Hedong District, Tianjin 300011, People's Republic of China; Tianjin Municipal Inspection Bureau for Health And Family Planning, 94 Guizhou Road, Heping District, Tianjin 300070, People's Republic of China. Electronic address:

To date, there are many people residing in areas with high levels of iodide in water. Our previous epidemiological study showed that exposure to high iodine in drinking water significantly reduced the intelligence of children although the mechanisms remain unclear. To explore whether high concentrations of iodide may cause cytotoxic effect and the role of autophagy in the high iodide-induced apoptosis, human neuroblastoma cells (SH-SY5Y cells) were exposed to high concentrations of iodide. Morphological phenotypes, cell viability, Hoechst 33258 staining, the expression levels of apoptosis and autophagy-related proteins were detected. A possible effect of an inhibitor (3-methyladenine, 3-MA) or an inducer (rapamycin) of autophagy on high iodide-induced apoptosis also was examined. Results indicated that high iodide changed cellular morphology, decreased cell viability and increased the protein's expression level of apoptosis and autophagy. In addition, high iodide-induced apoptosis was enhanced by inhibition of autophagy and inhibited by activation of autophagy in SH-SY5Y cells. Collectively, high concentrations of iodide are toxic to SH-SY5Y cells, as well as induce apoptosis and autophagy. Furthermore, autophagy plays a regulatory role in high concentrations of iodide-induced apoptosis in SH-SY5Y cells.
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http://dx.doi.org/10.1016/j.toxlet.2017.12.007DOI Listing
March 2018

Role of endoplasmic reticulum stress-induced apoptosis in rat thyroid toxicity caused by excess fluoride and/or iodide.

Environ Toxicol Pharmacol 2016 Sep 9;46:277-285. Epub 2016 Aug 9.

Department of Environmental Health and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, 430030 Hubei, PR China. Electronic address:

Excess fluoride and iodide coexist in drinking water in many regions, but few studies have investigated the single or interactive effects on thyroid in vivo. In our study, Wistar rats were exposed to excess fluoride and/or iodide through drinking water for 2 or 8 months. The structure and function of the thyroid, cells apoptosis and the expression of inositol-requiring enzyme 1 (IRE1) pathway-related factors were analyzed. Results demonstrated that excess fluoride and/or iodide could change thyroid follicular morphology and alter thyroid hormone levels in rats. After 8 months treatment, both single and co-exposure of the two microelements could raise the thyroid cells apoptosis. However, the expressions of IRE1-related factors were only increased in fluoride-alone and the combined groups. In conclusion, thyroid structure and thyroid function were both affected by excess fluoride and/or iodide. IRE1-induced apoptosis were involved in this cytotoxic process caused by fluoride or the combination of two microelements.
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http://dx.doi.org/10.1016/j.etap.2016.08.007DOI Listing
September 2016

Estimating Temperature-Mortality Exposure-Response Relationships and Optimum Ambient Temperature at the Multi-City Level of China.

Int J Environ Res Public Health 2016 Mar 3;13(3). Epub 2016 Mar 3.

Department of Occupational and Environmental Health, School of Public Health, Peking University, Xueyuan Road, Haidian District, Beijing 100191, China.

Few studies have explored temperature-mortality relationships in China, especially at the multi-large city level. This study was based on the data of seven typical, large Chinese cities to examine temperature-mortality relationships and optimum temperature of China. A generalized additive model (GAM) was applied to analyze the acute-effect of temperature on non-accidental mortality, and meta-analysis was used to merge data. Furthermore, the lagged effects of temperature up to 40 days on mortality and optimum temperature were analyzed using the distributed lag non-linear model (DLNM). We found that for all non-accidental mortality, high temperature could significantly increase the excess risk (ER) of death by 0.33% (95% confidence interval: 0.11%, 0.56%) with the temperature increase of 1 °C. Similar but non-significant ER of death was observed when temperature decreased. The lagged effect of temperature showed that the relative risk of non-accidental mortality was lowest at 21 °C. Our research suggests that high temperatures are more likely to cause an acute increase in mortality. There was a lagged effect of temperature on mortality, with an optimum temperature of 21 °C. Our results could provide a theoretical basis for climate-related public health policy.
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http://dx.doi.org/10.3390/ijerph13030279DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4808942PMC
March 2016

Modifying effect of COMT gene polymorphism and a predictive role for proteomics analysis in children's intelligence in endemic fluorosis area in Tianjin, China.

Toxicol Sci 2015 Apr 1;144(2):238-45. Epub 2015 Jan 1.

*Department of Environmental Health and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, Tianjin Center for Disease Control and Prevention, Tianjin 300011, Tianjin, Department of Environmental Health and MOE Key Lab of Public Health and Safety, School of Public Health, Fudan University, Shanghai 200032, Shanghai and Department of Pathology, Guiyang Medical College, Guiyang 550004, Guizhou, People's Republic of China.

Cumulative fluoride exposure has adverse influences on children's intelligence quotient (IQ). In addition, catechol-O-methyltransferase (COMT) gene Val158Met polymorphism (rs4680) is associated with cognitive performance. This study aimed to evaluate the associations of COMT polymorphism and alterations of protein profiles with children's intelligence in endemic fluorosis area. We recruited 180 schoolchildren (10-12 years old) from high fluoride exposure (1.40 mg/l) and control areas (0.63 mg/l) in Tianjin City, China. The children's IQ, fluoride contents in drinking water (W-F), serum (S-F), and urine (U-F); serum thyroid hormone levels, COMT Val158Met polymorphism, and plasma proteomic profiling were determined. Significant high levels of W-F, S-F, U-F, along with poor IQ scores were observed in the high fluoride exposure group compared with those in control (all P < 0.05). S-F and U-F were inversely related with IQ (r(s) = -0.47, P < 0.01; r(s) = -0.45, P = 0.002). Importantly, higher fluoride exposure was associated with steeper cognitive decline among children with the reference allele Val compared with those homozygous or heterozygous for the variant allele Met (95% CI, -16.80 to 2.55; P interaction < 0.01). Additionally, 5 up-regulated protein spots related to cell immunity and metabolism were detected in children with high fluoride exposure compared with the control. In conclusion, fluoride exposure was adversely associated with children's intelligence, whereas the COMT polymorphism may increase the susceptibility to the deficits in IQ due to fluoride exposure. Moreover, the proteomic analysis can provide certain basis for identifying the early biological markers of fluorosis among children.
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http://dx.doi.org/10.1093/toxsci/kfu311DOI Listing
April 2015

The effects and underlying mechanism of excessive iodide on excessive fluoride-induced thyroid cytotoxicity.

Environ Toxicol Pharmacol 2014 Jul 27;38(1):332-40. Epub 2014 Jun 27.

Department of Environmental Health and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Hubei, Wuhan 430030, PR China. Electronic address:

In many regions, excessive fluoride and excessive iodide coexist in groundwater, which may lead to biphasic hazards to human thyroid. To explore fluoride-induced thyroid cytotoxicity and the mechanism underlying the effects of excessive iodide on fluoride-induced cytotoxicity, a thyroid cell line (Nthy-ori 3-1) was exposed to excessive fluoride and/or excessive iodide. Cell viability, lactate dehydrogenase (LDH) leakage, reactive oxygen species (ROS) formation, apoptosis, and the expression levels of inositol-requiring enzyme 1 (IRE1) pathway-related molecules were detected. Fluoride and/or iodide decreased cell viability and increased LDH leakage and apoptosis. ROS, the expression levels of glucose-regulated protein 78 (GRP78), IRE1, C/EBP homologous protein (CHOP), and spliced X-box-binding protein-1 (sXBP-1) were enhanced by fluoride or the combination of the two elements. Collectively, excessive fluoride and excessive iodide have detrimental influences on human thyroid cells. Furthermore, an antagonistic interaction between fluoride and excessive iodide exists, and cytotoxicity may be related to IRE1 pathway-induced apoptosis.
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http://dx.doi.org/10.1016/j.etap.2014.06.008DOI Listing
July 2014

The role of the IRE1 pathway in excessive iodide- and/or fluoride-induced apoptosis in Nthy-ori 3-1 cells in vitro.

Toxicol Lett 2014 Jan 11;224(3):341-8. Epub 2013 Nov 11.

Department of Environmental Health and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Hubei, Wuhan 430030, People's Republic of China. Electronic address:

Excessive iodide and fluoride coexist in the groundwater in many regions, causing a potential risk to the human thyroid. To investigate the mechanism of iodide- and fluoride-induced thyroid cytotoxicity, human thyroid follicular epithelial cells (Nthy-ori 3-1) were treated with different concentrations of potassium iodide (KI), with or without sodium fluoride (NaF). Cell morphology, viability, lactate dehydrogenase (LDH) leakage, apoptosis, and expression of inositol-requiring enzyme 1 (IRE1) pathway-related molecules were assessed. Results showed 50 mM of KI, 1 mM of NaF, and 50 mM of KI +1 mM of NaF changed cellular morphology, decreased viability, and increased LDH leakage and apoptosis. Elevated expression of binding protein (BiP), IRE1, and C/EBP homologous protein (CHOP) mRNA and protein, as well as spliced X-box-binding protein-1 (sXBP-1) mRNA, were observed in the 1 mM NaF and 50 mM KI +1 mM NaF groups. Collectively, excessive iodide and/or fluoride is cytotoxic to the human thyroid. Although these data do not manifest iodide could induce the IRE1 pathway, the cytotoxicity followed by exposure to fluoride alone or in combination with iodide may be related to IRE1 pathway-induced apoptosis. Furthermore, exposure to the combination of excessive iodide and fluoride may cause interactive effects on thyroid cytotoxicity.
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http://dx.doi.org/10.1016/j.toxlet.2013.11.001DOI Listing
January 2014

Low glucose utilization and neurodegenerative changes caused by sodium fluoride exposure in rat's developmental brain.

Neuromolecular Med 2014 Mar 28;16(1):94-105. Epub 2013 Aug 28.

Department of Environmental Health and MOE Key Lab of Environment and Health, School of Public, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, Wuhan, 430030, Hubei, People's Republic of China.

Fluorine, a toxic and reactive element, is widely prevalent throughout the environment and can induce toxicity when absorbed into the body. This study was to explore the possible mechanisms of developmental neurotoxicity in rats treated with different levels of sodium fluoride (NaF). The rats' intelligence, as well as changes in neuronal morphology, glucose absorption, and functional gene expression within the brain were determined using the Morris water maze test, transmission electron microscopy, small-animal magnetic resonance imaging and Positron emission tomography and computed tomography, and Western blotting techniques. We found that NaF treatment-impaired learning and memory in these rats. Furthermore, NaF caused neuronal degeneration, decreased brain glucose utilization, decreased the protein expression of glucose transporter 1 and glial fibrillary acidic protein, and increased levels of brain-derived neurotrophic factor in the rat brains. The developmental neurotoxicity of fluoride may be closely associated with low glucose utilization and neurodegenerative changes.
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http://dx.doi.org/10.1007/s12017-013-8260-zDOI Listing
March 2014

Fluoride-elicited developmental testicular toxicity in rats: roles of endoplasmic reticulum stress and inflammatory response.

Toxicol Appl Pharmacol 2013 Sep 22;271(2):206-15. Epub 2013 May 22.

Department of Environmental Health and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, Wuhan 430030, Hubei, People's Republic of China.

Long-term excessive fluoride intake is known to be toxic and can damage a variety of organs and tissues in the human body. However, the molecular mechanisms underlying fluoride-induced male reproductive toxicity are not well understood. In this study, we used a rat model to simulate the situations of human exposure and aimed to evaluate the roles of endoplasmic reticulum (ER) stress and inflammatory response in fluoride-induced testicular injury. Sprague-Dawley rats were administered with sodium fluoride (NaF) at 25, 50 and 100mg/L via drinking water from pre-pregnancy to gestation, birth and finally to post-puberty. And then the testes of male offspring were studied at 8weeks of age. Our results demonstrated that fluoride treatment increased MDA accumulation, decreased SOD activity, and enhanced germ cell apoptosis. In addition, fluoride elevated mRNA and protein levels of glucose-regulated protein 78 (GRP78), inositol requiring ER-to-nucleus signal kinase 1 (IRE1), and C/EBP homologous protein (CHOP), indicating activation of ER stress signaling. Furthermore, fluoride also induced testicular inflammation, as manifested by gene up-regulation of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), in a nuclear factor-κB (NF-κB)-dependent manner. These were associated with marked histopathological lesions including injury of spermatogonia, decrease of spermatocytes and absence of elongated spermatids, as well as severe ultrastructural abnormalities in testes. Taken together, our results provide compelling evidence that ER stress and inflammation would be novel and significant mechanisms responsible for fluoride-induced disturbance of spermatogenesis and germ cell loss in addition to oxidative stress.
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http://dx.doi.org/10.1016/j.taap.2013.04.033DOI Listing
September 2013

JNK pathway decreases thyroid hormones via TRH receptor: a novel mechanism for disturbance of thyroid hormone homeostasis by PCB153.

Toxicology 2012 Dec 4;302(1):68-76. Epub 2012 Aug 4.

MOE Key Lab of Environment and Health, Department of Occupational and Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan 430030, PR China.

PCBs, widespread and well-characterized endocrine disruptors, cause the disruption of thyroid hormone (TH) homeostasis in humans and animals. In order to verify the hypotheses that MAPK pathways would play roles in disturbance of TH levels caused by PCBs, and that TH-associated receptors could function in certain MAPK pathway, Sprague-Dawley rats were dosed with PCB153 intraperitoneally (i.p.) at 0, 4, 16 and 32mg/kg for 5 consecutive days, and Nthy-ori 3-1 cells were treated with PCB153 (0, 1, 5, 10μM) for 30min. Results showed that after the treatment with PCB153, serum total thyroxine (TT4), free thyroxine (FT4), total triiodothyronine (TT3) and thyrotropin releasing hormone (TRH) were decreased, whereas free triiodothyronine (FT3) and serum thyroid stimulating hormone (TSH) were not altered. In vivo and in vitro studies indicated that JNK pathway was activated after PCB153 exposure. Moreover, TRH receptor (TRHr) level was suppressed after the activation of JNK pathway and was elevated after the inhibition of JNK pathway, but TSH receptor (TSHr) level was not affected by the status of JNK pathway though it was reduced after PCB153 treatment. The activated signs of ERK and P38 pathways were not observed in this study. Taken together, observed effects suggested that JNK pathway could decrease TH levels via TRHr, and that would be one novel mechanism of PCB153-mediated disruption of THs.
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http://dx.doi.org/10.1016/j.tox.2012.07.016DOI Listing
December 2012
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