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1.
Neurotox Res ; 2020 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-31970651

RESUMO

Aluminum (Al) is an environmental neurotoxin with extensive exposure by humans, but the molecular mechanism of its toxicity is still unclear. Several studies have indicated that exposure to aluminum can impair learning and memory function. The purpose of this study was to investigate the mechanism of LTP injury and the effect of aluminum exposure on related signal pathways. The results showed that the axonal dendrites of neurons in the hippocampal CA1 area of rats exposed to maltol aluminum showed neuritic beading and the dendritic spines were reduced. This resulted in dose-dependent LTP inhibition and led to impaired learning and memory function in rats. The PI3K-Akt-mTOR pathway may play a crucial role in this process.

2.
Neurotoxicology ; 76: 144-152, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31722248

RESUMO

BACKGROUND: Aluminum (Al) exerts neurotoxic effects following overexposure. We previously reported worse cognitive performance in workers exposed to Al than non-exposed individuals. Cognition involves multiple domains. The effect of Al on multi-domain cognition has been studied for decades, but still remains controversial. OBJECTIVE: To explore the relationship between plasma Al levels and multi-domain cognitive performance among in-service aluminum-exposed workers at the SH Aluminum Factory in China and identify possible types of early cognitive damage caused by exposure to aluminum. METHODS: Eight hundred thirty-one in-service aluminum-exposed workers at the SH Aluminum Factory in China were investigated. The plasma Al concentrations were measured using inductively coupled plasma-mass spectrometry (ICP-MS) and served as an internal exposure indicator. The participants were divided into four subgroups based on the quartiles of plasma Al concentrations, namely, the Q1, Q2, Q3, and Q4 subgroups. Cognitive function was assessed using the Mini-mental State Examination (MMSE) and the clock-drawing test (CDT). Multi-domain cognition was evaluated using sub-tests of the MMSE and the CDT. RESULTS: The average plasma Al concentration was 15.26 (8.28, 27.02) µg/L. The neurobehavioral tests showed negative correlations between plasma Al levels and total CDT scores and executive/visuospatial cognitive performance, and a positive correlation between plasma Al levels and CDT-position errors (all P<0.05). Additionally, dose-response relationships between higher plasma Al levels and lower total CDT scores, worse executive/visuospatial cognitive performance, and more error rates in the CDT-position were observed (all Ptrend<0.05). However, no significant correlations or trends were observed between plasma Al levels and other cognitive domains (all P>0.05). The results from the multivariate logistic regression model and restricted cubic spline models of dose-response relationships were consistent with the results obtained from the general linear model. All potential confounders, such as age, marital status, education, income, type of work, and smoking and drinking habits, were considered. CONCLUSION: Based on the results, aluminum exposure may exert a substantial effect on impairing executive/visuospatial functions in multi-domain cognition at the early stage, particularly the identification of spatial positions.

3.
Chemosphere ; 238: 124602, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31545211

RESUMO

Polybrominated diphenyl ethers (PBDEs) have been known to exhibit neurotoxicity in rats; however, the underlying mechanism remains unknown and there is no available intervention. In this study, we aimed to investigate the role of oxidative and nitrosative stress in the neurotoxicity in the cerebral cortex and primary neurons in rats following the BDE-153 treatment. Compared to the untreated group, BDE-153 treatment significantly induced the neurotoxic effects in rats, as manifested by the increased lactate dehydrogenase (LDH) activities and cell apoptosis rates, and the decreased neurotrophic factor contents and cholinergic enzyme activities in rats' cerebral cortices and primary neurons. When compared to the untreated group, the oxidative and nitrosative stress had occurred in the cerebral cortex or primary neurons in rats following the BDE-153 treatment, as manifested by the increments in levels of reactive oxygenspecies (ROS), malondialdehyde (MDA), nitric oxide (NO), and neuronal nitric oxide synthase (nNOS) mRNA and protein expressions, along with the decline in levels of superoxide dismutase (SOD) activity, glutathione (GSH) content, and peroxiredoxin I (Prx I) and Prx II mRNA and protein expressions. In addition, the ROS scavenger N-acetyl-l-cysteine (NAC) or NO scavenger NG-Nitro-l-arginine (L-NNA) significantly rescued the LDH leakage and cell survival, reversed the neurotrophin contents and cholinergic enzymes, mainly via regaining balance between oxidation/nitrosation and antioxidation. Overall, our findings suggested that oxidative and nitrosative stresses are involved in the neurotoxicity induced by BDE-153, and that the antioxidation is a potential targeted intervention.


Assuntos
Córtex Cerebral/patologia , Éteres Difenil Halogenados/toxicidade , Síndromes Neurotóxicas/patologia , Estresse Nitrosativo/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Bifenil Polibromatos/toxicidade , Acetilcisteína/farmacologia , Animais , Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Córtex Cerebral/efeitos dos fármacos , Glutationa/metabolismo , Éteres Difenil Halogenados/metabolismo , Masculino , Malondialdeído/metabolismo , Fatores de Crescimento Neural/metabolismo , Neurônios/efeitos dos fármacos , Neurotrofina 3/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo I/metabolismo , Estresse Nitrosativo/fisiologia , Estresse Oxidativo/fisiologia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos
4.
Chemosphere ; 244: 125445, 2019 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-31835052

RESUMO

Aluminium is an environmental neurotoxin that comes extensively in contact with human being. The molecular mechanism of aluminium toxicity remains unclear. A number of studies have indicated that exposure to aluminium can impair learning and memory function. The purpose of this study was to investigate the mechanism of long-term potentiation(LTP) injury and the related signalling pathway activated by aluminium exposure. The results showed that aluminium treatment produced dose-dependent inhibition of LTP and reduced the activity of Histone H3K9 demethylation (H3K9me2) demethylase and the expression of the PHD (plant homeodomain) finger protein 8 (PHF8). Interestingly, there was no statistically significant difference in the expression of the PHF8 gene, suggesting that aluminium exposure only affects the translation process. Decrease in brain-derived neurotrophic factor (BDNF) expression may be related to the effect of aluminium. With correlation analysis between the hippocampal standardised field excitatory postsynaptic potential (fEPSP) amplitude and the expression of various proteins in the aluminium-exposed rat, the hippocampal standardised fEPSP amplitude was positively correlated with the expression of hippocampal PHF8 and BDNF proteins, and negatively correlated with the expression of hippocampal H3K9me2 protein. The correlation between H3K9me2 and BDNF was also considered negative. The results suggest that changes in synaptic plasticity might be related to changes in these proteins, which were induced by aluminium exposure. In conclusion, chronic aluminium exposure may inhibit PHF8 and prevent it from functioning as a demethylase. This may block H3K9me2 demethylation, decrease BDNF protein expression, and lead to LTP impairment.

5.
Biol Trace Elem Res ; 2019 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-31845204

RESUMO

This study investigated the effects of chronic aluminum exposure on apoptosis of hippocampal neurons, and synaptic plasticity in the hippocampus in rats. Rats were divided into the control, low-dose (L-Al), mid-dose (M-Al), and high-dose (H-Al) groups. After chronic exposure of aluminum, the Morris water maze (MWM) and open-field (OF) tests were performed to assess the behavioral performance. Electrophysiological measurements were conducted. Flow cytometry was used to assess the apoptotic processes. Quantitative real-time PCR and ELISA were performed to measure mRNA and protein expression levels of caspases. After 90 days of aluminum exposure, the aluminum contents in the brain of the rats were increased, with the increasing exposure dose. The MWM and OF tests showed that chronic exposure of aluminum significantly impaired the neurobehavior of rats. Moreover, after high-frequency stimulation (HFS), the average amplitudes of field excitatory postsynaptic potentials (fEPSPs) for the M-Al and H-Al groups were lower than the control group at 10, 20, 30, 40, 50, and 60 min. Furthermore, the apoptotic rates in the M-Al and H-Al groups were significantly higher than the control group. The qRT-PCR and ELISA showed that, compared with the control group, the mRNA and protein expression levels of caspases-3, -8, and -9 were significantly increased in the aluminum-treated groups compared with the control group. Long-term exposure to aluminum could induce the apoptosis of hippocampal neurons, damage the synaptic plasticity, and impair the learning and memory functions in rats. There might be a close relationship between the neuronal apoptosis and synaptic plasticity damage.

6.
Neurotox Res ; 2019 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-31721047

RESUMO

The brain is one of organs vulnerable to aluminum insult. Aluminum toxicity is involved in neurobehavioral deficit, neuronal cell dysfunction, and death. The aim of this study are as follows: (1) to evaluate the repairing efficiency of Necrostatin-1 (Nec-1), a cell death inhibitor, and Z-VAD-FMK, a pan-caspase inhibitor, on Al-induced neurobehavioral deficit and neuronal cell death, in order to evidence the cell death inducing ability of aluminum, and (2) to primarily explore the possibility of treating neuronal cell loss-related disease, such as Alzheimer's disease, with Nec-1 and Z-VAD in Al-induced dementia animal model. We found Nec-1 and Z-VAD-FMK alone or in combination could reduce aluminum-induced learning and memory impairment in mice. Pathohistological results indicated that Nec-1 and Z-VAD-FMK can decrease Al-induced neuronal death cell. In addition, some cell death-associated proteins in cell death signal pathway were inhibited by Nec-1 and Z-VAD-FMK in Al-exposed mice. In conclusions, Nec-1 and Z-VAD-FMK can repair the injury of learning and memory induced by aluminum in mice. Furthermore, Nec-1 was more obvious to repair the injury of learning and memory function compared with Z-VAD-FMK. Nec-1 and Z-VAD-FMK can repair the Al-induced morphological injury of cell and reduce the amounts of dead cell, and repairing effects were more significant at higher doses. The effect of Nec-1 was stronger than Z-VAD-FMK, though their mechanism was different. The combination of them had the strongest effect. Our study evidenced Al-induced neuronal necroptosis and apoptosis existing in animal model and suggested potential therapeutic effects of Nec-1 and Z-VAD-FMK on neuronal cell death in neurodegenerative diseases.

7.
Chronobiol Int ; 36(10): 1439-1446, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31368363

RESUMO

We investigated the association between the period of exposure and changes in urinary excretion of chromium and nickel among rotating shift workers in a stainless-steel plant. The study participants were composed of two groups: the workers who were occupationally exposed to metals ("exposed group") and those who were not occupationally exposed to metals ("unexposed group"). The exposed and unexposed groups consisted of 56 and 40 male rotating shift workers, respectively. Urine samples were collected immediately before and immediately after the day shift, evening shift, and night shift. Urinary chromium and nickel were measured using inductively coupled plasma mass spectrometry. To correct for variations in urine dilution, urinary metal concentrations were expressed as a ratio to urinary creatinine concentration. In the exposed group, post-shift urinary excretion of chromium was significantly higher than pre-shift excretion. However, although urinary chromium excretion clearly increased after the day and night shift [63% (p < .0001) and 87% (p < .0001), respectively], urinary chromium excretion after the evening shift was only slightly higher than that measured before the evening shift (8%, p = .028). Similar patterns were found for urinary nickel excretion (p = .0001, 0.20, and 0.18 for the day, evening, and night shifts, respectively). Non-uniform urinary excretion of metals between the day shift, evening shift, and night shift were observed in the exposed group; specifically, urinary metal excretion increased only slightly during the evening shift. In the unexposed group, no significant increase or decrease was found in median urinary chromium or nickel excretion (p= .63-0.87). Work shift-specific permissible exposure level would be necessary.

8.
Chemosphere ; 232: 121-129, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31152896

RESUMO

It is widely accepted that aluminium is neurotoxic; it primarily causes cognitive dysfunction, which has been confirmed in human and animal tissue and cell experiments (Bondy, 2010), but its toxic mechanism has yet to be fully elucidated. Epigenetics is the study of changes in gene expression that may be triggered by both genetic and environmental factors and is independent from changes in the underlying DNA sequence, resulting in a change in phenotype without a change in genotype, which in turn affects how cells read genes. Some findings emphasize the potential significance of histone lysine methylation for orderly brain development and as a molecular toolbox to study chromatin function in vivo and in vitro. The H3K4-specific methyltransferase MLL is essential for hippocampal synaptic plasticity and might be involved in cognitive dysfunction. In the present study, we established that chronic aluminium exposure results in cognitive dysfunction, causing deficits in exploratory behaviour and learning and memory, in a dose- and time-dependent manner. Furthermore, we demonstrated in vivo and in vitro that chronic aluminium exposure reduces expression of histone H3K4 tri-methylation (H3K4me3) and the activity and expression of MLL. Taken together, these results indicate that chronic aluminium exposure may reduce H3K4me3 levels through suppressing activation of MLL, which in turn affects cognitive ability.


Assuntos
Alumínio/toxicidade , Histonas/metabolismo , Alumínio/metabolismo , Animais , Disfunção Cognitiva , Epigênese Genética , Expressão Gênica , Histona-Lisina N-Metiltransferase/metabolismo , Histonas/genética , Humanos , Memória , Metilação , Proteína de Leucina Linfoide-Mieloide/metabolismo
9.
BMJ Open ; 9(6): e027154, 2019 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-31209090

RESUMO

OBJECTIVES: To investigate the prevalence of mild cognitive impairment and the relationship with plasma aluminium among aluminium workers. DESIGN: This was a cross-sectional case-control study in the SH Aluminium Factory, China. SETTING: The university and affiliated hospital cooperated in the study. PARTICIPANTS: There were 910 aluminium workers on duty, among whom 853 participated in our study. Participants, such as those with cerebral vascular disease, epilepsy, brain trauma, Parkinson's and mental diseases, aluminium-containing drug and mental drug use, and any family history of dementia in first-degree relatives were excluded. PRIMARY AND SECONDARY OUTCOME MEASURES: Blood samples were collected, and plasma aluminium was measured by inductively coupled plasma-mass spectrometry. For each case, four age-matched controls were evaluated to determine the relationship between aluminium exposure and mild cognitive impairment. Conditional logistic regression was used to explore influential factors in mild cognitive impairment. RESULTS: Among 910 workers, 93.74% participated in stage 1; 53 cases were finally diagnosed. The crude prevalence of mild cognitive impairment among aluminium workers on duty was 6.21%. There was a significant difference in plasma aluminium concentration between the two groups. In the multivariate analysis, we found that a higher level of plasma aluminium was associated with a high risk of cognitive impairment when compared with a lower aluminium level (AOR=2.24, 95% CI=1.17 to 4.26), and a high education level was a protective factor (AOR=0.36, 95% CI=0.18 to 0.70). No other factor was statistically significant. CONCLUSIONS: Mild cognitive impairment is no longer a disease specific to elderly people. High plasma aluminium exposure might be associated with an increased risk of cognitive impairment, but a reduced risk was observed with a high education level. The cognitive function of aluminium workers on duty must be considered seriously.

10.
Neurotox Res ; 36(2): 334-346, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31055771

RESUMO

Aluminum (Al) exposure impairs learning and memory function in humans and in animal models. Several studies have shown that the neurotoxicity of Al is associated with damage to mitochondrial morphology and mitochondrial dysfunction, but the molecular mechanism is unclear. The present study was performed to elucidate the possible molecular mechanism related to the Al-induced abnormal mitochondrial dynamics that lead to learning and memory disorders. SD rats were exposed to Al-maltolate complex (Al(mal)3) (blank, 0, 0.41, 0.81, or 1.62 mg/kg) for 30, 60, or 90 days, and neurobehavior, mitochondrial morphology, mitochondrial function, the levels of fission proteins such as dynamin-related protein 1 (Drp1) and fission protein 1 (Fis1), and the levels of fusion proteins such as optic atrophy 1 (Opa1), mitofusin 1 (Mfn1), and mitofusin 2 (Mfn2) were explored. The results indicated that exposure to Al(mal)3 increased the concentration of Al in the brain in a time- and dose-dependent manner and impaired spatial learning and memory. Al(mal)3 damaged mitochondrial morphology and impaired mitochondrial function in the hippocampus. Dose-dependent elevations in the levels of mitochondrial fission (Drp1 and Fis1) and fusion (Opa1, Mfn1, and Mfn2) proteins were observed. In addition, the upregulation of calcineurin (CaN) and the reduced phosphorylation of Drp1 (s637) may have disturbed the balance of mitochondrial fission and fusion in the hippocampus. These results showed that Al-induced learning and memory impairment may be related to mitochondrial fission and fusion disorders.


Assuntos
Alumínio/toxicidade , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Aprendizagem em Labirinto/efeitos dos fármacos , Dinâmica Mitocondrial/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Hipocampo/metabolismo , Masculino , Aprendizagem em Labirinto/fisiologia , Dinâmica Mitocondrial/fisiologia , Ratos , Ratos Sprague-Dawley
11.
Environ Res ; 174: 105-113, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31055168

RESUMO

BACKGROUND: Prenatal exposure to polycyclic aromatic hydrocarbon (PAH) is a potential risk factor for child neurobehavioral development. Telomere length (TL) has important implications for health over the life course. OBJECTIVE: In this study, we aimed to investigate whether prenatal urinary PAH metabolites were associated with adverse neonatal neurobehavioral development and altered cord blood TL and to explore whether the change of TL was a predictor of neonatal neurobehavioral development. METHOD: We enrolled 283 nonsmoking pregnant women in Taiyuan city. Eleven PAH metabolites were measured in maternal urine samples. TL in cord blood was measured by real time quantitative polymerase chain reaction. Neonatal behavioral neurological assessment (NBNA) tests were conducted when the infants were three days old. Multiple linear regression models were used to analyze the associations of maternal urinary PAH metabolites with NBNA scores and cord blood TL, and restricted cubic spline models were further used to examine the shapes of dose-response relationships. A mediation analysis was also conducted. RESULT: We observed dose-response associations of maternal urinary 2-hydroxyfluorene (2-OHFlu) and 2-hydroxyphenanthrene (2-OH Phe) with decreased active tone scores, sum of NBNA scores, and cord blood TL (P for trend<0.05). Each 1 unit increase in urinary levels of Ln (2-OH Flu) or Ln (2-OH Phe) was associated with a 0.092 or 0.135 decrease in the active tone scores and a 0.174 or 0.199 decrease in the sum of NBNA scores. Mediation analysis showed TL could explained 21.74% of the effect of sum of NBNA scores change related to prenatal exposure to 2-OH Phe (P for mediator = 0.047). CONCLUSION: Our data indicates maternal urinary specific PAH metabolites are inversely associated with neonatal neurobehavioral development and cord blood TL. TL mediates the associations of 2-OH Phe with neonatal neurobehavioral development and partly explains the effect of 2-OH Phe on neonatal neurobehavioral development.


Assuntos
Desenvolvimento Infantil , Poluentes Ambientais/metabolismo , Exposição Materna/estatística & dados numéricos , Hidrocarbonetos Policíclicos Aromáticos/metabolismo , Telômero , Criança , Cidades , Feminino , Sangue Fetal , Humanos , Lactente , Recém-Nascido , Gravidez
12.
Toxicol Lett ; 311: 37-48, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31029751

RESUMO

Polybrominated diphenyl ether-153 (BDE-153) has been demonstrated to induce neuronal apoptosis in rat cerebral cortex and primary neurons, however, the roles of mitochondria and endoplasmic reticulum (ER) remain unclear in the BDE-153-induced neuronal apoptosis. To this purpose, we observed the mitochondria and ER ultrastructure changes in the neuronal apoptosis in rats following BDE-153 treatment, detected the mitochondrial membrane potential (MMP), Ca2+-Mg2+-ATP enzyme activity, and the changes of mitochondria and ER apoptosis related molecules in rat cerebral cortex and in primary neurons following BDE-153 treatment. Results showed that compared to the control group, neuronal apoptosis was significantly increased in a dose-dependent manner in rat cerebral cortex and in primary neurons following BDE-153 treatment. In comparison with control, BDE-153 treatment induced remarkable ultrastructural changes in ER rather than in mitochondria, and the severity of ER damage was worse with the increasing BDE-153 dose. Meanwhile, ER apoptosis related molecules including caspase-12 (at mRNA level), cleaved caspase-12 (at protein level), and Tmem132a (at mRNA and protein levels) were significantly increased in the cerebral cortex in rats following BDE-153 treatment, while procaspase-12 protein was significantly decreased, comparing with control. In contrast, mitochondria apoptosis related molecules (MMP, Ca2+-Mg2+-ATP enzyme activity, cyt-C protein, caspase-3, 8, 9 mRNA, caspase-8, 9 enzyme activities) did not significantly changed in the cerebral cortex of rats or in primary neurons following BDE-153 treatment, except for the elevated caspase-3 mRNA and enzyme activity. Therefore, we conclude that BDE-153 induced neuronal apoptosis was dependent on p53, and mediated more by ER than mitochondria in the cerebral cortex of rats and in primary neurons. The findings suggest that ER is a potential sensitive target of BDE-153 neurotoxicity, providing a scientific evidence for the mechanism and intervention study on PBDE's neurotoxicity.


Assuntos
Apoptose/efeitos dos fármacos , Córtex Cerebral/efeitos dos fármacos , Retículo Endoplasmático/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Degeneração Neural , Neurônios/efeitos dos fármacos , Síndromes Neurotóxicas/etiologia , Bifenil Polibromatos/toxicidade , Animais , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Células Cultivadas , Córtex Cerebral/metabolismo , Córtex Cerebral/ultraestrutura , Relação Dose-Resposta a Droga , Retículo Endoplasmático/metabolismo , Retículo Endoplasmático/ultraestrutura , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Masculino , Mitocôndrias/metabolismo , Mitocôndrias/ultraestrutura , Neurônios/metabolismo , Neurônios/ultraestrutura , Síndromes Neurotóxicas/metabolismo , Síndromes Neurotóxicas/patologia , Ratos Sprague-Dawley , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
13.
Neurotox Res ; 35(4): 931-944, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30649678

RESUMO

To investigate the effect of aluminum-maltolate [Al(mal)3] on the expression of ApoER2, VLDLRs, and LRP1 in PC12-ApoE4 cells. The lentiviral vector carrying human ApoE4 gene was transfected into PC12 cells; after screening with puromycin, PC12 cells carrying ApoE4 gene (PC12-ApoE4 cells) were established. After 24-h treatment with Al(mal)3, the cell survival rate was measured by CCK-8 assay. The expression of Aß40 and Aß42 was detected by ELISA assay; the expression of the APP, ApoER2, LRP1, and VLDLRs genes was detected by RT-PCR, and Western blot assay was used to detect the expression of the APP, ApoER2, LRP1, and VLDLRs proteins. Factorial experiment design was performed to analyze interaction between cell type and Al dose. Al(mal)3 treatment induced dose-dependent decreases of survival rate in the two cell groups and dose-dependent increases of Aß42 content(P < 0.05). The expressions of ApoER2, LRP1, and VLDLR proteins and their mRNA transcription decreased gradually with the increase of Al(mal)3 doses (P < 0.05), while the expression of APP protein and mRNA transcription gradually increased with the increase of Al(mal)3 doses (P < 0.05). As regard to the interaction of cell type and Al dose, the decrease of cell survival rate and the increase of the Aß42 were both statistically significant (P < 0.05). And the decrease of ApoER2 and LRP1 proteins was both statistically significant too (P < 0.05). The effect of Al(mal)3 and ApoE4 gene on the survival rate and the increase of Aß content in PC12 cells. That is to say, there is interaction between ApoE4 gene and aluminum on the Aß content, especially the change of the Aß42 content, which may be related to the down-regulation of the expression of ApoER2 and LRP1 proteins.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Apolipoproteínas E/metabolismo , Proteínas Relacionadas a Receptor de LDL/metabolismo , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Compostos Organometálicos/toxicidade , Pironas/toxicidade , Receptores de LDL/metabolismo , Animais , Apolipoproteínas E/genética , Sobrevivência Celular/efeitos dos fármacos , Vetores Genéticos , Humanos , Células PC12 , Ratos
14.
Toxicology ; 412: 55-62, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30508566

RESUMO

Both animal study and epidemiological survey revealed the associations between defects of cognitive function and the developmental exposure to perfluorooctane sulfonate (PFOS), while the mechanism is not well known. The SD rats were exposed PFOS at 1.7, 5 and 15 mg/L by drinking water from gestation to the adulthood of the pups for evaluating the effects of PFOS exposure on long-term potentiation (LTP) and the role of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors trafficking. Whole-life exposure of PFOS beginning in utero to adulthood significantly inhibited the induction and expression of LTP, and the input/output curve (I/O) and paired-pulse facilitation (PPF) were moderately suppressed, suggesting that PFOS might affect the synaptic transmission and plasticity both in pre- and post-synaptic cells. Meanwhile, PFOS decreased the mRNA levels of AMPA receptor subunits GluA1 and GluA2, and the protein amounts in the membrane, with the total GluA1 and GluA2 protein amounts increased, indicating the internalization of AMPA receptors. Furthermore, tests in the primary hippocampal neurons also support the decreased mRNA levels of GluA1 and GluA2 induced by PFOS. After the pretreatment of AMPA antagonist (NBQX), PFOS decreased the expression of GluA1 and GluA2 and increased internal cellular calcium at much lower levels than that in the neurons without NBQX treatment. The results provide electrophysiological evidence for the impaired cognitive function induced by PFOS exposure and revealed the critical role of AMPA receptor involved.


Assuntos
Ácidos Alcanossulfônicos/toxicidade , Região CA1 Hipocampal/efeitos dos fármacos , Poluentes Ambientais/toxicidade , Fluorcarbonetos/toxicidade , Potenciação de Longa Duração/efeitos dos fármacos , Receptores de AMPA/fisiologia , Animais , Região CA1 Hipocampal/fisiologia , Cálcio/metabolismo , Células Cultivadas , Feminino , Troca Materno-Fetal , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Gravidez , Transporte Proteico/efeitos dos fármacos , Ratos Sprague-Dawley
16.
Environ Health ; 17(1): 91, 2018 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-30572877

RESUMO

BACKGROUND: 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. METHOD: 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. RESULT: 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 linear = 0.0293 for 2-OH NAP and BW; P linear = 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. CONCLUSION: 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.


Assuntos
Poluentes Atmosféricos/efeitos adversos , Recém-Nascido de Baixo Peso , Exposição Materna/efeitos adversos , Naftalenos/efeitos adversos , Naftóis/urina , Gravidez/urina , Adulto , Encéfalo/efeitos dos fármacos , Encéfalo/crescimento & desenvolvimento , China , Monitoramento Ambiental , Feminino , Humanos , Recém-Nascido , Masculino , Troca Materno-Fetal , Adulto Jovem
17.
Adv Exp Med Biol ; 1091: 1-31, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30315446

RESUMO

Aluminum is a type of ubiquitously existing naturally and widely used metal in our world. It is combined with other elements and forms different compounds. In different pH and due to other conditions, it can be released into ions of different valence states. Our century is an "aluminum age"; aluminum is used in many fields of our daily life, such as vaccine adjuvant, antacids, food additives, skin care products, cosmetics, and cooking wares, and may be as elements or contaminants appeared in a lot of foods, including infant formulae, milk products, juice, wine, sea foods, and tea. It also appears in drinking water due to the water treatment process, or naturally coming from weathering rocks and soils, or released from rocks and soils caused by pollution-induced acid rain. Due to good physical and chemical property, aluminum is being tremendously utilized in many industries. In a lot of production and process procedures, aluminum particulates are seriously exposed by workers. Many factors, such as silicon, citrate, iron, calcium, fluoride, etc., can affect absorption of aluminum in human body. Human being ingests aluminum through the respiratory and digestive system and skin. Aluminum can affect our health, especially impair central nervous system. The important damage is cognitive impairment in Al-exposed peoples, Alzheimer's disease and other neurodegenerative disorders have been related with aluminum exposure, and aluminum has been proposed as etiology.


Assuntos
Alumínio/toxicidade , Doença de Alzheimer , Sistema Nervoso Central , Culinária , Humanos
18.
Front Pharmacol ; 9: 253, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29615914

RESUMO

Alumina nanoparticles (AlNP) have been shown to accumulate in organs and penetrate biological barriers which lead to toxic effects in many organ systems. However, it is not known whether AlNP exposure to female mice during pregnancy can affect the development of the central nervous system or induce neurodevelopmental toxicity in the offspring. The present study aims to examine the effect of AlNP on neurodevelopment and associated underlying mechanism. ICR strain adult female mice were randomly divided into four groups, which were treated with normal saline (control), 10 µm particle size of alumina (bulk-Al), and 50 and 13 nm AlNP during entire pregnancy period. Aluminum contents in the hippocampus of newborns were measured and neurodevelopmental behaviors were tracked in the offspring from birth to 1 month of age. Furthermore, oxidative stress and neurotransmitter levels were measured in the cerebral cortex of the adolescents. Our results showed that aluminum contents in the hippocampus of newborns in AlNP-treated groups were significantly higher than those in bulk-Al and controls. Moreover, the offspring delivered by AlNP-treated female mice displayed stunted neurodevelopmental behaviors. Finally, the offspring of AlNP-treated mice demonstrated significantly increased anxiety-like behavior with impaired learning and memory performance at 1 month of age. The underlying mechanism could be related to increased oxidative stress and decreased neurotransmitter levels in the cerebral cortex. We therefore conclude that AlNP exposure of female mice during pregnancy can induce neurodevelopmental toxicity in offspring.

19.
Toxicol Lett ; 291: 29-38, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29621559

RESUMO

Polybrominated diphenyl ether-153 (BDE-153) has been demonstrated to induce neuronal apoptosis in rat cerebral cortex and primary neurons. Neurotrophins and cholinergic enzymes play critical roles in the neuronal survival, maintenance, synaptic plasticity and learning memory, however, their roles in neuronal apoptosis following the BDE-153 treatment remain unclear. In this study, we firstly explored the possible predominant pathway underlying the neuronal apoptotic induced by the BDE-153 treatment in rat cerebral cortex, by measuring expression levels (mRNA and protein) of p53, caspase-3, 8, 9, calpain-1, and calpain-2, detected the levels (protein contents and mRNA) of neurotrophins including brain-derived neurotrophic factor (BDNF), glial-derived neurotrophic factor (GDNF), nerve growth factor (NGF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4), and measured acetylcholinesterase (AchE) and choline acetyltransferase (ChaT) activities in rat cerebral cortex and primary neurons following BDE-153 treatment with or without pretreatment with inhibitors. Results showed that the neuronal apoptosis induced by BDE-153 was dependent on p53, and dependent on more calpain-2 than caspase-3 in the cerebral cortex of rats. Following the BDE-153 treatment, the protein contents and mRNA levels of BDNF, GDNF, NGF, NT-3, and NT-4, as well as the AchE and ChaT activities were significantly decreased in the cerebral cortex and primary neurons when compared to the untreated group. When pretreated primary neurons with calpain inhibitor PD150606 or cyclin-dependent kinase (cdk5, the downstream complex of calpain) inhibitor Roscovitine, the neurotrophins contents and activities of ChaT and AchE were reverted, along with the improvement of neuron survival compared with BDE-153 treatment alone. We conclude that neurotrophins and cholinergic enzymes were regulated by the calpain-2 activation and its downstream cdk5 pathway, and which was involved in the neuronal apoptosis induced by the BDE-153 treatment.


Assuntos
Acetilcolinesterase/metabolismo , Apoptose/efeitos dos fármacos , Calpaína/fisiologia , Colina O-Acetiltransferase/metabolismo , Fatores de Crescimento Neural/farmacologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Bifenil Polibromatos/toxicidade , Animais , Córtex Cerebral/citologia , Córtex Cerebral/efeitos dos fármacos , Quinase 5 Dependente de Ciclina/metabolismo , Feminino , Proteínas do Tecido Nervoso/biossíntese , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Ratos , Ratos Sprague-Dawley , Transdução de Sinais
20.
Neurotox Res ; 34(2): 220-232, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29460113

RESUMO

Aluminum (Al) is an environmental neurotoxicant with a wide exposure, but the molecular mechanism underlying its toxicity remains unclear. We used RNA sequencing (RNA-seq) in the hippocampus of Al-treated rats to identify 96 upregulated and 652 downregulated mRNAs, and 37 dysregulated long non-coding (lnc)RNAs. Gene ontology analysis showed that dysregulated genes were involved in glial cell differentiation, neural transmission, and vesicle trafficking. Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed clustering of differentially expressed mRNAs and lncRNA target genes in several pathways, including the "adenosine monophosphate-activated protein kinase signaling pathway," "extracellular matrix receptor interaction," "the phosphatidylinositol 3 kinase-protein kinase B signaling pathway," and "focal adhesion" signaling pathway. RNA-seq results were validated by reverse transcription (RT)-PCR. Additionally, Al induced changes to the number and morphology of glial cells in the hippocampus of rats, as shown by glial fibrillary acidic protein (GFAP) and ionized calcium binding adaptor molecule 1 (Iba1) immunochemistry. RT-PCR and western blotting validated the significant increase in expression of glial cell-related genes GFAP and SOX10 following Al exposure compared with control rats, consistent with RNA-seq results. Collectively, these results suggest that aberrant mRNAs and lncRNAs respond to Al neurotoxicity, and that glial cell-related genes play important roles in the Al neurotoxicity mechanism. These findings provide the basis for designing targeted approaches for the treatment or prevention of Al-induced neurotoxicity.


Assuntos
Alumínio/farmacologia , Hipocampo/metabolismo , RNA Longo não Codificante/metabolismo , Transcriptoma/efeitos dos fármacos , Animais , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Eritropoetina/genética , Eritropoetina/metabolismo , Ontologia Genética , Hipocampo/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/metabolismo , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Neuroglia/efeitos dos fármacos , Neuroglia/metabolismo , Peptídeos Cíclicos/genética , Peptídeos Cíclicos/metabolismo , RNA Longo não Codificante/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Tempo de Reação/efeitos dos fármacos
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