RESUMO
The neurotoxicity of bisphenol A (BPA) exposure has been confirmed in vitro and in vivo, and inflammatory response is considered the main pathway. Green tea is a healthy life habit as it is rich in various anti-inflammatory components. To confirm that green tea diet is an effective measure to antagonize BPA-induced neurotoxicity, mice were treated with 0.5 and 5000 µg/kg/day of BPA from postnatal days (PNDs) 10-50 and supplemented with green tea on PND 21. From PND 51, behavioral tests were conducted on mice to assess their emotional, cognitive, and spatial learning memory capabilities. The open field test and elevated plus maze test indicated anxiety-like behaviors induced by BPA. Interestingly, green tea diet significantly alleviated BPA-induced anxiety-like behaviors. Meanwhile, the green tea diet effectively reversed BPA-induced microglia activation and morphological changes in the hippocampus of mice. Molecularly, green tea inhibited hippocampal neuroinflammation of mice by reducing BPA-induced expressions of NLRP3, ASC, cleaved-caspase-1, GSDMD-N, IL-6, and IL-1ß, as well as significantly reducing the expression of Bak1, Bax, caspase-9, and Cytc c genes (p < 0.05). Molecular docking suggests that various anti-inflammatory components of green tea can competitively bind to the estrogen receptors with BPA. In general, a green tea diet alleviates BPA-induced emotional disorders by inhibiting microglial polarization and hippocampal pyroptosis, indicating its effective antagonistic ability against the neurotoxicity induced by environmental BPA exposure.
RESUMO
Epidemiological studies have suggested a correlation between bisphenol A (BPA) and type 2 diabetes (T2DM). The effects of BPA on ß-cell dysfunction may reveal the risks from an in vitro perspective. We used the rat insulinoma (INS-1) cell lines (a type of ß-cells) to set up normal or damaged models (DM), which were exposed to various concentrations of BPA (0.001, 0.01, 0.1, 1, 10 and 100 µM). An increase in reactive oxygen species (ROS) and apoptosis, and a decrease in cell viability were observed in INS-1 cells exposed to high doses of BPA for 48 h. Interestingly, exposure to lower doses of BPA for 24 h resulted in increased ROS levels and apoptosis rates in INS-1 in the DM group, along with decreased cell viability, suggesting that BPA exerts toxicity to INS-1 cells, particularly to the DM group. Insulin levels and Glut2 expression, glucose consumption, intracellular Ca2+ and insulin secretion were increased in INS-1 cells after 48 h exposure to high dose of BPA. Stronger effects were observed in the DM group, even those exposed to low doses of BPA for 24 h. Moreover, BPA inhibited high glucose-stimulated insulin secretion in these cells. Our research suggests that low doses of BPA exacerbate the dysfunction caused by glucolipotoxicity, implying environmental BPA exposure poses a risk for individuals with prediabetes or T2DM.
Assuntos
Apoptose , Compostos Benzidrílicos , Sobrevivência Celular , Diabetes Mellitus Tipo 2 , Transportador de Glucose Tipo 2 , Glucose , Insulina , Insulinoma , Fenóis , Espécies Reativas de Oxigênio , Fenóis/toxicidade , Compostos Benzidrílicos/toxicidade , Animais , Ratos , Diabetes Mellitus Tipo 2/induzido quimicamente , Linhagem Celular Tumoral , Espécies Reativas de Oxigênio/metabolismo , Glucose/metabolismo , Glucose/toxicidade , Insulinoma/metabolismo , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Insulina/metabolismo , Transportador de Glucose Tipo 2/metabolismo , Cálcio/metabolismo , Poluentes Ambientais/toxicidade , Secreção de Insulina/efeitos dos fármacos , Neoplasias Pancreáticas/induzido quimicamenteRESUMO
Polycyclic aromatic hydrocarbons (PAHs) exposure is related to the occurrence of cardiovascular diseases (CVDs). Endothelial dysfunction is considered an initial event of CVDs. To confirm the relationship of PAHs exposure with endothelial dysfunction, 8-week-old male SD rats and primary human umbilical vein endothelial cells (HUVECs) were co-treated with environmental doses of 16 priority-controlled PAHs for 90 d and 48 h, respectively. Results showed that 10× PAHs exposure remarkably raised tumor necrosis factor-α and malonaldehyde levels in rat serum (p < 0.05), but had no effects on interleukin-8 levels and superoxide dismutase activity. The expressions of SIRT1 in HUVECs and rat aorta were attenuated after PAHs treatment. Interestingly, PAHs exposure did not activate the expression of total endothelial nitric oxide synthase (eNOS), but 10× PAHs exposure significantly elevated the expression of phosphorylated eNOS (Ser1177) in HUVECs and repressed it in aortas, accompanied with raised nitrite level both in serum and HUVECs by 48.50-253.70 %. PAHs exposure also led to the augment of endothelin-1 (ET-1) levels by 19.76-38.54 %, angiotensin (Ang II) levels by 20.09-39.69 % in HUVECs, but had no effects on ET-1 and Ang II levels in serum. Additionally, PAHs exposure improved endocan levels both in HUVECs and serum by 305.05-620.48 % and stimulated the THP-1 cells adhered to HUVECs (p < 0.05). After PAHs treatment, the smooth muscle alignment was disordered and the vascular smooth muscle locally proliferated in rat aorta. Notably, the systolic blood pressure of rats exposed to 10× PAHs increased significantly compared with the control ones (131.28 ± 5.20 vs 116.75 ± 5.33 mmHg). In summary, environmental chronic PAHs exposure may result in endothelial dysfunction in SD rats and primary HUVECs. Our research can confirm the cardiovascular damage caused by chronic exposure to PAHs and provide ideas for the prevention or intervention of CVDs affected by environmental factors.
Assuntos
Hidrocarbonetos Policíclicos Aromáticos , Masculino , Humanos , Ratos , Animais , Hidrocarbonetos Policíclicos Aromáticos/toxicidade , Hidrocarbonetos Policíclicos Aromáticos/metabolismo , Ratos Sprague-Dawley , Células Endoteliais da Veia Umbilical Humana , Pressão Sanguínea , Óxido Nítrico/metabolismoRESUMO
The Beijiang River, one of the Pearl River tributaries located in Guangdong, China, plays a critical role in providing water and fishery resources for the Pearl River Delta and receiving a large amount of domestic and industrial wastewater. However, due to the lack of historical monitoring data, we are unable to fully understand the relationship between the industrial and agricultural development and the environment. In this study, fish specimens collected from the Beijiang River Basin over a span of nearly 60 years (1963-2021) are used as research objects and the concentrations of ten trace metals (TMs) in two locally dominant fish species were determined by an inductively coupled plasma mass spectrometer. The human health risks caused by consuming fishes were assessed. Results show a correlation between the levels of TMs in fish muscle and the degree of industrialization. The concentrations of Cr, Mn, Ni, and Cu peaked during the period of 1981-1983, when China's industrial development was rapidly expanding while the environmental protection facilities were incomplete. However, with the implementation of Ecological Civilization policy, the levels of Cr, Mn, Ni, Cu, Cd, and Ba showed a downward trend in the period from 2018 to 2021. Cu concentrations in both fish muscle and viscera exhibit analogous change patterns across different periods, indicating that Cu serves as a significant indicator of TM pollution in the Beijiang River Basin. The presence of TMs in fish muscle often exhibits long-term enrichment, while those in the viscera demonstrate short-term accumulation. Based on the estimated daily intake, the target hazard quotient (THQ), and total THQ value, the overall health risk associated with TMs in fish from the Beijiang River Basin is low. However, certain TMs in the fish rebounded during 2018-2021, posing a potential risk for aquatic biology and ecosystems, which is worth our attention.
Assuntos
Metais Pesados , Oligoelementos , Poluentes Químicos da Água , Animais , Humanos , Rios , Metais Pesados/análise , Monitoramento Ambiental/métodos , Seguimentos , Ecossistema , Peixes , Medição de Risco , China , Oligoelementos/análise , Poluentes Químicos da Água/análiseRESUMO
Bisphenols (BPs) can negatively affect neurobehaviors in rats, whereas the mechanism remains unclear. Here, the mechanism of BPs-induced neurodevelopmental toxicity and its effective detoxification measures were investigated in vitro and in vivo. In in vitro experiments, primary hippocampal neurons from neonatal rats of different genders were treated with bisphenol A (BPA), bisphenol S (BPS) and bisphenol B (BPB) at 1 nM-100 µM, epigallocatechin gallate (EGCG) and G15, an antagonist of G protein-coupled estrogen receptor (GPER) for 7 d. Results indicated that BPs affected neuronal morphogenesis, impaired GABA synthesis and Glu/GABA homeostasis. Neuronal morphogenetic damage induced by low-doses BPA may be mediated by GPER. Neurotoxicity of BPS is weaker than BPA and BPB. In in vivo studies, exposure to BPA (0.5 µg/kg·bw/day) on PND 10-40 caused oxidative stress and inflammation in rat hippocampus, disrupted neuronal morphogenesis and neurotransmitter homeostasis, ultimately impaired spatial memory of rats. Males are more sensitive to BPA exposure than females. Both in vivo and in vitro studies indicated that EGCG, a phytoestrogen, can alleviate BPA-induced neurotoxicity. Taken together, low-doses BPA exposure sex-specifically disrupted neurodevelopment and further impaired learning and memory ability in rats, which may be mediated by GPER. Promisingly, EGCG effectively mitigated the BPA-induced neurodevelopmental toxicity.
Assuntos
Compostos Benzidrílicos , Estresse Oxidativo , Ratos , Masculino , Feminino , Animais , Compostos Benzidrílicos/toxicidade , Estrogênios/farmacologia , Ácido gama-AminobutíricoRESUMO
To rapidly assess the toxicity of bisphenols (BPs) via the activation of G protein-coupled estrogen receptor (GPER), eight BPs action on GPER were evaluated by molecular docking and molecular dynamics (MD) simulation and then confirmed with IMR-32 cells. The target BPs significantly promoted the production of reactive oxygen species (ROS), reduced cell viability, activated the expression of apoptosis-related proteins and increased the apoptosis rate of IMR-32 cells. Intracellular Ca2+ level increased significantly after the treatments with bisphenol A (BPA), bisphenol E (BPE), bisphenol C (BPC) and bisphenol AP (BPAP), suggesting the activation of GPER. Moreover, the stable binding conformations between GPER and BPA, BPE, BPC and BPAP and their dynamic changes of GPER-BPs via MD simulation also suggest that these BPs may activate GPER. The interaction between bisphenol G/bisphenol P/bisphenol PH and GPER are weak, which is consistent with their low GPER activity in vitro. Notably, after the pretreatment of GPER antagonist, Ca2+ accumulation and ROS production induced by BPA, BPE, BPC and BPAP in IMR-32 cells were attenuated. Overall, MD simulation and in vitro results mutually verified the activation of GPER by BPs, and MD simulation can rapidly evaluate the neurocytotoxicity of BPs.
Assuntos
Compostos Benzidrílicos , Receptores de Estrogênio , Compostos Benzidrílicos/toxicidade , Estrogênios/metabolismo , Simulação de Acoplamento Molecular , Espécies Reativas de Oxigênio , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Estrogênio/metabolismoRESUMO
Bisphenol A (BPA) induces neurotoxicity via enhancing cell apoptosis and inflammation potently (effective at nanomolar concentrations), but its mechanisms remain unidentified. In this study, human neuroblastoma cell lines, IMR-32 and SK-N-SH cells, isolated from a male and a female subject, respectively, were exposed to BPA at various concentrations, with epigallocatechin gallate (EGCG, an antioxidant from green tea), Z-YVAD-FMK (a caspase-1 inhibitor), and ICI182.780 [an estrogen receptor (ER) inhibitor] as modulators. The results showed that BPA increased the mRNA levels of IL-18, ASC, GSDMD and protein levels of NLRP3, caspase-1 and GSDMD in both cell lines in a nonlinear manner. Noticeably, the direction of changes in the mRNA levels of caspase-1 and IL-1ß were opposite, so did each of them in different cell lines: caspase-1 was enhanced in IMR-32 cells but suppressed in SK-N-SH cells, while IL-1ß was suppressed in IMR-32 cells but enhanced in SK-N-SH cells. The level of GSDMD in situ increased along with the leakage of IL-1ß, IL-18, caspase-1 and lactate dehydrogenase (LDH). Moreover, all the above effects of BPA were reversed by Z-YVAD-FMK, ICI182.780, and EGCG. Besides, BPA significantly increased reactive oxygen species production, LDH leakage and apoptosis, with reduced cell viability and mitochondrial membrane potential, in both cell lines, whereas Z-YVAD-FMK and ICI182.780 significantly alleviated the induction of Bak1, Bax, Bcl-2 and caspase-3 proteins by BPA. In summary, BPA may induce pyroptosis in neuroblastoma cells through NLRP3/caspase-1/GSDMD pathway, as mediated by ER; caspase-1-dependent pyroptosis may also contribute to BPA-induced apoptosis, an effect alleviated by EGCG.
Assuntos
Neuroblastoma , Piroptose , Apoptose , Compostos Benzidrílicos , Caspase 1/metabolismo , Feminino , Humanos , Inflamassomos/metabolismo , Interleucina-18 , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Masculino , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Fenóis , Proteínas de Ligação a Fosfato/metabolismo , Proteínas Citotóxicas Formadoras de Poros , RNA MensageiroRESUMO
Epidemiological studies have shown that cardiovascular diseases caused by PM2.5 pollution account for the second death rate in China. Polycyclic aromatic hydrocarbons (PAHs) are one important group of persistent organic pollutants absorbed on PM2.5. Though individual PAH is related to vascular disease, the relationship between environmental PAHs exposure and vascular damages is still unclear. To explore the effect of PAHs on blood vessel, human umbilical vein endothelial cells (HUVECs) are treated with 16 priority-controlled PAHs at various concentrations to study their cytotoxicity and morphological alteration. Results showed that, after 48 h treatment, PAHs mixture generally attenuated the ability of wound healing, transwell migration and tube formation of HUVECs (p < 0.01) except for 1 × PAHs in transwell migration. Moreover, PAHs increased the levels of ROS and 8-hydroxy-2'-deoxyguanosine (p < 0.05), indicating that it exceeded the scavenging ability of superoxide dismutase activity. However, PAHs mixture did not increase apoptosis rate, which may be attribute to the difference of PAH concentration and composition between this study and previous reports. Downstream signaling cascades significantly and generally upregulated the relative expression of proteins in Nrf2/HO-1 and NF-ÆB/TNF-α pathway with the activation of oxidative stress, including HO-, TNF-α and Nrf2. In summary, this study suggests that environmental mixture of 16 priority-controlled PAHs can induce the damages of vascular endothelial cells involved in cellular oxidative stress and inflammation.
Assuntos
Células Endoteliais/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Hidrocarbonetos Policíclicos Aromáticos/toxicidade , 8-Hidroxi-2'-Desoxiguanosina/metabolismo , Poluentes Atmosféricos/toxicidade , Apoptose/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana , Humanos , Inflamação , Espécies Reativas de Oxigênio/metabolismoRESUMO
Although humans are generally exposed to second-hand smoke (SHS), volatile organic compounds (VOCs) exposure derived from SHS and its health hazard to non-smokers are rarely investigated. Thus, we examined the effects of SHS on VOCs exposure and oxidative stress damage via a passive smoking simulation experiment in 6 children and 7 adults. To further validate the studied urinary VOC metabolites as biomarkers for passive smoking, 259 children were recruited. The levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG), malonaldehyde (MDA), trans-3'-hydroxycotinine (OH-Cot) and 31 VOC metabolites in urine were determined. The results showed that the geomean concentrations of 17 VOC metabolites in urine of children were 26.5%-138% higher than those of adults after passive smoking. The levels of urinary 8-OHdG, MDA and OH-Cot increased by 24.6%, 18.8% and 600% in children, but only 1.25%, 10.3% and 116% in adults, respectively. Therefore, children are more vulnerable to SHS than adults. After exposure to SHS, the levels of 8 urinary VOC metabolites of benzene, acrylonitrile, 1-bromopropane, propylene oxide, toluene, methyl methacrylate and cyanide increased by 60.9%-538% within 23 h. These 8 VOC metabolites were also significantly associated with 8-OHdG or MDA in urine (p < 0.01). Therefore, exposure to VOCs caused by SHS increases body oxidative stress damage. OH-Cot level higher than 2.00 µg/g Cr can be used as a threshold of passive smoking. The levels of urinary s-benzylmercapturic acid (BMA) and s-phenylmercapturic acid (PMA) in children increased by 494% and 728% within 6 h after passive smoking, respectively. Population validation study indicated that BMA and PMA levels were significantly elevated in children exposed to SHS. Therefore, in addition to OH-Cot, urinary BMA and PMA are potentially useful short-term biomarkers of passive smoking. Future studies should focus on the differences in VOC metabolism and detoxification mechanisms between children and adults.
Assuntos
Poluição por Fumaça de Tabaco , Compostos Orgânicos Voláteis , 8-Hidroxi-2'-Desoxiguanosina , Adulto , Biomarcadores/urina , Criança , Humanos , Estresse Oxidativo , Poluição por Fumaça de Tabaco/efeitos adversos , Poluição por Fumaça de Tabaco/análiseRESUMO
The ban of some antibacterial ingredients, such as triclosan (TCS) and triclocarban (TCC), in personal care products (PCPs) in some countries (but not in China) has resulted in the increasing use of antibacterial alternatives, such as chloroxylenol (PCMX). However, the underlying human health risks and environmental impacts of PCMX exposure are largely unknown. Thus, the distribution characteristics of PCMX in PCPs and susceptible populations and the major routes and health risks of human exposure to PCMX were investigated. The PCMX, TCS, and TCC concentrations in PCPs, urine, drinking water, and surface water were determined using high-performance liquid chromatograph system equipped with diode array detector or triple quadrupole mass spectrometer. Results showed that PCMX is widely used in antibacterial hand sanitizers and household disinfectants in China. The addition of PCMX as an antibacterial ingredient in PCPs showed an increasing trend. The geomean concentrations of urinary PCMX in children and pregnant women were 21.6 and 31.9 µg·L-1, respectively, which were much higher than TCS and TCC. A considerable concentration of PCMX ranging from 1.62 to 9.57 µg·L-1 was observed in the aquatic environment, suggesting a potential massive-use of PCMX by humans. Human PCMX exposure via drinking was negligible because the PCMX concentrations in drinking water were less than 2.00 ng·L-1. During human simulation experiment, we found that dermal contact was the dominant route of human PCMX exposure, accounting for 92.1% of the urinary PCMX concentration. The estimated daily intake of PCMX in 9.68% of children and 5.66% of pregnant women was higher than the reference dose. However, the urinary 8-hydroxy-2'-deoxyguanosine concentrations remained stable despite the elevated PCMX concentrations, thereby suggesting that daily PCMX exposure may not cause oxidative DNA damage in humans. Nevertheless, the potential ecotoxicity and health risks induced by chronic PCMX exposure cannot be ignored because of its increasing use.
Assuntos
Carbanilidas , Cosméticos , Triclosan , Antibacterianos , Carbanilidas/análise , Criança , China , Feminino , Humanos , Gravidez , Medição de Risco , Triclosan/análise , Triclosan/toxicidade , XilenosRESUMO
Volatile organic compounds (VOCs) are important and ubiquitous air pollutants, which may lead to a significant increase in the prevalence of respiratory diseases. To investigate the relationships between VOCs exposure and childhood asthma, 252 asthmatic children and 69 healthy children were recruited. Urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG, a biomarker of oxidative DNA damage), trans-3'-hydroxycotinine (OH-Cot, a biomarker of passive smoking) and 27 VOC metabolites were simultaneously determined by an ultra-high-performance liquid chromatography-tandem mass spectrometer. Results showed that levels of 8-OHdG and most VOC metabolites in asthmatic children were significantly higher than those in healthy children. More than half of the VOC metabolites were significantly and positively associated with OH-Cot with maximal ß coefficient of 0.169, suggesting that second-hand smoking is one important source of VOCs exposure for children in Guangzhou. Significant dose-response relationships between most VOC metabolites and 8-OHdG were observed. Each unit increase in ln-transformed VOC metabolite levels was significantly associated with 5.5-32% increase in ln-transformed 8-OHdG level. Moreover, each unit increase in ln-transformed 8-OHdG level was associated with an 896% increased odd ratios (OR) of asthma in children (OR = 9.96, 95% confidence intervals (CI): 4.75, 20.9), indicating that oxidative stress induced by VOCs exposure may have a significant impact on childhood asthma. Urinary 3-&4-Methylhippuric acid (3-&4-MHA, OR: 5.78, 95% CI: 3.50, 9.54), rac 2-Aminothiazoline-4-carboxylic acid (ATCA, OR: 2.90, 95% CI: 1.69, 4.99) and N-Acetyl-S-(3,4-dihydroxybutyl)-L-cysteine (DHBMA, OR: 2.76, 95% CI: 1.73, 4.43) which may derive from m/p-xylene, cyanide and 1,3-butadiene exposure, respectively, could significantly and maximally increase the odds of asthma. Interestingly, they also had the strongest associations with 8-OHdG among all investigated VOC metabolites. Moreover, DHBMA strongly correlated with most VOC metabolites. Hence, DHBMA is a suitable biomarker to indicate not only VOCs exposure profile, but also the DNA damage-mediated asthma induced by VOCs.
Assuntos
Asma/urina , Poluentes Ambientais/urina , Estresse Oxidativo , Poluição por Fumaça de Tabaco/efeitos adversos , Compostos Orgânicos Voláteis/urina , 8-Hidroxi-2'-Desoxiguanosina/urina , Asma/epidemiologia , Monitoramento Biológico , Biomarcadores/urina , Criança , China/epidemiologia , Cotinina/análogos & derivados , Cotinina/urina , Poluentes Ambientais/metabolismo , Feminino , Humanos , Masculino , Compostos Orgânicos Voláteis/metabolismoRESUMO
Exposure to benzo[a]pyrene (B[a]P) may be a risk factor for pulmonary diseases. To investigate the correlations among B[a]P exposure level, DNA strand breaks and pulmonary inflammation, we recruited 83 children diagnosed with pulmonary diseases and 63 healthy children from Guangzhou, China. Results showed that the levels of Benzo[a]pyrene diol epoxide (BPDE) DNA adduct in blood and IL-8 in serum in case group were significantly higher than those in control group (p < 0.01). Moreover, levels of atmospheric B[a]P in case group was about twice of those in control group, which was consistent with the levels of BPDE-DNA adduct in blood. Significant positive correlations were observed among the levels of BPDE-DNA adduct, IL-8 and DNA strand breaks (p < 0.05). Our findings indicate that environmental air is an important exposure source of B[a]P and higher B[a]P exposure may contribute to the occurrence of pulmonary inflammation and lead to high health risks.
Assuntos
Adutos de DNA/sangue , Interleucina-8/sangue , Pneumopatias/sangue , 7,8-Di-Hidro-7,8-Di-Hidroxibenzo(a)pireno 9,10-óxido , Adolescente , Poluentes Atmosféricos/análise , Poluentes Atmosféricos/urina , Monitoramento Biológico , Criança , Pré-Escolar , China , Ensaio Cometa , Quebras de DNA , Feminino , Humanos , Pneumopatias/genética , Linfócitos , Masculino , Hidrocarbonetos Policíclicos Aromáticos/análise , Hidrocarbonetos Policíclicos Aromáticos/urina , Medição de RiscoRESUMO
The analogues of biphenol A (BPA), including bisphenol S (BPS) and bisphenol B (BPB), are commonly used to replace the application of BPA in containers and wrappers of daily life. However, their safeties are questioned due to their similar chemical structure and possible physiological effects as BPA. To investigate the neurotoxic effects of BPA, BPS, and BPB as well as their underlying mechanism, IMR-32 cell line from male and SK-N-SH cell line from female were exposed respectively to BPA, BPS and BPB with concentrations of 1 nM, 10 nM, 100 nM, 1 µM, 10 µM, and 100 µM for 24 h. Additionally, 24 h exposure of BPA combining epigallocatechin gallate (EGCG) (4 µM and 8 µM for IMR-32 and SK-N-SH respectively) were conducted. Results demonstrated that BPs exposure could promote reactive oxygen species production and increase level of malondialdehyde (MDA) while decrease levels of superoxide dismutase (SOD). Intensive study revealed that after exposure to BPA mitochondrial membrane potential (MMP) dropped down and the protein expression levels of Bak-1, Bax, cytochrome c and Caspase-3 were up-regulated but Bcl-2 were down-regulated significantly. Moreover, apoptosis rate was raised and cell activity declined remarkably in the neuroblastoma cells. All the effects induced by BPA could be alleviated by the adding of EGCG, which similar alleviations could be inferred in IMR-32 and SK-N-SH cells induced by BPS and BPB. Furthermore, BPS showed lower neurotoxic effects compared to BPA and BPB. Interestingly, the neurotoxic effects of BPA on IMR-32 cells were significantly higher than those on SK-N-SH cells. In conclusion, the results suggested that BPA, BPS and BPB could induce oxidative stress and apoptosis via mitochondrial pathway in the neuroblastoma cells and male is more susceptible to BPs than female.
Assuntos
Apoptose/efeitos dos fármacos , Compostos Benzidrílicos/toxicidade , Disruptores Endócrinos/toxicidade , Mitocôndrias/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Fenóis/toxicidade , Sulfonas/toxicidade , Caspase 3/metabolismo , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Caracteres SexuaisRESUMO
BPA analogs, including bisphenol S (BPS) and bisphenol B (BPB), have been used to replace BPA since it was banned to be added. To investigate whether BPA and its analogs cause oxidative damage effects on primary hippocampal neurons of rats, reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase (SOD), mitochondrial membrane potential (MMP), apoptosis and cell viability assays were conducted after hippocampal neurons exposure to different concentrations of BPA, BPS, and BPB (1, 10, 100 nM and 1, 10, 100 µM). Moreover, the effects of EGCG (5 and 6 µM for male and female, respectively) added on neurons exposed to BPA were assessed. Results showed that 24 h exposure to these bisphenols (BPs) could increase the levels of ROS and contents of MDA, but reduce the activity of SOD significantly. A decline of cell viabilities accompanied with the increasing of apoptosis rates was observed after 7 d exposure to BPs and the reduction of MMP was also observed after 7 d exposure to BPA. Interestingly, BPS has the lower toxicity to hippocampal neurons compared with BPA and BPB. Non-monotonic dose-effect relationships between the concentrations of BPs and the cytotoxic effects were observed, and the effects of BPs on male hippocampal neurons are greater than those of female ones in general. While EGCG can protect neurons free of oxidative damages. In conclusion, the results suggest that BPs may induce sex-specific neurotoxic effects involving oxidative stress, which can be attenuated by EGCG, and males are more sensitive to BPs than females.
Assuntos
Compostos Benzidrílicos , Estresse Oxidativo , Animais , Compostos Benzidrílicos/toxicidade , Feminino , Hipocampo , Masculino , Potencial da Membrana Mitocondrial , Neurônios , Ratos , Espécies Reativas de OxigênioRESUMO
As previous studies found that the direct associations between urinary polycyclic aromatic hydrocarbon (PAH), benzene and toluene (BT) metabolites and the decreased lung function were not conclusive, we further investigated relationship of oxidative damage and airway inflammation induced by PAHs and BTs exposure with lung function. A total of 262 children diagnosed with asthma and 72 heathy children were recruited. Results showed that asthmatic children had higher levels of PAHs and BTs exposure, as well as Malonaldehyde (MDA) and 8-hydroxy-2'-deoxyguanosine (8-OHdG) compared with healthy children. Furthermore, binary logistic regression showed that each unit increases in level of urinary 2-&3-hydroxyfluorene (2-&3-OHF), 2-hydroxyphenanthrene (2-OHPhe), 1-hydroxyphenanthrene (1-OHP) and S-phenylmercapturic acid (S-PMA) were significantly associated with an elevated risk of asthma in children with odds ratios of 1.5, 2.3, 1.7 and 1.4, respectively, suggesting that PAHs and BTs exposure could increase the risk of asthma for children. Neither PAH nor BT metabolite could comprehensively indicate the decreased lung function as only 2-&3-OHF and 1-OHP were significantly and negatively correlated with forced vital capacity (FVC). Moreover, levels of most individual PAH and BT metabolite were significantly correlated to MDA and 8-OHdG. Further hierarchical regression analysis indicated that MDA and 8-OHdG levels did not show significant effects on the decreased lung function, suggesting that they are not the suitable biomarkers to indirectly indicate the altered lung function induced by PAHs and BTs. Urinary 2-OHPhe and 1-&9-hydroxyphenanthrene (1-&9-OHPhe) were significantly correlated with fractional exhaled nitric oxide (FeNO). Moreover, FeNO significantly contributed to decreased lung function and explained 7.7% of variance in ratio of forced expiratory volume in 1 s (FEV1) and FVC (FEV1/FVC%). Hence, FeNO, rather than oxidative damage indicators or any urinary PAH and BT metabolite, is more sensitive to indirectly reflect the decreased lung function induced by PAHs and BTs exposure for asthmatic children.
Assuntos
Asma , Hidrocarbonetos Policíclicos Aromáticos , Benzeno , Biomarcadores , Criança , Humanos , Inflamação , Estresse Oxidativo , ToluenoRESUMO
Attention deficit hyperactivity disorder (ADHD) is associated with heavy metal exposure during adolescent development. However, the direct clinical evidence is limited. To investigate the possible association between environmental heavy metal exposure and ADHD, a case-control study was conducted with children aged 6-14 years in Guangzhou, China. Results showed that median concentrations of chromium (Cr), manganese (Mn), cobalt (Co), nickel (Ni), copper (Cu), molybdenum (Mo), tin (Sn), barium (Ba), and lead (Pb) in the urine of the case group were significantly higher than those of the control group. Children with ADHD had significantly higher levels of 8-OHdG and MDA compared with those from the control group. In addition, correlations between urinary Co, Ni, Cu, Mo, and Sn were significantly correlated with 8-OHdG and MDA concentrations in urine. After the case and control groups were combined together and the first quartile was used as the reference category, odds ratios (ORs) of ADHD for children increased significantly with the quartile increasing of urinary Co, Cu, and Sn. Our study provides a clinical evidence that Co, Cu, and Sn exposure, particularly Sn exposure, may be an environmental risk of the incurrence of ADHD for children. Furthermore, Co, Ni, Cu, Mo, and Sn exposures were significantly correlated with DNA and lipid damage.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Metais Pesados/análise , Adolescente , Estudos de Casos e Controles , Criança , China , Monitoramento Ambiental , Humanos , ManganêsRESUMO
Humans from fetal to adult stages are chronically and passively exposed to bisphenol A (BPA, an endocrine disruptor) due to its ubiquitous existence in daily life. To investigate the long-term neurotoxicity of maternal exposure to BPA for offspring, mice were used as the animal model. In this study, pregnant mice (F0) were orally dosed with BPA (i.e. mice from low-, medium- and high-exposed groups were treated with 0.5, 50, 5000 µg/kg·bw of BPA per day) until weaning. Then, the first generation (F1) mice were used to generate the F2 ones. The offspring of mice not exposed to BPA served as the control groups. The Y-maze test, comet assay, hematoxylin-eosin (HE) staining method, Golgi-Cox assay and liquid chromatography-tandem mass spectrometry (LC/MS/MS) were conducted to study any alterations to learning and memory abilities, the morphological variations in hippocampal neurons and transmitter levels of F1 and F2 mice induced by BPA exposure. Results showed that even a low-dose of maternal BPA exposure could sex-dependently and significantly impair the learning and memory ability of F1 male mice, but not of generation F2. Furthermore, decreased neuron quantities and spine densities in hippocampi were observed in both F1 and F2 generations after maternal BPA exposure. However, DNA damage of brain cells were only limited to F1 offspring, in which DNA damage was only observed in the low-exposed male mice and medium-exposed female mice. Additionally, maternal BPA exposure leads to variations in hippocampal neurotransmitter levels, indicated by the decreased ratio of Glu/GABA in F1 offspring. In conclusion, maternal exposure to an environmental dose of BPA resulted in lasting adverse effects on neurological development for offspring mice.
Assuntos
Compostos Benzidrílicos/toxicidade , Disruptores Endócrinos/toxicidade , Hipocampo/efeitos dos fármacos , Exposição Materna/efeitos adversos , Neurônios/efeitos dos fármacos , Síndromes Neurotóxicas/patologia , Síndromes Neurotóxicas/psicologia , Fenóis/toxicidade , Animais , Ensaio Cometa , Dano ao DNA , Espinhas Dendríticas/efeitos dos fármacos , Espinhas Dendríticas/patologia , Feminino , Hipocampo/metabolismo , Hipocampo/patologia , Aprendizagem/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Camundongos , Neurônios/metabolismo , Neurotransmissores/metabolismo , Gravidez , Caracteres SexuaisRESUMO
Human beings are inevitably exposed to volatile organic compounds (VOCs) of anthropogenic emissions as they are ubiquitous atmospheric pollutants. Smoking is an important exposure route of VOCs for the general population. Health effects induced by VOC exposure raise more concerns as they are identified with carcinogenicity, genotoxicity, neurotoxicity, and reproductive toxicity. trans-3'-Hydroxycotinine (OH-Cot) is a urinary biomarker of smoking, and 8-hydroxy-2'-deoxyguanosine (8-OHDG) is a urinary biomarker of DNA oxidative damage. To develop a method for quantifying VOC exposure levels of the general population and assessing the health risks induced by VOCs from second-hand smoking, an effective, rapid, and high-throughput method for the simultaneous determination of 31 metabolites of VOCs, 8-OHDG, and OH-Cot using solid-phase extraction coupled with UPLC-MS/MS was developed and validated. Method precision and accuracy, extraction recoveries, matrix effects, and storage stabilities of most analytes met the criterion (80-120%). Extraction recoveries increased from 85.1 to 100% after adjustment by isotoped internal standards (ISs). Furthermore, 13C- and 15N-labeled ISs were more effective to reduce the influence of matrix effects on recoveries and precisions than the deuterated analogs (73.0-116% vs. 53.6-140%). This developed method was successfully applied to determine urine samples collected from children. Results showed that N-acetyl-S-(3,4-dihydrobutyl)-L-cysteine, 2,2'-thiodiacetic acid (TGA), and N-acetyl-S-(3-hydroxypropyl-1-methyl)-L-cysteine (HPMMA) were well correlated with 8-OHDG with coefficients higher than 0.82, indicating those VOCs might easily lead to DNA damage. In conclusion, our co-monitoring of metabolites of VOCs with 8-OHDG and OH-Cot in one method provides a robust analytical method, which not only suggests the potential adverse health effects induced by VOCs but also discriminates and evaluates the contribution of passive smoking in human VOC exposure. Graphical abstract.
Assuntos
8-Hidroxi-2'-Desoxiguanosina/urina , Cromatografia Líquida/métodos , Cotinina/análogos & derivados , Espectrometria de Massas em Tandem/métodos , Compostos Orgânicos Voláteis/urina , 8-Hidroxi-2'-Desoxiguanosina/normas , Estudos de Casos e Controles , Cotinina/normas , Cotinina/urina , Humanos , Isótopos de Nitrogênio , Padrões de Referência , Fumar/urina , Compostos Orgânicos Voláteis/normasRESUMO
To investigate the developmental neurotoxicity of environmental bisphenol A (BPA) exposure for infants and children, postnatal rats were used as the animal model and were divided into four groups. Then, they were treated with different concentrations of BPA (i.e., 0, 0.5, 50, or 5000⯵g/kg·bw/day of BPA as the control, low-, medium- and high-exposed group) from postnatal days 7 to 21. Y-maze tests, Golgi-Cox assays and liquid chromatography-tandem mass spectrometry (LC/MS/MS) were performed to test the changes of learning and memory ability, hippocampal neuromorphology and neurotransmitter levels, respectively. The results showed that the BPA-exposed rats, especially the low- and high-exposed rats, needed more trials and longer times to qualify for the learned criterion than the control rats. Additionally, rats after low- or high-exposure to BPA exhibited decreased DG dendritic complexity and reduced CA1 and DG dendritic spine densities in the hippocampus. Low-dosage BPA treatment could significantly alter the neurotransmitter contents in the hippocampus. In male rats, the levels of glutamic acid (Glu) and acetylcholine increased, while the 5-hydroxytryptamine (5-HT) and γ-aminobutyric acid (GABA) levels decreased, which lead to an unbalanced Glu/GABA ratio. However, in female rats, only 5-HT levels decreased. In conclusion, postnatal exposure to BPA could sex- and dose-dependently disrupt dendritic development and neurotransmitter homeostasis in the rat hippocampus. The impaired spatial learning and memory ability of rats induced by low-dose BPA is associated with both disrupted dendritic development and neurotransmitter homeostasis in the hippocampus.
Assuntos
Compostos Benzidrílicos/toxicidade , Encéfalo/efeitos dos fármacos , Disruptores Endócrinos/toxicidade , Neurotransmissores/metabolismo , Fenóis/toxicidade , Animais , Comportamento Animal/efeitos dos fármacos , Memória/efeitos dos fármacos , Ratos , Testes de ToxicidadeRESUMO
Analysis of neurotransmitters in brain tissue is useful for mechanistic studies of the central nervous system. Isotope dilution coupled with ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was developed for the simultaneous determination of glutamic acid, γ-amino butyric acid, acetylcholine, dopamine, and serotonin in the hippocampus tissue. A 2% (v/v) acetic acid in water-methanol (9:1, v/v) solution was used to prepare the standards and re-dissolute samples after nitrogen drying. An Ultimate AQ-C18 column (150 mm×4.6 mm, 3 µm) was used as the analytical column and 0.1% (v/v) formic acid in water and methanol were used as the mobile phase. Gradient elution was performed and all target compounds were eluted over 3 min at 28â. Vitamin C spiked during the sample pretreatment and storage periods significantly retarded the oxidation of dopamine and serotonin and improved the neurotransmitter stability. The developed method showed good linearities (correlation coefficient (R2)>0.998), low detection limits (0.15-1.0 µg/L), good inter-and intra-day precisions (relative standard deviations:0.39%-13.6%), good accuracy (92.9%-119%), low carry-over, and excellent stability. Moreover, the method was successfully applied and validated in the determination of rat hippocampus exposed to bisphenol A.