Publications by authors named "Guoyu Zhou"

51 Publications

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 Jun 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
June 2021

Resveratrol improved hippocampal neurogenesis following lead exposure in rats through activation of SIRT1 signaling.

Environ Toxicol 2021 May 12. Epub 2021 May 12.

Department of Environmental Health, College of Public Health, Zhengzhou University, Zhengzhou, China.

Lead (Pb) poses a potential environmental risk factor for cognitive dysfunction during early life and childhood. Resveratrol is considered a promising antioxidant with respect to the prevention of cognitive deficits and act as a potent SIRT1 agonist. Here in, this study aims to investigate the profile of neurogenesis markers following Pb exposure and to determine the regulatory role of resveratrol in this process. We confirmed firstly the protective effects of resveratrol against Pb-induced impairments of hippocampal neurogenesis in Male SD rats. Pb exposure early in life caused the altered expression of Ki-67, NeuN, caspase-3 and SIRT1signaling, thereby resulting in spatial cognitive impairment of adolescent rats. As expected, resveratrol reduced cognitive damage and promoted neurogenesis in Pb-induced injury by regulation of SIRT1 pathway. Collectively, our study establishes the efficacy of resveratrol as a neuroprotective agent and providesa strong rationale for further studies on SIRT1-mediated mechanisms of neuroprotective functions.
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http://dx.doi.org/10.1002/tox.23162DOI Listing
May 2021

Reduction in pericyte coverage leads to blood-brain barrier dysfunction via endothelial transcytosis following chronic cerebral hypoperfusion.

Fluids Barriers CNS 2021 May 5;18(1):21. Epub 2021 May 5.

Department of Neurology, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Henan University People's Hospital, Zhengzhou, 450003, Henan, China.

Background: Chronic cerebral hypoperfusion (CCH) is the leading cause of cerebral small vessel disease (CSVD). CCH is strongly associated with blood-brain barrier (BBB) dysfunction and white matter lesions (WMLs) in CSVD. However, the effects of CCH on BBB integrity and components and the cellular and molecular mechanisms underlying the effects of BBB dysfunction remain elusive. Whether maintaining BBB integrity can reverse CCH-induced brain damage has also not been explored.

Methods: In this study, we established a rat model of CSVD via permanent bilateral common carotid artery occlusion (2VO) to mimic the chronic hypoperfusive state of CSVD. The progression of BBB dysfunction and components of the BBB were assessed using immunostaining, Western blotting, transmission electron microscopy (TEM) and RNA sequencing. We also observed the protective role of imatinib, a tyrosine kinase inhibitor, on BBB integrity and neuroprotective function following CCH. The data were analyzed using one-way or two-way ANOVA.

Results: We noted transient yet severe breakdown of the BBB in the corpus callosum (CC) following CCH. The BBB was severely impaired as early as 1 day postoperation and most severely impaired 3 days postoperation. BBB breakdown preceded neuroinflammatory responses and the formation of WMLs. Moreover, pericyte loss was associated with BBB impairment, and the accumulation of serum protein was mediated by increased endothelial transcytosis in the CC. RNA sequencing also revealed increased transcytosis genes expression. BBB dysfunction led to brain damage through regulation of TGF-β/Smad2 signaling. Furthermore, imatinib treatment ameliorated serum protein leakage, oligodendrocyte progenitor cell (OPC) activation, endothelial transcytosis, microglial activation, and aberrant TGF-β/Smad2 signaling activation.

Conclusions: Our results indicate that reduced pericyte coverage leads to increased BBB permeability via endothelial transcytosis. Imatinib executes a protective role on the BBB integrity via inhibition of endothelial transcytosis. Maintenance of BBB integrity ameliorates brain damage through regulation of TGF-β/Smad2 signaling following CCH; therefore, reversal of BBB dysfunction may be a promising strategy for CSVD treatment.
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http://dx.doi.org/10.1186/s12987-021-00255-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8101037PMC
May 2021

Incidence and prevalence of moyamoya disease in urban China: a nationwide retrospective cohort study.

Stroke Vasc Neurol 2021 May 3. Epub 2021 May 3.

Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Centre, Beijing, China

Background And Objective: Moyamoya disease (MMD) is an increasingly recognised cause of stroke, mainly described in East Asia. China is the largest nation in Asia, but few studies reported the epidemiology of MMD, especially at a national level. We aimed to estimate the incidence and prevalence of MMD in China.

Methods: We performed a population-based study using data from the national databases of Urban Basic Medical Insurance between 2013 and 2016, covering approximately 0.50 billion individuals. MMD cases were identified by diagnostic code (International Classification of Diseases, 10th Revision I67.5) or related diagnostic text.

Results: A total of 1987 MMD patients (mean age 44.45±14.30 years, female-to-male ratio 1.12) were identified, representing a national crude incidence of 0.59 (95% CI: 0.49 to 0.68) and a prevalence of 1.01 (95% CI: 0.81 to 1.21) per 100 000 person-years in 2016. Rates were higher in females than in males for the incidence (0.66 vs 0.52) and prevalence (1.05 vs 0.90). And the age-specific rates showed a bimodal distribution, with the highest peak in middle-aged group and the second peak in child group.

Conclusions: Our results confirm that MMD is relatively common in East Asians, but the rates in China were lower than those in other East Asian countries such as Japan and Korea. The unique epidemiological features, including a relatively weak female predominance and a shift in the highest peak of incidence from children to adults, revealed new sight into MMD. Further research is expected to explore the potential pathogenesis of MMD.
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http://dx.doi.org/10.1136/svn-2021-000909DOI Listing
May 2021

α Promoter Methylation May Modify the Association Between Lipid Metabolism and Type 2 Diabetes in Chinese Farmers.

Front Public Health 2021 4;9:578134. Epub 2021 Mar 4.

Department of Environment Health & Environment and Health Innovation Team, School of Public Health, Zhengzhou University, Zhengzhou, China.

This study is aimed to explore the potential association among the estrogen receptor alpha (α) promoter methylation, lipid metabolism and the risk of type 2 diabetes mellitus (T2DM). A total of 1143 rural residents were recruited randomly from Henan Province, China. The circulating methylation levels in α promoter region were determined by quantitative methylation-specific polymerase chain reaction. Serum high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), triglyceride (TG), total cholesterol (TC) and fasting plasma-glucose (FPG) were measured. The α promoter methylation levels were negatively associated with HDL-C levels whether gender stratification was performed ( < 0.05) and positively correlated with LDL-C in men ( < 0.05). Each unit standard deviation (SD) increment in TG was associated with a 43% increase (95% CI: 1.25, 1.64) in the risks of T2DM in all participants, a 36% increase (95% : 1.13, 1.64) in the risks of T2DM in men and a 49% increase (95% CI: 1.21, 1.83) in the risks of T2DM in women. Furthermore, each SD increment in HDL-C was associated with a reduction of 25% (OR = 0.75, 95% CI: 0.58, 0.97) in the risks of T2DM in men, and the risk of T2DM in men may be more susceptible to HDL-C than that in women ( for interaction < 0.05). Additionally, we found that the risk of T2DM in participants with lower methylation levels (≤4.07%) were more susceptible to HDL-C ( for interaction < 0.05). These findings suggested that lipid metabolism was associated with α promoter methylation levels and the risk of T2DM. Besides, the levels of α promoter methylation and gender can modify the association of HDL-C and T2DM.
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http://dx.doi.org/10.3389/fpubh.2021.578134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7969800PMC
May 2021

Roles and Mechanisms of Axon-Guidance Molecules in Alzheimer's Disease.

Mol Neurobiol 2021 Mar 5. Epub 2021 Mar 5.

Department of Environmental Health, School of Public Health, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang, 110122, Liaoning, China.

Alzheimer's disease (AD) is a neurodegenerative disease that is characterized by progressive memory decline and cognitive dysfunctions. Although the causes of AD have not yet been established, many mechanisms have been proposed. Axon-guidance molecules play the roles in the occurrence and development of AD by participating in different mechanisms. Therefore, what roles do axon-guidance molecules play in AD? This study aimed at elucidating how axon-guidance molecules Netrins, Slits, Semaphorins, and Ephrins regulate the levels of Aβ, hyperphosphorylation of tau protein, Reelin, and other ways through different signaling pathways, in order to show the roles of axon-guidance molecules in the occurrence and development of AD. And it is hoped that this study can provide a theoretical basis and new perspectives in the search for new therapeutic targets for AD.
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http://dx.doi.org/10.1007/s12035-021-02311-2DOI Listing
March 2021

Iodine Modifies the Susceptibility of Thyroid to Fluoride Exposure in School-age Children: a Cross-sectional Study in Yellow River Basin, Henan, China.

Biol Trace Elem Res 2021 Jan 21. Epub 2021 Jan 21.

Department of Environmental Health & Environment and Health Innovation Team, School of Public Health, Zhengzhou University, Zhengzhou, 450001, Henan, People's Republic of China.

Excessive fluoride exposure has detrimental effects on the thyroid gland, which may be modified by iodine. However, the role of iodine in it remains unclear. This study aims to evaluate the role of iodine in thyroid abnormalities caused by fluoride exposure in school-age children. A total of 446 children aged 7-12 years were recruited from Tongxu County, Henan province, in 2017 (ZZUIRB 2017-018). We obtained demographic information through questionnaire surveys. The concentrations of urinary fluoride (UF) and urinary iodine (UI) were determined by the ion-selective electrode method and the catalytic spectrophotometric method, respectively. The radiation immunoassay was used to determine the serum concentrations of total triiodothyronine (TT3), total thyroxine (TT4), and thyroid-stimulating hormone (TSH). The B-mode ultrasound was performed to assess thyroid volumes (Tvols). The associations between fluoride exposure and thyroid-related indicators were tested by linear regression models. We found that Tvols increased by 0.22 (95% CI: 0.14, 0.31) cm with each standard deviation increment of UF. Moreover, Tvols in boys were more susceptible to fluoride exposure than those in girls, and the Tvols of children with high urinary iodine are less susceptible to fluoride exposure (P for interaction < 0.05). We also observed that TT3 levels were negatively related to UF concentrations at moderate urinary iodine levels (≤ 300 μg/l). Fluoride exposure can elevate the Tvols of school-age children, especially in boys, and high levels of iodine may alleviate this effect to some extent.
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http://dx.doi.org/10.1007/s12011-020-02519-8DOI Listing
January 2021

Fluorinated chitosan-mediated intracellular catalase delivery for enhanced photodynamic therapy of oral cancer.

Biomater Sci 2021 Feb;9(3):658-662

Department of Oral & Maxillofacial-Head & Neck Oncology, Department of Laser and Aesthetic Medicine, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai 200011, China.

A pH-responsive fluorinated chitosan-chlorin e6 (FC-Ce6) was employed here for the intracellular delivery of catalase to relieve the hypoxic micro-environment. Upon simple mixing, FC-Ce6 and catalase co-assemble to form stable nanoparticles, which show a greatly improved cross-membrane penetration capacity compared with catalase alone or nonfluorinated CS-Ce6/catalase nanoparticles. Under catalase catalysis, a high concentration of intracellular H2O2 can be transformed into O2. Upon irradiation, due to the continuous formation of cytotoxic singlet oxygen (1O2), our nanoparticles showed superior anti-cancer activity in contrast to free Ce6 and nonfluorinated CS-Ce6/catalase nanoparticles. Our study proposes an effective intracellular catalase delivery system to overcome hypoxia for enhanced PDT against oral cancer.
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http://dx.doi.org/10.1039/d0bm01898hDOI Listing
February 2021

Fluoride exposure and intelligence in school-age children: evidence from different windows of exposure susceptibility.

BMC Public Health 2020 Nov 4;20(1):1657. Epub 2020 Nov 4.

Department of Environmental Health, School of Public Health, Zhengzhou University, Zhengzhou, 450001, Henan, China.

Background: The intellectual loss induced by fluoride exposure has been extensively studied, but the association between fluoride exposure in different susceptibility windows and children's intelligence is rarely reported. Hence, we conducted a cross-sectional study to explore the association between fluoride exposure in prenatal and childhood periods and intelligence quotient (IQ).

Methods: We recruited 633 local children aged 7-13 years old randomly from four primary schools in Kaifeng, China in 2017. The children were divided into four groups, of which included: control group (CG, n = 228), only prenatal excessive fluoride exposure group (PFG, n = 107), only childhood excessive fluoride exposure group (CFG, n = 157), both prenatal and childhood excessive fluoride exposure group (BFG, n = 141). The concentrations of urinary fluoride (UF) and urinary creatinine (UCr) were determined by fluoride ion-selective electrode assay and a creatinine assay kit (picric acid method), respectively. The concentration of UCr-adjusted urinary fluoride (CUF) was calculated. IQ score was assessed using the second revision of the Combined Raven's Test-The Rural in China (CRT-RC2). Threshold and saturation effects analysis, multiple linear regression analysis and logistic regression analysis were conducted to analyze the association between fluoride exposure and IQ.

Results: The mean IQ score in PFG was respectively lower than those in CG, CFG and BFG (P < 0.05). The odds of developing excellent intelligence among children in PFG decreased by 51.1% compared with children in CG (OR = 0.489, 95% CI: 0.279, 0.858). For all the children, CUF concentration of ≥1.7 mg/L was negatively associated with IQ scores (β = - 4.965, 95% CI: - 9.198, - 0.732, P = 0.022). In children without prenatal fluoride exposure, every 1.0 mg/L increment in the CUF concentration of ≥2.1 mg/L was related to a reduction of 11.4 points in children's IQ scores (95% CI: - 19.2, - 3.5, P = 0.005).

Conclusions: Prenatal and childhood excessive fluoride exposures may impair the intelligence development of school children. Furthermore, children with prenatal fluoride exposure had lower IQ scores than children who were not prenatally exposed; therefore the reduction of IQ scores at higher levels of fluoride exposure in childhood does not become that evident.
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http://dx.doi.org/10.1186/s12889-020-09765-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7640398PMC
November 2020

Preconception ambient temperature and preterm birth: a time-series study in rural Henan, China.

Environ Sci Pollut Res Int 2021 Feb 3;28(8):9407-9416. Epub 2020 Nov 3.

Department of Environmental Health & Environment and Health Innovation Team, School of Public Health, Zhengzhou University, Zhengzhou, 450001, Henan, People's Republic of China.

Changes in the preconception ambient temperature (PAT) can affect the gametogenesis, disturbing the development of the embryo, but the health risks of PAT on the developing fetus are still unclear. Here, based on the National Free Preconception Health Examination Project in the rural areas of Henan Province, we evaluate the effects of PAT on preterm birth (PTB). Data of 1,231,715 records from self-reported interviews, preconception physical examination, early gestation follow-up, and postpartum follow-up were collected from 1 January 2013 to 31 December 2016. Generalized additive models were used to assess the cumulative and lag effects of PAT upon PTB. The significant cumulative effects of mean temperature within 2 weeks and 3 weeks on the risk of PTB, especially upon late PTB (34-36 weeks) (P < 0.05), were observed. Exposure to extreme heat (> 90th percentile) within 2 weeks (RR = 1.470) and 3 weeks (RR = 1.375) before conception could increase the risk of PTB. After stratifying PTB, exposure to extreme heat within 2 weeks before conception can increase the risks of early (< 34 weeks) and late PTB (P < 0.05). Besides, exposure to extreme cold (< 10th percentile) within 3 weeks or longer before conception can elevate the risk of PTB, especially late PTB. The significant lag effects of temperature changes on the risk of early PTB (lag-8 days or earlier) were observed. In conclusion, the risk of PTB was susceptible to PAT changes within 2 weeks or longer before conception. Our findings provide (i) guidance for rural couples to make pregnancy plans and (ii) scientific evidence for the government to formulate policies to prevent PTB.
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http://dx.doi.org/10.1007/s11356-020-11457-wDOI Listing
February 2021

Impaired sperm quantity and motility in adult rats following gestational and lactational exposure to environmentally relevant levels of PBDE-47: A potential role of thyroid hormones disruption.

Environ Pollut 2021 Jan 6;268(Pt A):115773. Epub 2020 Oct 6.

Department of Occupational and Environmental Health, MOE Key Laboratory of Environment and Health, State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, China. Electronic address:

Polybrominated diphenyl ethers (PBDEs) are flame retardants and the congener 2, 2', 4, 4'-tetrabromodiphenyl ether (PBDE-47) is capable of inducing thyroid endocrine disruption and developmental toxicity. However, little is known about whether developmental PBDE-47 exposure-elicited alterations in semen quality is associated with thyroid hormones (THs) perturbation. In this research, we sought to explore the impacts of gestational and lactational PBDE-47 exposure on adult sperm quantity and motility, and its link with THs levels. For this purpose, female Sprague-Dawley rats were administered environmentally relevant PBDE-47 levels (0.1, 1.0, 10 mg/kg/day) by oral gavage from prepregnancy through lactation cessation to achieve early-life exposure of offspring and to mimic the actual exposure. Sperm quantity and motility together with serum THs levels from male offspring were determined on postnatal day 88. In utero and lactational exposure to PBDE-47 boosted the weight gain while reduced the relative testis weight in adult male offspring. These were accompanied with the reductions in sperm counts (total and living sperm counts), the percentage of progressive sperm motility, sperm velocities (curvilinear velocity, straight-line velocity and average path velocity), motion path (beat cross frequency, linearity and wobble) and linear motile sperm parameters (count, motility and concentration). Further studies identified that the levels of serum triiodothyronine (T) were increased by PBDE-47 exposure and negatively associated with those differential semen parameters on quantity and motility. Collectively, our results indicate that exposure to low-level PBDE-47 during early-life development impairs semen quality in adult rats, which could be mediated partially by abnormal T levels.
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http://dx.doi.org/10.1016/j.envpol.2020.115773DOI Listing
January 2021

Reflectance confocal microscopy characteristics of oral lichen planus: An analysis of 47 cases in a Chinese cohort.

Exp Ther Med 2020 Nov 25;20(5). Epub 2020 Aug 25.

Department of Oral and Maxillofacial-Head Neck Oncology, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology and Shanghai Research Institute of Stomatology, Shanghai 200011, P.R. China.

Reflectance confocal microscopy (RCM) is a non-invasive tool that provides real-time microscopic images and relatively high-resolution tissue images. This technique provides a link between clinical examination and histopathology. RCM has been used to detect skin diseases and has also recently been applied to diseases of the oral mucosa. The present study aimed to explore the features of oral lichen planus (OLP) using RCM. A total of 47 patients with OLP exhibiting a reticular pattern, were included in the present study. The lesion sites and healthy adjacent sites were examined using RCM, with the lesion being histopathologically confirmed after RCM examination. The confocal images were reviewed, and the features were described. Sensitivity and specificity analysis of the RCM features was also performed. RCM examination presented parakeratosis, acanthosis and connective tissue papillae disappearance, with the presence of large melanocytes and roundish inflammatory cell infiltration, as well as dilated vessels in the lesion tissue. The sensitivity and specificity of OLP for dorsal tongue lesions were not as satisfactory as those on other sites. The results implied that RCM may be a promising technique to detect OLP non-invasively .
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http://dx.doi.org/10.3892/etm.2020.9134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7471943PMC
November 2020

Association between low-to-moderate fluoride exposure and bone mineral density in Chinese adults: Non-negligible role of RUNX2 promoter methylation.

Ecotoxicol Environ Saf 2020 Oct 25;203:111031. Epub 2020 Jul 25.

Department of Occupational and Environmental Health, School of Public Health, Zhengzhou University, Zhengzhou, Henan, 450001, PR China; Environment and Health Innovation Team, School of Public Health, Zhengzhou University, Zhengzhou, Henan, 450001, PR China; Yellow River Institute for Ecological Protection & Regional Coordinated Development, Zhengzhou University, Zhengzhou, Henan, 450001, PR China. Electronic address:

Bone mineral density (BMD) changes were reported to be associated with excessive fluoride exposure and abnormal expression of RUNX2. However, whether the alteration of methylation status, a most commonly used marker for the alteration of gene expression in epidemiological investigation, of RUNX2 is associated with low-to-moderate fluoride exposure and BMD changes has not been reported. Our study aims to explore the role of RUNX2 promoter methylation in BMD changes induced by low-to-moderate fluoride exposure. A total of 1124 adults (413 men and 711 women) were recruited from Kaifeng City in 2017. We measured BMD using ultrasound bone densitometer. Concentrations of urinary fluoride (UF) were measured using ion-selective electrode, and the participants were grouped into control group (CG) and excessive fluoride group (EFG) according to the concentration of UF. We extracted DNA from fasting peripheral blood samples and then detected the promoter methylation levels of RUNX2 using quantitative methylation-specific PCR. Relationships between UF concentration, RUNX2 promoter methylation and BMD changes were analyzed using generalized linear model and logistic regression. Results showed in EFG (UF concentration > 1.6 mg/L), BMD was negatively correlated with UF concentration (β: -0.14; 95%CI: -0.26, -0.01) and RUNX2 promoter methylation (β: -0.13; 95%CI: -0.22, -0.03) in women. The methylation rate of RUNX2 promoter increased by 2.16% for each 1 mg/L increment in UF concentration of women in EFG (95%CI: 0.37, 3.96). No any significant associations between UF concentration, RUNX2 promoter methylation, and BMD were observed in the individuals in CG. Mediation analysis showed that RUNX2 promoter methylation mediated 18.2% (95% CI: 4.2%, 53.2%) of the association between UF concentration and BMD of women in EFG. In conclusion, excessive fluoride exposure (>1.6 mg/L) is associated with changes of BMD in women, and this association is mediated by RUNX2 promoter methylation.
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http://dx.doi.org/10.1016/j.ecoenv.2020.111031DOI Listing
October 2020

methylation in cord blood: a potential target of prenatal exposure to air pollutants.

Int J Environ Health Res 2020 Jun 1:1-10. Epub 2020 Jun 1.

Department of Environmental Health, Zhengzhou University School of Public Health, Zhengzhou, China.

To explore the impact of air pollutants exposure during pregnancy on infant DNA methylation, we identified correlated methylated genes in maternal and cord blood samples using the Illumina Human Methylation 27 k BeadChip. Quantitative methylation-specific PCR (QMS-PCR) was performed to validate the target gene methylation pattern in 568 participants. Then the association between air pollutants exposure and DNA methylation level in the target gene was investigated. The gene with a higher methylation level both in mothers and newborns was identified as the target gene, and we found a positive mother-infant DNA methylation correlation in the promoter region of . Air pollutants exposure during entire pregnancy was associated with maternal and infant DNA methylation. After adjusting confounding variables, maternal air pollutants exposure was still associated with infant DNA methylation. In summary, methylation in cord blood may be a potential target of prenatal exposure to air pollutants.
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http://dx.doi.org/10.1080/09603123.2020.1773414DOI Listing
June 2020

The role of maternal methylation in the association between prenatal meteorological conditions and neonatal H19/H19-DMR methylation.

Ecotoxicol Environ Saf 2020 Jul 18;197:110643. Epub 2020 Apr 18.

Department of Environmental Health, School of Public Health, Zhengzhou University, Zhengzhou, Henan, 450001, PR China; Environment and Health Innovation Team, School of Public Health, Zhengzhou University, Zhengzhou, Henan, 450001, PR China. Electronic address:

Meteorological conditions during pregnancy can affect birth outcome, which has been linked to the H19/H19-differentially methylated region (DMR). However, the detailed mechanisms underlying this association are unclear. This was investigated in the present study to provide epidemiological evidence for elucidating the pathogenesis of adverse birth outcomes. A total of 550 mother-newborn pairs were recruited in Zhengzhou, China from January 2010 to January 2012. Meteorological data including temperature (T), relative humidity (RH), and sunshine duration (SSD) were obtained from the China Meteorological Data Sharing Service System. Bisulfite sequencing PCR was performed to determine the methylation levels of H19/H19-DMR using genomic DNA extracted from maternal peripheral and umbilical cord blood. The results showed that H19-DMR methylation status in cord blood was positively associated with that in maternal blood. Neonatal H19-DMR methylation was negatively associated with T and RH during the first trimester and positively associated with these variables during the third trimester. There was a positive correlation between neonatal H19-DMR methylation and SSD during the second trimester and a negative correlation during the third trimester. Similar associations were observed between maternal H19-DMR methylation and prenatal meteorological conditions. We also observed significant interaction effects of maternal H19/H19-DMR methylation and most prenatal meteorological factors on neonatal methylation, and found that changes in the methylation status of maternal H19-DMR were responsible for the effects of prenatal meteorological conditions on neonatal methylation. In summary, neonatal H19-DMR methylation was significantly associated with prenatal meteorological conditions, which was modified and mediated by maternal H19-DMR methylation changes. These findings provide insights into the relationship between meteorological factors during pregnancy and adverse birth outcomes or disease susceptibility in offspring, and can serve as a reference for environmental policy-making.
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http://dx.doi.org/10.1016/j.ecoenv.2020.110643DOI Listing
July 2020

SIRT1-dependent mitochondrial biogenesis supports therapeutic effects of resveratrol against neurodevelopment damage by fluoride.

Theranostics 2020 26;10(11):4822-4838. Epub 2020 Mar 26.

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.

: Potential adverse effects of fluoride on neurodevelopment has been extensively explored and mitochondria have been recognized as critical targets. Mitochondrial biogenesis serves a crucial role in maintaining mitochondrial homeostasis and salubrious properties of resveratrol (RSV) has been well-defined. However, the molecular mechanisms governing mitochondrial biogenesis in developmental fluoride neurotoxicity remain unclear and the related therapeutic dietary agent is lacking. : neuroblastoma SH-SY5Y cells and Sprague-Dawley rat model of developmental fluoride exposure were adopted. A total population of 60 children under long-term stable fluoride exposure were also recruited. This work used a combination of biochemical and behavioral techniques. Biochemical methods included analysis of mitochondrial function and mitochondrial biogenesis, as well as mRNA and protein expression of mitochondrial biogenesis signaling molecules, including silent information regulator 1 (SIRT1), peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), nuclear respiratory factor 1 (NRF1) and mitochondrial transcription factor A (TFAM). Behavioral studies investigated spatial learning and memory ability of rats. : Both and experiments showed that sodium fluoride (NaF) caused mitochondrial dysfunction and impaired mitochondrial biogenesis. Also, NaF elevated SIRT1 levels and suppressed SIRT1 deacetylase activity along with decreased levels of PGC-1α, NRF1 and TFAM, suggestive of dysregulation of mitochondrial biogenesis signaling molecules. Moreover, enhancement of mitochondrial biogenesis by TFAM overexpression alleviated NaF-induced neuronal death through improving mitochondrial function . Further and studies identified RSV, the strongest specific SIRT1 activator, improved mitochondrial biogenesis and subsequent mitochondrial function to protect against developmental fluoride neurotoxicity via activating SIRT1-dependent PGC-1α/NRF1/TFAM signaling pathway. Noteworthy, epidemiological data indicated intimate correlations between disturbed circulating levels of mitochondrial biogenesis signaling molecules and fluoride-caused intellectual loss in children. : Our data suggest the pivotal role of impaired mitochondrial biogenesis in developmental fluoride neurotoxicity and the underlying SIRT1 signaling dysfunction in such neurotoxic process, which emphasizes RSV as a potential therapeutic dietary agent for relieving developmental fluoride neurotoxicity.
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http://dx.doi.org/10.7150/thno.42387DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7163447PMC
May 2021

Fluoride exposure and CALCA methylation is associated with the bone mineral density of Chinese women.

Chemosphere 2020 Aug 29;253:126616. Epub 2020 Mar 29.

Department of Environmental Health, School of Public Health, Zhengzhou University, Zhengzhou, Henan, 450001, China; Environment and Health Innovation Team, School of Public Health, Zhengzhou University, Zhengzhou, Henan, 450001, China. Electronic address:

Excessive exposure to fluoride has been reported to affect bone mineral density (BMD). CALCA expression plays a critical part in bone formation. However, the role of CALCA in the association between fluoride and BMD is not known. We conducted a cross-sectional study and recruited 722 women in rural areas of Henan Province, China, to assess the relationship between fluoride exposure, CALCA methylation, and BMD. Urinary levels of fluoride, CALCA methylation, and BMD were measured by a fluoride ion-selective electrode, standalone ultrasound bone densitometer, and quantitative methylation-specific polymerases chain reaction, respectively. The association among fluoride exposure, CALCA methylation, and BMD was age-specific. Specifically, BMD was negatively correlated with methylation (β: -0.008; 95% CI: -0.016, 0.000) and fluoride exposure (β: -0.063; 95% CI: -0.129, -0.002) in women over 45 years and 50-54 years of age, respectively, whereas methylation was positively correlated with fluoride exposure (β: 4.953; 95% CI: 1.162, 8.743) in women aged 40-44 years. Besides, increased BMD in women aged 45-49 years induced by the interactive effect of the highest methylation of CALCA exon 1 (tertile 3) and fluoride exposure was observed (P for interaction < 0.05). Our findings suggest an age-specific association between exposure to excessive fluoride, CALCA methylation, and BMD in a rural population of women in China. Notably, the susceptibility of BMD to fluoride exposure may be modified by CALCA methylation.
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http://dx.doi.org/10.1016/j.chemosphere.2020.126616DOI Listing
August 2020

Association between fluoride exposure and behavioural outcomes of school-age children: a pilot study in China.

Int J Environ Health Res 2020 Apr 13:1-10. Epub 2020 Apr 13.

Department of Environment Health, School of Public Health, Zhengzhou University, Zhengzhou, Henan, P. R. China.

To assess the association between fluoride exposure and children's behavioural outcomes, we recruited 325 resident school-age children (7-13 years old) lived in Tongxu County of Henan Province in China. We measured urinary fluoride (UF) concentrations using the ion-selective electrode method. Children's behavioural outcomes were assessed by Conners' Parent Rating Scale-Revised, including conduct problems, learning problems, psychosomatic problems, impulsive-hyperactive, anxiety, and ADHD index. It turned out that each 1.0 mg/L increment in UF concentration corresponded with an elevation in the psychosomatic problem score of 4.01 (95% : 2.74, 5.28) and a 97% (= 1.97, 95% : 1.19, 3.27) increase in the prevalence of psychosomatic problems after adjusting for potential influencing factors. The sensitivity analysis results were consistent with those observed in our preliminary analysis. Our study suggests that fluoride exposure is positively related to the behavioural problem in school-age children, psychosomatic problem in particular.
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http://dx.doi.org/10.1080/09603123.2020.1747601DOI Listing
April 2020

Perinatal low-dose PBDE-47 exposure hampered thyroglobulin turnover and induced thyroid cell apoptosis by triggering ER stress and lysosomal destabilization contributing to thyroid toxicity in adult female rats.

J Hazard Mater 2020 06 10;392:122265. Epub 2020 Feb 10.

Department of Occupational and Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, Hubei, 430030, China; Key Laboratory of Environment and Health, Ministry of Education, State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, Hubei, 430030, China. Electronic address:

Evidence demonstrates that 2,2',4,4'-tetrabromodiphenyl ether (PBDE-47) is able to disturb thyroid hormones (THs) homeostasis, yet the mechanisms remain unknown. We sought to investigate the effects of PBDE-47 on endoplasmic reticulum (ER) and lysosomes in thyroids. Using female Sprague-Dawley rats orally administered PBDE-47 at environmentally relevant doses (0.1, 1.0, 10 mg/kg/day) beginning ten days before breeding and ending at weaning, we showed that perinatal PBDE-47 exposure resulted in a reduction in serum THs levels and relative thyroid weight in adult female rats. These were accompanied by thyroid structural abnormalities with cell apoptosis. Mechanistically, PBDE-47 caused ER stress and activation of unfolded protein response (UPR). Moreover, PBDE-47 elicited lysosomal membrane permeabilization and the release of cathepsin. Importantly, the apoptotic cells co-localized with IRE1α, a stress sensor protein of UPR branch that mediates ER stress-induced apoptosis, or cathepsin B, a lysosomal cysteine protease that is involved in thyroglobulin, the precursor of THs, degradation and apoptosis induction. Interestingly, thyroglobulin was accumulated and predominantly presented in cells harboring compromised ER or lysosomal activity. Collectively, our findings suggest that perinatal low-dose PBDE-47 exposure hampers thyroglobulin turnover and induces thyroid cell apoptosis by triggering ER stress and lysosomal destabilization contributing to thyroid toxicity in adult female rats.
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http://dx.doi.org/10.1016/j.jhazmat.2020.122265DOI Listing
June 2020

Promotion of mitochondrial fusion protects against developmental PBDE-47 neurotoxicity by restoring mitochondrial homeostasis and suppressing excessive apoptosis.

Theranostics 2020 1;10(3):1245-1261. Epub 2020 Jan 1.

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.

Polybrominated diphenyl ethers (PBDEs)-induced neurotoxicity is closely associated with mitochondrial abnormalities. Mitochondrial fusion and fission dynamics are required for the maintenance of mitochondrial homeostasis. However, little is known about how PBDEs disrupt this dynamics and whether such disruption contributes to impaired neurodevelopment. : We investigated the effects of 2, 2', 4, 4'-tetrabromodiphenyl ether (PBDE-47), the dominant congener in human samples, on mitochondrial fusion and fission dynamics using PC12 cells, a well-defined neurodevelopmental model. We also evaluated the effects of perinatal low-dose PBDE-47 exposure on hippocampal mitochondrial dynamics and its association with neurobehavioral changes in adult Sprague-Dawley rats. : , PBDE-47 disrupted mitochondrial dynamics by inhibiting mitochondrial fusion and fission simultaneously, accompanied by mitochondrial fragmentation, membrane potential dissipation, ATP loss, and apoptosis activation. Specifically, enhancing mitochondrial fusion by the chemical promoter M1 or adenovirus-mediated overexpression rescued PBDE-47-caused mitochondrial dynamic, morphological and functional impairments, prevented the resultant apoptosis and promoted neuronal survival. Unexpectedly, either stimulating mitochondrial fission by adenovirus-mediated overexpression or suppressing mitochondrial fission by the mitochondrial division inhibitor-1 (Mdivi-1) failed to reverse whereas aggravated PBDE-47-induced mitochondrial damage and neuronal death. Importantly, promoting mitochondrial fusion by overexpression neutralized the detrimental effects elicited by overexpression after PBDE-47 treatment. Finally, perinatal oral administration of PBDE-47 elicited neurobehavioral deficits and hippocampal neuronal loss via apoptosis in adult rats, which were associated with mitochondrial dynamics alterations manifested as a fragmented phenotype. : Our results suggest that PBDE-47 disrupts mitochondrial dynamics to induce mitochondrial abnormalities, triggering apoptosis and thus contributing to neuronal loss and subsequent neurobehavioral deficits. Targeting mitochondrial fusion may be a promising therapeutic intervention against PBDE-47 neurotoxicity.
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http://dx.doi.org/10.7150/thno.40060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6956817PMC
April 2021

High prevalence of sleep disorders and behavioral and psychological symptoms of dementia in late-onset Alzheimer disease: A study in Eastern China.

Medicine (Baltimore) 2019 Dec;98(50):e18405

Department of Geriatric Neurology, Qilu Hospital, Shandong University, Jinan.

Alzheimer disease (AD) is the most common neurodegenerative brain disease that causes cognitive impairment in the elderly. Behavioral and psychological symptoms of dementia (BPSD), also known as neuropsychiatric symptoms, represent a heterogeneous group of non-cognitive symptoms and behaviors for AD patients. Sleep disorder is one closely-related psychiatric symptom of AD. In this cross-section study, we aimed to investigate the characteristics of sleep status and BPSD among AD patients in Eastern China and to assess the relationship among sleep disorder, BPSD, and cognition.A total of 176 participants were enrolled in the study, including 84 AD patients and 92 healthy individuals as controls. Mini-mental state examination (MMSE), cooperative study-activities of daily living (ADCS-ADL) and clinical dementia rating (CDR) were used to measure cognition, the competence in basic and instrumental activities of daily living, and severity of dementia, respectively. BPSD were evaluated by neuropsychiatric inventory (NPI). Pittsburgh sleep quality index (PSQI) and Epworth sleepiness scale were designed to assess the sleep status and daytime naps. Spearman correlation analyses were performed to determine the relations between PSQI, MMSE, ADCS-ADL, and NPI scores and CDR.Sleep disorders occurred in 55.9% of AD patients versus only 15.2% of controls. 89.2% of AD patients had BPSD while only 22.9% of controls did, with apathy (64.2%) the most common among AD patients. Among AD patients, PSQI was negatively correlated with both MMSE (r = -0.600, P < .01) and ADCS-ADL (r = -0.725, P < .01), and was positively correlated with total NPI score (r = 0.608, P < .01). PSQI was closely associated with depression (r = 0.653, P < .01) and apathy (r = 0.604, P < .01).This study showed that AD patients have a higher prevalence of sleep disorders and BPSD than healthy elderly adults. Sleep disorders affect cognition of AD patients and increase apathy and depression. These results can help investigate new therapeutic targets in AD treatments.
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http://dx.doi.org/10.1097/MD.0000000000018405DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6922506PMC
December 2019

Thyroid function, intelligence, and low-moderate fluoride exposure among Chinese school-age children.

Environ Int 2020 01 4;134:105229. Epub 2019 Nov 4.

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: Thyroid hormones (THs) are critical for brain development. Whether low-moderate fluoride exposure affects thyroid function and what the impact is on children's intelligence remain elusive.

Objectives: We conducted a cross-sectional study to examine the associations between low-moderate fluoride exposure and thyroid function in relation to children's intelligence.

Methods: We recruited 571 resident children, aged 7-13 years, randomly from endemic and non-endemic fluorosis areas in Tianjin, China. We measured fluoride concentrations in drinking water and urine using the national standardized ion selective electrode method. Thyroid function was evaluated through the measurements of basal THs [(total triiodothyronine (TT), total thyronine (TT), free triiodothyronine (FT), free thyronine (FT)] and thyroid-stimulating hormone (TSH) levels in serum. Multivariable linear and logistical regression models were used to assess associations among fluoride exposure, thyroid function and IQ scores.

Results: In adjusted models, every 1 mg/L increment of water fluoride was associated with 0.13 uIU/mL increase in TSH. Every 1 mg/L increment of urinary fluoride was associated with 0.09 ug/dL decrease in TT, 0.009 ng/dL decrease in FT and 0.11 uIU/mL increase in TSH. Fluoride exposure was inversely related to IQ scores (B = -1.587; 95% CI: -2.607, -0.568 for water fluoride and B = -1.214; 95% CI: -1.987, -0.442 for urinary fluoride). Higher TT, FT were related to the increased odds of children having high normal intelligence (OR = 3.407, 95% CI: 1.044, 11.120 for TT; OR = 3.277, 95% CI: 1.621, 6.623 for FT). We detected a significant modification effect by TSH on the association between urinary fluoride and IQ scores, without mediation by THs.

Conclusions: Our study suggests low-moderate fluoride exposure is associated with alterations in childhood thyroid function that may modify the association between fluoride and intelligence.
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http://dx.doi.org/10.1016/j.envint.2019.105229DOI Listing
January 2020

Impaired Cerebral Autoregulation in Alzheimer's Disease: A Transcranial Doppler Study.

J Alzheimers Dis 2019 ;72(2):623-631

Department of Geriatric Neurology, Qilu Hospital of Shandong University, Jinan, China.

Background: Vasculature changes have been observed in Alzheimer's disease (AD). AD-related vascular pathology might impair cerebral autoregulation (CA).

Objective: This study was designed to evaluate CA of AD patients by using transcranial doppler (TCD).

Methods: A total of 61 participants were included in the study, including 31 AD patients and 30 controls. The trend curves of cerebral blood flow velocities (CBFV), pulsatility index, and resistance index were obtained using TCD during supine-to-standing posture changes. CA was measured by the changes of CBFV curves during supine-to-standing test.

Results: There were two spikes named X spike and W spike that appeared in the CBFV curve when the subjects stood abruptly. The slope of the X spike descending branch, the slope of the W spike ascending branch, and the angle between X and W spikes (α angle), showed significant differences between the experimental and control groups (2.34±0.99 versus 3.15±1.61 cm/s2, p = 0.021; 2.31±0.81 versus 3.38±1.18 cm/s2, p < 0.001; and 52.71±20.26 versus 41.4±12.87 degrees, p = 0.012, respectively). ROC analysis showed that AUCαangle is 0.664 (p = 0.028) and that AUCSAB and AUCadjustedSAB are 0.775 and 0.738, respectively (both p < 0.001).

Conclusions: Our study demonstrated that supine-to-standing TCD test is a valuable tool for the evaluation of CA in AD patients. Impaired CA in AD patients manifested as decreased efficiency of changes in the CBFV curve. Neurovascular units were involved in the pathogenesis of AD.
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http://dx.doi.org/10.3233/JAD-190296DOI Listing
November 2020

Autophagy impairment contributes to PBDE-47-induced developmental neurotoxicity and its relationship with apoptosis.

Theranostics 2019 9;9(15):4375-4390. Epub 2019 Jun 9.

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.

Apoptosis is involved in 2,2',4,4'- tetrabromodiphenyl ether (PBDE-47)-induced developmental neurotoxicity. However, little is known about the role of autophagy, especially its relationship with apoptosis underlying such neurotoxic process. : Using female Sprague-Dawley rats exposed to low-dose PBDE-47 (0.1, 1.0 and 10 mg/kg/day) from pre-pregnancy until weaning of offspring to mimic human exposure, we investigated the effects of PBDE-47 on autophagy and apoptosis in relation to cognitive impairment of adult offspring rats. We also evaluated relationship between autophagy and apoptosis using neuroendocrine pheochromocytoma (PC12) cells, a widely used neuron-like cell line for neuronal development. : , perinatal exposure to PBDE-47 induced memory deficits in adult rats. This is accompanied by hippocampal neuronal loss partly as a result of apoptosis, as evidenced by caspase-3 activation and PARP cleavage. Further study identified that PBDE-47 triggered autophagic vesicles accumulation, increased levels of microtubule-associated protein 1 light chain 3 (LC3)-II, an essential protein for autophagosomes formation, and autophagy substrate sequestosome 1 (SQSTM1/p62), but reduced levels of autophagy-related protein (ATG) 7, a key protein for autophagosomes elongation, suggestive of autophagy impairment. These findings were further demonstrated by an model of PBDE-47-treated PC12 cells. Mechanistically, autophagy alteration is more sensitive to PBDE-47 treatment than apoptosis induction. Importantly, while stimulation of autophagy by the chemical inducer rapamycin and adenovirus-mediated overexpression aggravated PBDE-47-induced apoptosis and cell death, inhibition of autophagy by the chemical inhibitor wortmannin and siRNA knockdown of reversed PBDE-47-produced detrimental outcomes. Interestingly, blockage of apoptosis by caspase-3 inhibitor Ac-DEVD-CHO ameliorated PBDE-47-exerted autophagy impairment and cell death, though in combination with autophagy inhibitor did not further promote cell survival. : Our data suggest that autophagy impairment facilitates apoptosis, which, in turn, disrupts autophagy, ultimately resulting in cell death, and that autophagy may act as a promising therapeutic target for PBDE-47-induced developmental neurotoxicity.
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http://dx.doi.org/10.7150/thno.33688DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6599662PMC
August 2020

Ferroptosis Promotes Photodynamic Therapy: Supramolecular Photosensitizer-Inducer Nanodrug for Enhanced Cancer Treatment.

Theranostics 2019 18;9(11):3293-3307. Epub 2019 May 18.

School of Chemistry and Chemical Engineering, Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, Shanghai Jiao Tong University, Shanghai 200240, China.

The noninvasive nature of photodynamic therapy (PDT) enables the preservation of organ function in cancer patients. However, PDT is impeded by hypoxia in the tumor microenvironment (TME) caused by high intracellular oxygen (O) consumption and distorted tumor blood vessels. Therefore, increasing oxygen generation in the TME would be a promising methodology for enhancing PDT. Herein, we proposed a concept of ferroptosis-promoted PDT based on the biochemical characteristics of cellular ferroptosis, which improved the PDT efficacy significantly by producing reactive oxygen species (ROS) and supplying O sustainably through the Fenton reaction. In contrast to traditional strategies that increase O based on decomposition of limited concentration of hydrogen peroxide (HO), our methodology could maintain the concentration of HO and O through the Fenton reaction. : For its association with sensitivity to ferroptosis, solute carrier family 7 member 11 (SLC7A11) expression was characterized by bioinformatics analysis and immunohistochemistry of oral tongue squamous cell carcinoma (OTSCC) specimens. Afterwards, the photosensitizer chlorin e6 (Ce6) and the ferroptosis inducer erastin were self-assembled into a novel supramolecular Ce6-erastin nanodrug through hydrogen bonding and π-π stacking. Then, the obtained Ce6-erastin was extensively characterized and its anti-tumor efficacy towards OTSCC was evaluated both and . : SLC7A11 expression is found to be upregulated in OTSCC, which is a potential target for ferroptosis-mediated OTSCC treatment. Ce6-erastin nanoparticles exhibited low cytotoxicity to normal tissues. More significantly, The over-accumulated intracellular ROS, increased O concentration and inhibited SLC7A11 expression lead to enhanced toxicity to CAL-27 cells and satisfactory antitumor effects to xenograft tumour mouse model upon irradiation. : Our ferroptosis promoted PDT approach markedly enhances anticancer actions by relieving hypoxia and promoting ROS production, thereby our work provides a new approach for overcoming hypoxia-associated resistance of PDT in cancer treatment.
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http://dx.doi.org/10.7150/thno.32867DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6567978PMC
July 2020

Prenatal ambient air pollution exposure and SOD2 promoter methylation in maternal and cord blood.

Ecotoxicol Environ Saf 2019 Oct 18;181:428-434. Epub 2019 Jun 18.

Department of Environment Health, School of Public Health, Zhengzhou University, Zhengzhou, Henan, China. Electronic address:

The evidence is increasing that prenatal air pollutant exposure contributes to elevated oxidative stress in children, but the underlying mechanism is unclear. A pilot study was conducted in China to explore the associations between prenatal ambient air pollution exposure and superoxide dismutase 2 (SOD2) promoter methylation in maternal and cord blood. After detection and analyses, SOD2 promoter methylation levels in umbilical cord blood were elevated as maternal SOD2 promoter methylation levels increased. In addition, the SOD2 promoter methylation levels in umbilical cord blood were positively associated with the particulate matter 10 (PM) exposure concentrations during the entire pregnancy and the second trimester. In maternal peripheral blood, the SOD2 promoter methylation levels were positively associated with the exposure concentrations of PM (during the entire pregnancy and the second trimester) and nitrogen dioxide (NO) (during the first trimester of pregnancy), whereas the levels were negatively associated with the exposure concentrations of NO during the third trimester of pregnancy. Additionally, interaction analyses revealed that the maternal SOD2 promoter methylation level and sulfur dioxide (SO) exposure (during the entire pregnancy and the third trimester), as well as NO exposure (during the third trimester of pregnancy), had an interaction effect on the SOD2 promoter methylation level in umbilical cord blood. Furthermore, mediation analysis revealed that the associations between SOD2 promoter methylation in umbilical cord blood and PM exposure during the entire pregnancy and the second trimester were partly mediated by maternal SOD2 promoter methylation. In conclusion, prenatal exposure to air pollutants was significantly associated with SOD2 promoter methylation levels in umbilical cord blood, and this association may be affected by SOD2 promoter methylation levels in maternal peripheral blood. These associations may be one of the mechanisms by which prenatal air pollutant exposure leads to oxidative stress in newborns.
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http://dx.doi.org/10.1016/j.ecoenv.2019.06.039DOI Listing
October 2019

Perigestational low-dose BDE-47 exposure alters maternal serum metabolome and results in sex-specific weight gain in adult offspring.

Chemosphere 2019 Oct 30;233:174-182. Epub 2019 May 30.

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

Emerging evidence suggests environmental contaminant exposures during critical windows of development may contribute to the increasing prevalence of obesity. It has been shown that early life polybrominated diphenyl ethers exposures have critical impacts on child weight trajectories, however, little is known about their maternal mechanisms responsible for offspring obesity development. In this study, we investigated the effects of perigestational low-dose 2, 2', 4, 4'-tetrabromodiphenyl ether (BDE-47) exposure on maternal metabolome, and its possible link to adult offspring bodyweight changes. Female Sprague-Dawley rats were exposed to daily doses of 0.1, or 1 mg/kg BDE-47 from 10 days prior to conception until offspring were weaned on postnatal day 21, and then a gas chromatography-mass spectrometry based metabolomics analysis was used to uncover the global metabolic response in dams. The pups continued to grow into adulthood for measurements of bodyweight. Perigestational BDE-47 exposure caused increased adult bodyweight in male but not in female offspring and dams. Metabolomics revealed significant changes in maternal serum metabolites that clearly distinguish BDE-47 from control rats. These differentially expressed metabolites were primarily implicated in amino acid, lipid, carbohydrate, and energy metabolisms, which was confirmed by pathway analysis. Importantly, most of these identified metabolites were decreased, a state similar to maternal malnutrition that can predispose adult male offspring to weight increase and adiposity in a postnatal environment with abundant calories. Collectively, our data suggest that perigestational exposure to low-dose BDE-47 produces altered maternal serum metabolome, which may be an additional contributing factor to weight gain in adult male offspring.
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http://dx.doi.org/10.1016/j.chemosphere.2019.05.277DOI Listing
October 2019

Effects of long-term fluoride exposure on cognitive ability and the underlying mechanisms: Role of autophagy and its association with apoptosis.

Toxicol Appl Pharmacol 2019 09 5;378:114608. Epub 2019 Jun 5.

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, People's Republic of China. Electronic address:

Autophagy and apoptosis are two important cellular processes that are crucial for neurodevelopment. Evidence shows that apoptosis is implicated in fluoride neurotoxicity. However, the biological roles of autophagy, especially its interplay with apoptosis in the neurotoxicity induced by long-term fluoride exposure remain unclear. Here we present in vivo and in vitro evidence that fluoride-induced defective autophagy elicits excessive apoptosis, thus inducing neurotoxicity. Using Sprague-Dawley rats exposed to sodium fluoride from 60 days before pregnancy until 6 months post-delivery as in vivo model, we showed that fluoride impaired the learning and memory abilities of offspring rats, with decreased neuronal number, suppressed autophagy and enhanced apoptosis in hippocampus. These results were validated in human neuroblastoma SH-SY5Y cells in vitro. Mechanistically, mTOR signaling, responsible for autophagy induction, was activated in vivo and in vitro, and targeting inhibition of mTOR with rapamycin protected SH-SY5Y cells from defective autophagy and excessive apoptosis, thereby enhancing neuronal survival. Furthermore, circulating levels of autophagy markers were low in children with higher fluoride body burden and lower intelligence quotient scores. Collectively, our results suggest that defective autophagy plays a pivotal role in fluoride neurotoxicity, and mTOR might be a promising target for the prevention and treatment of fluoride neurotoxicity.
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http://dx.doi.org/10.1016/j.taap.2019.114608DOI Listing
September 2019

Repurposing Ponatinib as a Potent Agent against Mutant Melanomas.

Theranostics 2019 16;9(7):1952-1964. Epub 2019 Mar 16.

Department of Oral and Maxillofacial-Head & Neck Oncology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, P.R. China.

Mutations in , a major cancer driver gene, are now considered as important drug targets for the treatment of melanomas arising from mucosal and acral tissues and from chronically sun-damaged sites. At present, imatinib is the only targeted drug for -mutation-bearing melanomas that is recommended by the National Comprehensive Cancer Network (NCCN) Clinical Practice guidelines. Patients with mutations, however, are either insensitive or rapidly progress to imatinib insensitivity, which restricts its clinical use. Thus, effective inhibitors of -mutation-bearing melanomas are urgently needed. A cohort of patient-derived tumor xenograft (PDX) models and corresponding PDX-derived cells (PDCs) from patients with melanomas harboring mutations (, and ) were established, characterized, and then used to test the and, subsequently, inhibitory effects of a panel of known inhibitors. Ponatinib was more potent than imatinib against cells bearing mutations. drug efficacy evaluation experiments showed that ponatinib treatment caused much stronger inhibition of -mutation-bearing melanomas than did imatinib. Mechanistically, molecular dynamics (MD) simulations revealed a plausible atomic-level explanation for the observation that ponatinib has a higher affinity for the mutant protein than does imatinib. Our study of -mutation-and -bearing melanomas demonstrates that ponatinib is a far more potent inhibitor than is imatinib for -mutation-bearing melanomas and thus underscores that ponatinib should be given priority consideration for the design of precision treatments for melanoma patients triaged to have mutations. Moreover, our work provides a rationale for undertaking clinical trials to examine the repurposing of ponatinib, which is already approved for use in leukemia, for use in treating a large subset of melanoma patients.
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http://dx.doi.org/10.7150/thno.30890DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6485277PMC
April 2020

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