Previous publications have indicated that polycyclic aromatic hydrocarbons (PAHs) exposures are associated with increased DNA damage and abnormal cell cycle arrest; however, the details of mechanisms ...remain largely unknown. This study aimed to quantify the associations of 8-oxoguanine DNA glycosylase (OGG1) methylation with urinary PAHs metabolites, DNA damage and cell cycle arrest, and further to assess the role of OGG1 methylation in mediating the association of urinary PAHs metabolites with DNA damage and cell cycle arrest. Urinary biomarkers of PAHs exposure and a marker of oxidative DNA damage (8-hydroxy-2′-deoxyguanosin, 8-OHdG) were measured by high performance liquid chromatography. Cell cycle of lymphocyte was analysed with flow cytometry and OGG1 methylation in venous blood was measured by pyrosequencing. After adjusting for covariates, urinary 1-OHP levels were positively associated with lymphocyte S phase arrest and oxidative DNA damage, while were negatively associated with G0/G1 phase arrest. OGG1 methylation was not only positively correlated with urinary 1-OHP in a dose-responsive manner (P trend = 0.008) but was also associated with G0/G1 phase arrest (OR: 0.63, 95% CI: 0.41–0.97), S phase arrest (OR: 1.55, 95% CI: 1.01–2.40) and oxidative DNA damage (OR: 1.71, 95% CI: 1.02–2.86). Mediation analysis estimated that OGG1 methylation mediated about 20% of associations between urinary 1-OHP levels and cell cycle arrest and oxidative DNA damage, respectively (all P < 0.05). Our findings suggested that urinary 1-OHP concentrations were associated with cell cycle arrest and oxidative DNA damage by a mechanism partly involving OGG1 methylation.
•Urinary 1-OHP was associated with cell cycle and oxidative DNA damage.•OGG1 methylation was associated with cell cycle and oxidative DNA damage.•OGG1 methylation showed a positive correlation with urinary 1-OHP.•OGG1 methylation mediated PAHs-related cell cycle arrest and oxidative DNA damage.
Exposure to polycyclic aromatic hydrocarbons (PAHs) during pregnancy is a risk factor for adverse neurobehavioral development outcomes. Mitochondrial DNA are sensitive to environmental toxicants due ...to the limited ability of repairing. The change of mitochondrial DNA copy number (mtDNAcn) might be a biologically mechanism linking PAH exposure and children’s neurobehavioral impairment. Our aims are to explore whether PAH metabolites in maternal urine were associated with children’s neurobehavioral development at 2 years old and umbilical cord blood mtDNAcn, and whether mtDNAcn was a mediator of PAH-related neurobehavioral development. We included 158 non-smoking pregnant women from Taiyuan City, Shanxi Province. Maternal urinary eleven PAH metabolites were detected by high performance liquid chromatography with tandem mass spectrometry (HPLC-MS/MS). MtDNAcn in cord blood was detected by real time quantitative polymerase chain reaction (RT-PCR). Children’s neurodevelopment was measured by Gesell Developmental Schedules (GDS) when children were two years age. Generalized linear models and restricted cubic spline models were applied to assess the relationships between PAH metabolites in maternal urine and GDS scores and mtDNAcn. A mediation analysis was also conducted. Generalized linear models showed the relationships of sum of PAH metabolites (Σ-OHPAHs) in maternal urine with decreased motor score, and Σ-OHPAHs with increased mtDNAcn (p for trend < 0.05). Urinary levels of Ln (Σ-OHPAHs) increased one unit was related to a 2.08 decreased in motor scores, and Ln (Σ-OHPAHs) increased one unit was related to 0.15 increased in mtDNAcn. Mediation analysis did not find mtDNAcn can be a mediator between PAH metabolites and neurobehavioral development. Our results suggest that prenatal exposure to PAH decreased children’s neurobehavioral development scores and increased mtDNAcn. And reducing exposure to PAH during pregnancy will benefit to improving neurobehavioral development in children.
In our present cohort study, sum of PAH metabolites in urine of pregnant women were related with motor score and were positively associated with umbilical cord blood mtDNA copy number.
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•Maternal sum of PAH metabolites was associated with motor score.•Maternal sum of PAH metabolites was associated with mitochondrial DNA content.•Mitochondrial DNA content was not associated with children’s neurobehavioral development.•Mitochondrial DNA content did not mediate the relationship between PAH exposure and children’s neurobehavioral development.
Benzoapyrene (BaP) is a widespread carcinogenic pollutant in the environment. Although previous studies have demonstrated the neurodevelopmental toxicity of BaP, the precise mechanisms underlying the ...neurotoxic effects induced by prenatal BaP exposure remain largely unknown. In the present study, pregnant Sprague-Dawley (SD) rats were injected intraperitoneally with 0, 10, 20, or 40 mg/kg-bw of BaP for three consecutive days on embryonic days 17–19. The learning and memory abilities of offspring were determined by Morris Water Maze (MWM) test, while the number of dendritic branches and the density of dendritic spines in hippocampal CA1 and DG regions were evaluated by Golgi-Cox staining at PND 45 and PND 75. The mRNA expression of BDNF, PSD-95, and SYP in offspring hippocampus were detected by qRT-PCR, and the protein expression of BDNF, PSD-95, SYP, HDAC2, acH3K9, and acH3K14 were measured by Western blotting or immunohistochemistry. CHIP-PCR was performed to further detect the levels of acH3K9 and acH3K14 in the promoter regions of BDNF and PSD-95 genes. Our results showed that rats prenatally exposed to BaP exhibited impaired spatial learning and memory abilities and the number of dendritic branches and the density of dendritic spines in the hippocampal CA1 and DG regions were significantly reduced during adolescence and adulthood. The expression of HDAC2 protein was significantly upregulated, while acH3K9, acH3K14, BDNF, PSD-95, and SYP protein levels were significantly downregulated in the hippocampus of BaP- exposed rats. In addition, CHIP results showed that prenatal BaP exposure markedly decreased the level of acH3K9 and acH3K14 in the promoter region of BDNF and PSD-95 gene in the hippocampus of PND 45 and PND 75 offspring. All of the results suggest that prenatal BaP exposure impairs cognitive function and hippocampal synaptic plasticity of offspring in adolescence and adulthood, and HDAC2-mediated histone deacetylation plays a crucial role in these deficits.
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•Prenatal BaP exposure impairs hippocampal synaptic plasticity and cognitive function in offspring.•Prenatal BaP exposure downregulates PSD-95, BDNF, and SYP in offspring hippocampus.•Prenatal BaP exposure upregulates HDAC2 and decreases histone acetylation in the offspring hippocampus.
Polycyclic aromatic hydrocarbons (PAH) are carcinogenic, neurotoxic environmental pollutants generated during incomplete combustion of fossil fuel and other organic material. PAH exposure has been ...associated with adverse fetal development and epigenetic alterations in cord blood. Several molecular epidemiology studies have established PAH-DNA adducts as biomarkers of PAH exposure.
We investigated the relationship between LINE1 DNA methylation and PAH-DNA adduct levels in cord blood, and with neurodevelopmental outcomes.
In Tongliang County, China, the current study enrolled two population-based cohorts of nonsmoking pregnant women before (2002) and after (2005) the closure of a local coal-fired power plant in May 2004. We analyzed cord blood samples collected from mothers in the two cohorts (n=110 from 2002 cohort and n=107 from 2005 cohort) for PAH-DNA adducts and genomic LINE1 DNA methylation. Neurodevelopmental data on children were collected using the Gesell Developmental Scales (GDS) at age 2 and using the Wechsler Intelligence Scale for Children (WISC) at age 5.
A significant inverse relationship was observed between PAH-DNA adducts and LINE1 DNA methylation (β=−0.010, p<0.038). A significant, positive association between LINE1 methylation and scores on WISC full scale and verbal (β=85.31, p<0.005; β=94.36, p<0.003) but not on the GDS. Mediation analysis did not find LINE1 to be a direct mediator between PAH-DNA adducts and IQ score.
LINE1 methylation in cord blood DNA was a positive predictor of IQ at age 5 and was decreased at higher levels of prenatal PAH exposure measured by PAH-DNA adducts in cord blood. However, the adverse effects of prenatal exposure to PAH on IQ scores did not appear to be directly mediated by altered LINE1 methylation.
•PAH-DNA adducts are an integrated index of biologically effective dose of PAH exposure.•LINE1 methylation was inversely associated with PAH-DNA adduct level.•LINE1 methylation could predict IQ scores at age 5.
Multiple factors, including co-exposure between lifestyle and environmental risks, are important in susceptibility to oxidative DNA damage. However, the underlying mechanism is not fully understood. ...This study was undertaken to evaluate whether Cytochrome P4501A1 (CYP1A1) methylation can mediate the co-exposure effect between smoking and occupational polycyclic aromatic hydrocarbons (PAH) in development of oxidative DNA damage.
We explored the associations between smoking and occupational PAH co-exposure effect, CYP1A1 methylation and oxidative DNA damage among 500 workers from a coke-oven plant in China. Urine biomarkers of PAH exposure (1-hydroxypyrene, 1-OHP; 2-hydroxynaphthalene, 2-NAP; 2-hydroxyfluorene, 2-FLU; and 9-hydroxyphenanthren, 9-PHE) and a marker of oxidative DNA damage (8-hydroxy- 2'- deoxyguanosine, 8-OHdG) were measured by high performance liquid chromatography. CYP1A1 methylation was measured by pyrosequencing. Finally, mediation analysis was performed to investigate whether CYP1A1 methylation mediated smoking and occupational PAH co-exposure effect on oxidative DNA damage.
We observed significant associations of smoking and 1-OHP co-exposure with CYP1A1 hypomethylation (OR: 1.87, 95% CI: 1.01-3.47) and high 8-OHdG (OR: 2.13, 95% CI: 1.14-3.97). There was a significant relationship between CYP1A1 hypomethylation and high 8-OHdG (1st vs. 3rd tertile = 1.58, 95% CI: 1.01-2.47, P for trend = 0.046). In addition, mediation analysis suggested CYP1A1 hypomethylation could explain 13.6% of effect of high 8-OHdG related to smoking and 1-OHP co-exposure.
Our findings suggested that the co-exposure effect of smoking and occupational PAH could increase the risk of oxidative DNA damage by a mechanism partly involving CYP1A1 hypomethylation.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
ObjectivesPolycyclic aromatic hydrocarbons (PAHs) have been proven to be a risk factor for cardiovascular disease in coke oven workers, and increased plasma viscosity is a signal for higher risk of ...catching up cardiovascular disease. We want to explore whether the plasma viscosity is affected by the concentration of PAHs.DesignOur study is a cross-sectional dose–response study.SettingParticipants in this study came from a coke plant in Taiyuan, Shanxi.ParticipantsWe used data of 693 coke oven workers in Taiyuan.Primary and secondary outcome measuresWe assumed that plasma viscosity would increase as the concentration of PAHs metabolites in urine increases. We found that 2-hydroxyfluorene (OHFLU2) and plasma viscosity have a stable linear relationship in different statistical methods.ResultsWe found that plasma viscosity increased by 1.14 (mPa.s,30/s) for each ng/mL of 2-OHFLU urinary (correlation coefficient range: 0.54–1.74, p<0.05).ConclusionsThe results of this study could provide evidence for coke oven workers to prevent cardiovascular disease by checking whether plasma viscosity is elevated.
Abstract Objective : To study the effects of 2,2′,4,4′,5,5′-hexa-brominated diphenyl ether (BDE-153) exposure during lactation on the learning and memory abilities, spontaneous behavior and brain ...cells of adult rats and to elicit basic information on PBDE’s developmental neurotoxicity. Methods : Newborn male rat pups were randomly categorized into the following groups (15 pups per group), according to their weights and litters: a control group, and 1 mg/kg, 5 mg/kg and 10 mg/kg BDE-153 groups. At postnatal day 10 (PND10), the pups in the BDE-153 groups were intraperitoneally injected once with BDE-153 plant oil solutions at 0.1 ml/10 g body weight, and the controls were injected with plant oil. Throughout the entire experiment, physiological measures were recorded, such as food and water consumption, body weight and clinical symptoms. At 1 month and 2 months after treatment, the learning and memory abilities of the rats were tested by the Morris water maze test, the step-down test, and the step-through test; spontaneous behavior was tested by the open-field test. After all tests were accomplished, rats were weighed and sacrificed, and the brain tissue was immediately isolated and divided into two parts. Sections were fabricated from one part, and changes in the morphology and ultrastructure in CA3 region of hippocampus were observed under an optical microscope and transmission electron microscope, along with the detection of apoptotic cells with the terminal-deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) method. The tissue of the second part was digested into single-cell suspension liquid, and the cell apoptosis was assayed with flow cytometry and the lactate dehydrogenase (LDH) leakage was detected with spectrophotometry. Results : There was no obvious change in food and water consumption, body weight and the ratio of brain to body weight, or any overt clinical symptoms in the BDE-153-treated rats. Compared to the control group, rats' latency time in the test session (LT2) in the step-down test was significantly increased in the 10 mg/kg BDE-153 group at 2 months after treatment ( P <0.05), and the BDE-153-treated rats' swimming times and distances in the target quadrant were significantly decreased at 1 month and 2 months after treatment ( P <0.05 or P <0.01). These parameters were also significantly increased in the opposite quadrant at 1 month after treatment ( P <0.05 or P <0.01). The spontaneous behavior was significantly reduced in the treated groups compared to the controls ( P <0.05 or P <0.01). The severity of neurobehavioral dysfunction was dependent on the exposure dose of BDE-153, and worsened with age. Under an optical microscope, the treated rats' neurons in the CA3 region of the hippocampus were observed to be reduced and disarranged, and the cell junctions were loosened and the intercellular spaces were enlarged. Under a transmission electron microscope, the cell nucleus was observed to shrink; the chromatin was condensed and gathered near the nuclear membrane, the Nissl bodies and other organelles in the perikaryon were reduced, and the vacuole was observed to degenerate and even disappear. Moreover, compared to the controls, the cell apoptosis rates were significantly increased in the 5 and 10 mg/kg BDE-153 groups ( P <0.05), and the LDH activity was significantly increased in the 10 mg/kg BDE-153 groups ( P <0.01). Conclusion : Lactation exposure to BDE-153 damaged adult rats' learning and memory abilities, disrupted their spontaneous behavior (hypoactivity) and induced hippocampus neuron apoptosis.
Naphthalene is the simplest polycyclic aromatic hydrocarbon (PAH). It is easily emitted into the atmosphere, posing a significant risk to human health. However, limited studies have described the ...impact of naphthalene exposure on birth outcomes. In this study, we investigated the association between the maternal urinary metabolites of naphthalene, 2-hydroxynaphthalene (2-OH NAP), and birth outcomes.
In the present study, four urinary PAH metabolites were measured in 263 pregnant women during late pregnancy. Multiple linear regression analysis was used to analyze the relationship between the concentrations of 2-OH NAP and birth outcomes, and restricted cubic spline models were further used to examine the shapes of the dose-response association.
General linear models showed that prenatal urinary 2-OH NAP was associated with lower birth weight (BW) (- 4.38% for the high vs. low exposure group of 2-OH NAP; p for trend = 0.049) and higher cephalization index (CI) (4.30% for the high vs. low exposure group of 2-OH NAP; p for trend = 0.038). These associations were linear and significant when 2-OH NAP was modeled as a continuous variable in restricted cubic spline models (P
= 0.0293 for 2-OH NAP and BW; P
= 0.0326 for 2-OH NAP and CI). Multiple linear regression data indicated that each 1 ln-unit increase in 2-OH NAP was significantly associated with a 2.09 g/cm increase in the CI. The associations among 2-OH NAP, BW, and CI were also observed in a subset of participants residing close to arterial traffic.
Our data indicated that prenatal exposure to naphthalene had an adverse effect on fetal birth outcomes, especially the brain development index. Reduced exposure to naphthalene may improve newborn health outcomes. In Taiyuan, naphthalene may result from traffic pollution.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Aluminum is a known neurotoxin that can induce Aβ deposition and abnormal phosphorylation of tau protein, leading to Alzheimer disease (AD)-like damages such as neuronal damage and decreased learning ...and memory functions. In this study, we constructed a rat model of subchronic aluminum maltol exposure, and the whole-transcriptome sequencing was performed on the hippocampus of the control group and the middle-dose group. A total of 167 miRNAs, 37 lncRNAs, 256 mRNAs, and 64 circRNAs expression changed. The Kyoto Encyclopedia of Genes and Genomes showed that PI3K/AKT pathway was the most enriched pathway of DEGs, and IRS1 was the core molecule in the PPI network. circRNA/lncRNA-miRNA-mRNA networks of all DEGs, DEGs in the PI3K/AKT pathway, and IRS1 were constructed by Cytoscape. Molecular experiment results showed that aluminum inhibited the IRS1/PI3K/AKT pathway and increased the content of Aβ and tau. In addition, we also constructed an AAV intervention rat model, proving that inhibition of miR-96-5p expression might resist aluminum-induced injury by upregulating expression of IRS1. In general, these results suggest that the ceRNA networks are involved in the neurotoxic process of aluminum, providing a new strategy for studying the toxicity mechanism of aluminum and finding biological targets for the prevention and treatment of AD.
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He et al. performed whole-transcriptome sequencing and verification on the hippocampus of aluminum-exposed rats, suggesting that the ceRNA network is involved in the neurotoxic process of aluminum, providing a new strategy for studying the neurotoxicity of aluminum and finding biological targets for the prevention and treatment of AD.
BackgroundAs a group of environmental pollutants, polycyclic aromatic hydrocarbons (PAHs) are neurotoxic and may cause mild cognitive impairment (MCI) by inducing inflammation. Whether ...neutrophil-lymphocyte ratio (NLR), an inflammatory indicator, plays a mediating role in the relationship between PAHs exposure and MCI is unclear yet. ObjectiveTo investigate a potential mediating role of NLR in the association between exposure to PAHs and MCI in coke oven plant workers. MethodsEleven urine hydroxylated PAHs (OH-PAHs) of 530 coke oven plant workers were determined by high performance liquid chromatography tandem mass spectrometry. NLR was derived from participants' routine blood examination results using a fully automated haematology analyser. The associations between urinary OH-PAHs and MCI were analyzed by binary logistic regression, the associations between urinary OH-PAHs and NLR were analyzed by multiple linear regression, and the role of NLR in the relationship between urinary OH-PAHs and MCI was evaluated by mediating effect analysis. ResultsAfter controlling for confounding factors and other OH-PAHs, the results of binary logistic regression showed that for every e-fold (e is the base of the natural logarithm) increase in the concentration of 2-hydroxynaphthalene (2-OHNap) and 1-hydroxyphenanthrene (1-OHPhe), the OR (95%CI) values of reporting MCI positive were 1.21 (1.02, 1.43) and 1.25 (1.04, 1.51) respectively. For each unit increase of NLR, the OR (95%CI) of reporting MCI positive was 1.56 (1.12, 2.18). The results of multiple linear regression showed that each unit increase in natural log-transformed levels of 1-OHPhe was associated with 0.05 (95%CI: 0.01, 0.10) increase of NLR. The results of mediating effect analysis showed that the association between urinary 1-OHPhe and MCI was partially mediated by peripheral blood NLR, with a mediation ratio of 9.8%. ConclusionExposure to PAHs in coke oven plant workers may increase the risk of reporting MCI positive partially through increased NLR in peripheral blood.
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