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1.
Ecotoxicol Environ Saf ; 208: 111432, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33075588

RESUMO

Humans are exposed to phthalates ubiquitously, which may threaten health. However, whether di-n-octyl phthalate can prevent pubertal sexual maturity is still elusive. In this study, male Sprague Dawley rats (age 35 days) were treated daily by gavage with 0, 10, 100, and 1000 mg/kg body weight of di-n-octyl phthalate from day 35 to day 49 after birth. Di-n-octyl phthalate significantly reduced serum testosterone levels at doses of 100 and 1000 mg/kg, but increased serum luteinizing hormone levels of 1000 mg/kg and decreased testosterone/luteinizing hormone ratio at ≥10 mg/kg, without affecting serum follicle-stimulating hormone levels. Di-n-octyl phthalate significantly induced Leydig cell hyperplasia (increased number of CYP11A1-positive Leydig cells) at 100 and 1000 mg/kg. Di-n-octyl phthalate down-regulates the gene expression of Cyp11a1, Hsd3b1 and Insl3 in individual Leydig cells. Di-n-octyl phthalate can also reduce the number of sperm in the epididymis. Di-n-octyl phthalate increased phosphorylated AKT1/AKT2 without affecting their total proteins, but increased the total protein and phosphorylated protein of ERK1/2 and GSK-3ß. Primary immature Leydig cells isolated from 35-day-old rats were treated with 0-50 µM di-n-octyl phthalate for 3 h. This phthalate inhibited androgen production under basal, LH-stimulated, and cAMP-stimulated conditions by 5 and 50 µM in vitro via down-regulating Cyp11a1 expression but up-regulating Srd5a1 expression in vitro. In conclusion, di-n-octyl phthalate induces hypergonadotropic hypogonadism caused by Leydig cell hyperplasia but reduced steroidogenic function and prevents sperm production.


Assuntos
Substâncias Perigosas/toxicidade , Hipogonadismo/induzido quimicamente , Ácidos Ftálicos/toxicidade , Androgênios/metabolismo , Animais , Regulação para Baixo , Glicogênio Sintase Quinase 3 beta/metabolismo , Hiperplasia/metabolismo , Hiperplasia/patologia , Hipogonadismo/metabolismo , Hipogonadismo/patologia , Células Intersticiais do Testículo/metabolismo , Células Intersticiais do Testículo/patologia , Hormônio Luteinizante/metabolismo , Masculino , Fosforilação , Ratos , Ratos Sprague-Dawley , Maturidade Sexual , Espermatozoides/metabolismo , Testículo/metabolismo , Testosterona/metabolismo , Regulação para Cima
2.
Ecotoxicol Environ Saf ; 208: 111472, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33091777

RESUMO

BACKGROUND: Mono-2-ethylhexyl phthalate (MEHP) is a major metabolite of di (2-ethylhexyl) phthalate (DEHP). Our previous researches have shown that MEHP can induce lipid accumulation in preadipocytes, while, the underlying mechanism is unclear. The present study was undertaken to clarify the effect of Notch pathway on lipid accumulation induced by MEHP. METHODS: 3T3-L1 preadipocytes were exposed to MEHP (0, 10, 50, 250 µM and 0.1%DMSO) for the whole differentiation phase. Then the level of TG and cell cycle were detected. RT-PCR was used to detect the mRNA expression and Western blot was used to detect the expression of protein by Notch pathway genes and lipid metabolic related genes. RESULTS: In this study, the level of TG in the 250 µM and 250 µM MEHP groups was significantly higher than that in the control, DMSO and 10 µM MEHP groups (P < 0.05). The relative mRNA level of Notch-1, Notch-3, Notch-4, Jagged-2 and Dll-4 in 250 µM group was higher than other groups (P < 0.05). The expression of Notch signal pathway proteins increased in MEHP treated groups, and the expression of Notch-2, Jagged-1, Jagged-2, Dll-1 and Dll-4 in 250 µM group were significantly higher than control group (P < 0.05). The expression of lipid metabolic related gene mRNA and protein increased in MEHP treated groups, and 250 µM MEHP group was higher than other groups (P < 0.05). The intracellular TG content was significantly correlated with the expression levels of Notch-1 and Jagged-2 mRNA (P < 0.05). CONCLUSION: In this study, we have found that MEHP exposure could increase the TG content in 3T3-L1 cells. The expression of Notch pathway mRNA and proteins were disturbed by the MEHP. Notch-1 and its ligand Jagged-2 play a critical role in the abnormal lipid metabolism in 3T3-L1 cells caused by MEHP.


Assuntos
Dietilexilftalato/análogos & derivados , Substâncias Perigosas/toxicidade , Metabolismo dos Lipídeos/efeitos dos fármacos , Células 3T3-L1 , Animais , Diferenciação Celular , Divisão Celular , Dietilexilftalato/toxicidade , Camundongos , Ácidos Ftálicos , Receptores Notch/metabolismo , Transdução de Sinais/efeitos dos fármacos
3.
Ecotoxicol Environ Saf ; 208: 111476, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33091778

RESUMO

Male fertility is linked with several well-orchestrated events including spermatogenesis, epididymal maturation, capacitation, the acrosome reaction, fertilization, and beyond. However, the detrimental effects of bisphenol A (BPA) on sperm maturation compared to spermatogenesis and sperm cells remain unclear. Therefore, this study was to investigate whether pubertal exposure to BPA induces male infertility via interruption of the immune response in the epididymis. CD-1 male mice (5 weeks old) were treated daily with vehicle (corn oil) and 50 mg BPA/kg-BW for 6 weeks by oral gavage. Following BPA exposure, we observed decreased intraepithelial projection of basal cells, indicative of changes to the luminal environment. We also observed decreased projection of macrophages and protrusion of apoptotic cells into the lumen induced by incomplete phagocytosis of apoptotic cells in the caput epididymis. Exposure to BPA also reduced the anti- and pro-inflammatory cytokines IL-10, IL-6, IFN-γ, and IL-7 in the epididymis, while the chemotaxis-associated cytokines CCL12, CCL17, CXCL16, and MCP-1 increased. This study suggests two possible mechanisms for BPA induction of male infertility. First, exposure to BPA may induce an imbalance of immune homeostasis by disrupting the ability of basal cells to perceive environmental changes. Second, exposure to BPA may lead to collapse of macrophage phagocytosis via downregulation of intraepithelial projection and inflammatory-related cytokines. In conclusion, the observed potential pathways can lead to autoimmune disorders such epididymitis and orchitis.


Assuntos
Compostos Benzidrílicos/toxicidade , Epididimo/efeitos dos fármacos , Substâncias Perigosas/toxicidade , Fenóis/toxicidade , Animais , Epididimo/metabolismo , Humanos , Infertilidade Masculina , Masculino , Camundongos , Tamanho do Órgão/efeitos dos fármacos , Espermatogênese/efeitos dos fármacos , Espermatozoides/efeitos dos fármacos
4.
Ecotoxicol Environ Saf ; 208: 111426, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33096358

RESUMO

Environmental mercury is a concern for coastal ecosystem health, and exerts adverse effects on human health. Despite the growing body of evidence showing the hepatoprotective roles of curcumin on mercury, the knowledge between the macroscopic descriptions and the actual mechanism(s) underlying these processes is getting larger remains elusive. Herein, mice received single injection of mercuric chloride (HgCl2) (5 mg/kg body weight) and/or curcumin (50 mg/kg, body weight, p.o.). Firstly, the results showed curcumin could decline HgCl2-induced up-regulated the levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Additionally, we also found that curcumin could suppress inflammatory damage, unbalance of trace elements (including sodium, magnesium, kalium, calcium overload), oxidative burst induced by HgCl2, which could be associated with cytochrome P450 (CYP450) signaling. Secondly, we found that curcumin could prevent HgCl2-induced cell death both in vivo and in vitro. Furthermore, curcumin significantly increased the nuclear translocation of nuclear factor E2-related factor 2 (Nrf2) and consequently upregulated the expression of heme oxygenase 1 (HO-1) under HgCl2 treatment. Meanwhile, inhibition of HO-1 by zinc protoporphyria could abolish the cytoprotective effects of curcumin in HgCl2-treated L02 hepatocytes. In conclusion, our data identify that curcumin could enhance Nrf2-mediated HO-1 to upregulate antioxidant ability, which might be associate with CYP450 signaling to suppress liver damage induced by HgCl2. The present study further enriches and perfects the mechanism theory of HgCl2 toxicity and suggest that the CYP450 signaling and Nrf2/HO-1 pathway is important in shedding light on curcumin's hepatoprotective effects in HgCl2 toxicity.


Assuntos
Curcumina/farmacologia , Sistema Enzimático do Citocromo P-450/metabolismo , Substâncias Perigosas/toxicidade , Cloreto de Mercúrio/toxicidade , Substâncias Protetoras/farmacologia , Alanina Transaminase/metabolismo , Animais , Antioxidantes/metabolismo , Doença Hepática Crônica Induzida por Substâncias e Drogas/metabolismo , Ecossistema , Heme Oxigenase-1/genética , Hepatócitos/efeitos dos fármacos , Humanos , Camundongos , Fator 2 Relacionado a NF-E2/metabolismo , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos
5.
Chemosphere ; 263: 128304, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33155548

RESUMO

Gap junction intercellular communication (GJIC) is necessary for ovarian function, and it is temporospatially regulated during follicular development and ovulation. At outermost layer of the antral follicle, theca cells provide structural, steroidogenic, and vascular support. Inter- and extra-thecal GJIC is required for intrafollicular trafficking of signaling molecules. Because GJIC can be altered by hormones and endocrine disrupting chemicals (EDCs), we tested if any of five common EDCs (bisphenol A (BPA), bisphenol S (BPS), bisphenol F (BPF), perfluorooctanesulfonic acid (PFOS), and triphenyltin chloride (TPT)) can interfere with theca cell GJIC. Since most chemicals are reported to repress GJIC, we hypothesized that all chemicals tested, within environmentally relevant human exposure concentrations, will inhibit theca cell GJICs. To evaluate this hypothesis, we used a scrape loading/dye transfer assay. BPS, but no other chemical tested, enhanced GJIC in a dose- and time-dependent manner in ovine primary theca cells. A signal-protein inhibitor approach was used to explore the GJIC-modulatory pathways involved. Phospholipase C and mitogen-activated protein kinase (MAPK) inhibitors significantly attenuated BPS-induced enhanced GJIC. Human theca cells were used to evaluate translational relevance of these findings. Human primary theca cells had a ∼40% increase in GJIC in response to BPS, which was attenuated with a MAPK inhibitor, suggestive of a conserved mechanism. Upregulation of GJIC could result in hyperplasia of the theca cell layer or prevent ovulation by holding the oocyte in meiotic arrest. Further studies are necessary to understand in vitro to in vivo translatability of these findings on follicle development and fertility outcomes.


Assuntos
Substâncias Perigosas/toxicidade , Fenóis/toxicidade , Sulfonas/toxicidade , Células Tecais/fisiologia , Animais , Compostos Benzidrílicos , Comunicação Celular , Comunicação , Conexina 43/metabolismo , Feminino , Junções Comunicantes/metabolismo , Humanos , Oócitos/metabolismo , Ovinos , Transdução de Sinais , Células Tecais/efeitos dos fármacos , Células Tecais/metabolismo
6.
Xenobiotica ; 51(2): 210-221, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32985913

RESUMO

We investigated the plasma toxicokinetic behavior of free (parent) and total (parent and conjugated forms) of bisphenol S (BPS) and bisphenol AF (BPAF) in plasma of adult male rats and mice following exposure via feed for 7 days to BPS (338, 1125, and 3375 ppm) or BPAF (338, 1125, and 3750 ppm). In rats, the exposure concentration-normalized maximum concentration [Cmax/D (ng/mL)/(ppm)] and area under the concentration time curve [AUC/D (h × ng/mL)/(ppm)] for free was higher for BPS (Cmax/D: 0.476-1.02; AUC/D: 3.58-8.26) than for BPAF (Cmax/D: 0.017-0.037; AUC/D:0.196-0.436). In mice, the difference in systemic exposure parameters between free BPS (Cmax/D: 0.376-0.459; AUC/D: 1.52-2.54) and free BPAF (Cmax/D: 0.111-0.165; AUC/D:0.846-1.09) was marginal. Elimination half-lives for free analytes (4.41-10.4 h) were comparable between species and analogues. When systemic exposure to free analyte was compared between species, in rats, BPS exposure was slightly higher but BPAF exposure was much lower than in mice. BPS and BPAF were highly conjugated; total BPS AUC values (rats ≥18-fold, mice ≥17-fold) and BPAF (rats ≥127-fold, mice ≥16-fold) were higher than corresponding free values. Data demonstrated that there are analogue and species differences in the kinetics of BPS and BPAF.


Assuntos
Compostos Benzidrílicos/farmacocinética , Substâncias Perigosas/farmacocinética , Fenóis/farmacocinética , Sulfonas/farmacocinética , Animais , Compostos Benzidrílicos/toxicidade , Substâncias Perigosas/toxicidade , Cinética , Masculino , Camundongos , Fenóis/toxicidade , Ratos , Sulfonas/toxicidade , Testes de Toxicidade , Toxicocinética
7.
Ecotoxicol Environ Saf ; 208: 111401, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33038730

RESUMO

Dibromoacetic acid (DBA) is a by-product of disinfection in drinking water, which could cause many adverse effects in test animals. However, little research on its neurotoxicity has been conducted, and its mechanism has not been elucidated. In the present study, ninety Sprague-Dawley rats were administered DBA at doses of 0, 30, and 90 mg/kg body weight for 28 days via oral gavage. We found that DBA could induce obvious neurotoxicity in the pineal gland as indicated by histological changes and impaired rhythm of melatonin in pineal and serum. In the mechanism study, transcriptome data showed that DBA exposure could induce 732 differential expression genes. Besides, GO and KEGG analysis results indicated that these genes were enriched in circadian rhythms, among which CREB1 had the most significant fold change. And immunofluorescence staining (IF) and immunohistochemical staining (IHC) results showed that the number of amber-colored masculine neurons for the p-CREB1 in the 90 mg/kg group was markedly lower, and staining for the p-CREB1 was weaker. Moreover, the results of PCR and western blot showed that DBA exposure could down-regulate the expressions of CREB1 and p-CREB1, leading to the decreased expressions of gene and protein of arylalkylamine N-acetyltransferase (AANAT), and then resulting in the impaired melatonin synthesis in the pineal and serum. In conclusion, DBA exposure is associated with abnormal melatonin rhythm via inhibition of the p-CREB1-AANAT signalling pathway.


Assuntos
Acetatos/toxicidade , Substâncias Perigosas/toxicidade , Melatonina/metabolismo , Acetiltransferases/metabolismo , Animais , Arilalquilamina N-Acetiltransferase/biossíntese , Ritmo Circadiano , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Regulação para Baixo , Masculino , Glândula Pineal/efeitos dos fármacos , Glândula Pineal/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais
8.
Ecotoxicol Environ Saf ; 208: 111391, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33039869

RESUMO

Hexavalent chromium [Cr(VI)] is a pervasive environmental pollutant that can enter the body through a variety of routes and cause organ toxicity, genetic damage, and cancer. Cr(VI)-induced apoptosis is a toxicant mechanism of Cr(VI). Studies have shown that Cr(VI) can induce p53-independent apoptosis, but the mechanisms are not fully understood. The intracellular calcium concentration affects cellular life. Apoptosis-inducing factor (AIF), a caspase-independent apoptotic effector, can induce DNA degradation. Using p53-null Hep3B cells, we investigated the effects of cytoplasmic calcium homeostasis and AIF on Cr(VI)-induced apoptosis. We found that 20 µM of Cr(VI) induced DNA damage and mitochondrial permeability transition pore (MPTP) openings, causing calcium overload that was accompanied by decreased Ca2+-Mg2+-ATPase and Na+-K+-ATP activities, downregulation of calmodulin (CaM) and Ca2+/CaM-dependent protein kinase II (CAMKII) mRNA, and increased expression of p-CaMKII/CaMKII protein. After treatment with calcium chelating agent BAPTA-AM, Cr(VI)-induced DNA damage, calcium overload, and apoptosis were reduced. AIF was released from the mitochondria and translocated into the nuclei. As the Cr(VI) treatment time progressed, the mRNA and protein expression of B cell lymphoma 2 (Bcl-2) and heat-shock protein 70 (HSP70) decreased, whereas the mRNA and protein expression of Bcl-2-associated X (Bax), cyclophilin A (CypA), and endonuclease G (EndoG) were upregulated. These results indicated that Cr(VI)-induced apoptosis of Hep3B cells (p53-null) was closely associated with calcium overload, and was accompanied by the activation of Ca2+/CaM/CaMKII signaling pathway. Besides, Cr(VI) triggered AIF nuclear translocation in Hep3B cells, accompanied by the changes in the levels of apoptosis-associated factors. These results provide additional experimental evidence of the molecular mechanisms involved in Cr(VI)-induced p53-independent apoptosis.


Assuntos
Cromo/toxicidade , Substâncias Perigosas/toxicidade , Apoptose/efeitos dos fármacos , Fator de Indução de Apoptose/metabolismo , Fator de Indução de Apoptose/farmacologia , Cálcio/metabolismo , Morte Celular , Ácido Egtázico/análogos & derivados , Humanos , Mitocôndrias/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais
9.
Ecotoxicol Environ Saf ; 208: 111415, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33091767

RESUMO

OBJECTIVES: We aim to investigate association between WNT3A methylation and risk of non-syndromic cleft lip and/or palate (NSCL/P), and examine mediating effect of WNT3A methylation on the association of NSCL/P and lead (Pb) exposure in fetuses. METHODS: DNA methylation of WNT3A in umbilical cord blood was determined among 59 NSCL/P cases and 118 non-malformed controls. Mediation analysis was performed to evaluate the potential mediating effect of WNT3A methylation on association between concentrations of Pb in umbilical cord and risk for NSCL/P. Additionally, an animal experiment in which cleft palates were induced by lead acetate was conducted. RESULTS: The overall average methylation level of WNT3A was significant higher in NSCL/P cases as compared to controls. The risk for NSCL/P was increased by 1.90-fold with hypermethylation of WNT3A. Significant correlation was observed between concentrations of Pb in umbilical cord and methylation level of WNT3A. The hypermethylation of WNT3A had a mediating effect by 9.32% of total effect of Pb on NSCL/P risk. Gender-specific association between WNT3A methylation and NSCL/P was observed in male fetuses, and the percentage of the mediating effect increased to 14.28%. Animal experiment of mice showed that maternal oral exposure to lead acetate may result in cleft palate in offspring. CONCLUSION: Hypermethylation of WNT3A was associated with the risk for NSCL/P and may be partly explain the association between exposure to Pb and risk for NSCL/P. The teratogenic and fetotoxic effects of Pb were found in mice.


Assuntos
Fenda Labial/genética , Fissura Palatina/genética , Metilação de DNA , Substâncias Perigosas/toxicidade , Chumbo/toxicidade , Proteína Wnt3A/genética , Animais , Estudos de Casos e Controles , Genótipo , Humanos , Masculino , Camundongos
10.
Ecotoxicol Environ Saf ; 208: 111528, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33157513

RESUMO

OBJECTIVE: Excess molybdenum (Mo) is harmful to the body, and the kidney is the vital target organ for Mo exposure. This study focused on the impacts of excess Mo on pyroptosis and the relationship between pyroptosis and apoptosis in kidney. METHODS: The duck renal tubular epithelial cells were treated with (NH4)6Mo7O24·4H2O (0, 480, 720 and 960 µM Mo), N-acetyl-L-cysteine (NAC) (100 µM), Z-YVAD-fluoromethylketone (YVAD) (10 µM) and the combination of Mo and NAC or YVAD for 12 h. The LDH release and IL-1ß, IL-18 contents of cell supernatant were detected by LDH and ELISA kits. The MMP and ROS level were measured using MMP and ROS kits by flow cytometry. The apoptotic rate of cell was detected by AO/EB counterstaining. Pyroptosis and apoptosis-related factors mRNA and protein levels were assayed by real-time qPCR and western blot, respectively. RESULTS: Excessive Mo markedly increased LDH, IL-18, IL-1ß releases and induced overproduction of ROS, pyroptosis-related factors mRNA and protein levels. NAC and YVAD dramatically decreased pyroptosis induced by Mo. Simultaneously, YVAD significantly changed apoptosis-related factors mRNA and protein levels, and reduced cell apoptotic rate. CONCLUSION: Excessive Mo exposure can induce pyroptosis by the ROS/NLRP3/Caspase-1 pathway in duck renal tubular epithelial cells, and restraining pyroptosis of Caspase-1 dependence might weaken excess Mo-induced apoptosis. The study provides theoretical basis for excess Mo exposure nephrotoxic researches on waterfowl and the interplay between pyroptosis and apoptosis highlights a new sight into the mechanism of Mo-induced nephrotoxicity.


Assuntos
Caspase 1/metabolismo , Substâncias Perigosas/toxicidade , Molibdênio/toxicidade , Piroptose/fisiologia , Espécies Reativas de Oxigênio/metabolismo , Acetilcisteína/metabolismo , Animais , Apoptose , Patos/metabolismo , Patos/fisiologia , Células Epiteliais/metabolismo , Humanos , Interleucina-1beta , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo
11.
J Environ Manage ; 278(Pt 2): 111567, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33129029

RESUMO

Communities with contaminated lands are also often the most vulnerable to the impacts of a changing climate such as sea-level rise, increased temperatures, and extreme storms and hurricanes due to socio-economic and historic reasons - some of the very factors that enable the creation of these contaminated sites in these communities. In spite of, and arguably because of, this double exposure and impact, the ability of these communities to clean up and reuse their contaminated lands has not kept up with their need. Researchers have often attributed this discrepancy to a lack of technical capacity and human resource. To address this lack, since January 2018, students enrolled in planning-related courses offered by the University of West Florida Department of Earth and Environmental Sciences have engaged with stakeholders on the redevelopment of superfund sites located in Pensacola, FL under the auspices of the USEPA's College Underserved Community Partnership Program. The engagement centered on the reuse of two of these superfund sites for the betterment of the stakeholders' socio-economies and their biophysical environments. I focus in this paper on four examples of engaging with students in planning for superfund site remediation and redevelopment. The examples are of engaging with county staff; collaboratively engaging with city staff and a private firm; engaging with county commissioners; and engaging with a private firm between two superfund sites over the course of one year. I highlight the contextual, unique needs, of each stakeholder group yet emphasize the applicable lessons across all four examples. I also focus on best practices to develop plans and outlines for mutually beneficial products and outcomes for both students and stakeholder groups in the process of land revitalization.


Assuntos
Recuperação e Remediação Ambiental , Eliminação de Resíduos , Florida , Substâncias Perigosas , Humanos , Estudantes
12.
Ecotoxicol Environ Saf ; 207: 111257, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-32890951

RESUMO

Cadmium has been widely detected in the environment and various foods. The association between cadmium burden and osteoporosis has been studied in cohorts. However, the effects and mechanisms of environmental cadmium exposure on bone metabolism is poorly understood. This study aims to investigate the altered metabolites in bone cells affected by low-level cadmium by metabolomics analysis. Specifically, we used the dosage of cadmium that do not decrease the cell viability (determined by MTT assay) to treat Saos-2 cells for 24 h. ICP-MS was applied to quantify the cadmium in culture medium and cell precipitate. The cellular metabolites were extracted and analyzed by liquid chromatography-mass spectrometry. The pathway analysis based on the identified differential metabolites showed that 1 µM cadmium significantly affected citric acid cycle and malate-aspartate shuttle, while 10 µM cadmium treatment affected citric acid cycle, alanine metabolism, glucose-alanine cycle, pyrimidine metabolism and glutamate metabolism. Taken together, 1 µM cadmium exposure could suppress the electrons transportation from the cytosol to mitochondrial matrix in Saos-2, and the impediment of the electron transport chain further inhibited downstream activities in citric acid cycle, which resulted in the accumulation of pyruvic acid. In addition, the suppressed pyrimidine degradation resulted in senescent nucleic acid accumulation and the decrease of mRNA transcription in Saos-2 cells. In general, our studies unveil the cadmium-induced metabolic perturbations in Saos-2 cells and demonstrate the feasibility of our established metabolomics pipeline to understand cadmium-induced effects on bone.


Assuntos
Cádmio/toxicidade , Substâncias Perigosas/toxicidade , Cádmio/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Cromatografia Líquida , Exposição Ambiental , Humanos , Espectrometria de Massas , Metabolômica/métodos , Mitocôndrias/metabolismo , Osteoblastos/efeitos dos fármacos , Oxirredução , Estresse Oxidativo/efeitos dos fármacos
13.
Ecotoxicol Environ Saf ; 207: 111231, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-32916527

RESUMO

Lead, a common metallic contaminant, is widespread in the living environment, and has deleterious effects on the reproductive systems of humans and animals. Although numerous toxic effects of lead have been reported, the effects and underlying mechanisms of the impacts of lead exposure on the female reproductive system, especially oocyte maturation and fertility, remain unknown. In this study, mice were treated by gavage for seven days to evaluate the reproductive damage and role of Nrf2-mediated defense responses during lead exposure. Lead exposure significantly reduced the maturation and fertilization of oocytes in vivo. Additionally, lead exposure triggered oxidative stress with a decreased glutathione level, increased amount of reactive oxygen species, and abnormal mitochondrial distribution. Moreover, lead exposure caused histopathological and ultrastructural changes in oocytes and ovaries, along with decreases in the activities of catalase, glutathione peroxidase, total superoxide dismutase, and glutathione-S transferase, and increases in the levels of malonaldehyde in mouse ovaries. Further experiments demonstrated that lead exposure activated the Nrf2 signaling pathway to protect oocytes against oxidative stress by enhancing the transcription levels of antioxidant enzymes. In conclusion, our study demonstrates that lead activates the Nrf2/Keap1 pathway and impairs oocyte maturation and fertilization by inducing oxidative stress, leading to a decrease in the fertility of female mice.


Assuntos
Substâncias Perigosas/toxicidade , Chumbo/toxicidade , Animais , Antioxidantes/metabolismo , Catalase/metabolismo , Feminino , Glutationa Peroxidase/metabolismo , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Chumbo/metabolismo , Malondialdeído/metabolismo , Camundongos , Fator 2 Relacionado a NF-E2/metabolismo , Oócitos/efeitos dos fármacos , Oogênese/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Superóxido Dismutase/metabolismo
14.
Ecotoxicol Environ Saf ; 207: 111262, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-32916531

RESUMO

Mercury (Hg) in its all forms, including inorganic Hg (iHg) is an environmental contaminant due to toxicity and diseases in human. However, a little is known about the underlying mechanisms responsible for iHg toxicity. Selenium (Se) is an essential trace element, recognized as an antioxidant and protective agent against metal toxicities. The purpose of this research was to investigate ameliorations of Se counter to iHg-mediated toxicity in PC12 cells. Cytotoxic assays have been shown that iHg (5 µM) caused oxidative stress and intrinsic apoptosis via ROS generation, oxidizing glutathione, damaging DNA, degrading cell membrane integrity, down-regulating mTOR, p-mTOR, akt and ERK1, and up-regulating cleaved caspase 3 and cytochrome c release in PC12 cells 48 h after incubation. Co-treatment of Se (5 µM) inhibited intrinsic apoptosis and oxidative stress induced by iHg (5 µM) via inhibiting ROS formation, boosting GPx contents, increasing reduced glutathione, limiting DNA degradation, improving cell membrane integrity, up-regulating mTOR, p-mTOR, akt, ERK1 and caspase 3, and down-regulating cleaved caspase 3 and cytochrome c leakage in PC12 cells. In conclusion, these results recommended that excessive ROS generation acts a critical role in iHg-influenced oxidative stress and co-treatment of Se attenuates iHg-cytotoxicity through its antioxidant properties.


Assuntos
Substâncias Perigosas/toxicidade , Mercúrio/toxicidade , Substâncias Protetoras/farmacologia , Selênio/farmacologia , Animais , Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Caspase 3 , Citocromos c/metabolismo , Glutationa/metabolismo , Humanos , Mercúrio/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Células PC12 , Ratos , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR
15.
Ecotoxicol Environ Saf ; 207: 111272, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-32927162

RESUMO

Tobacco smoke is a common global environmental pollutant. Maternal tobacco smoke/nicotine exposure has long-term toxic effects on immune organs. We previously found that prenatal nicotine exposure (PNE)-induced programmed immune diseases caused by fetal thymic hypoplasia, but the mechanism still unknown. Autophagy has important functions in maintaining thymopoiesis, whether autophagy was involved in PNE-inhibited fetal thymocytes development is also obscure. Therefore, this study aimed to investigate how nicotine changed the development of fetal thymocytes from the perspective of autophagy in vivo and in vitro. PNE model was established by 3 mg/kg nicotine administration in Balb/c mice from gestational day 9 to 18. The results showed that PNE reduced the percentage and absolute number of CD69-CD4+SP cells, suggesting a block of fetal thymocytes mature. PNE promoted autophagosome formation, autophagy related proteins (Beclin1, LC3I/II) expression, and upregulated α7 nAChR as well as AMPK phosphorylation in fetal thymus. Moreover, PNE promoted Bcl10 degradation via autophagy-mediated proteolysis and inhibited p65 activation, blocking the transition of thymocytes between the DP to SP stage. Further, primary thymocytes were treated with nicotine in vitro and showed induced autophagy in a dose- and time-dependent manner. In addition, nicotine-inhibited CD69-CD4+SP cells and the Bcl10/p-p65 pathway have been reversed by an autophagy inhibitor. The α7 nAChR specific antagonist abrogated nicotine-induced AMPK phosphorylation and autophagy initiation. In conclusion, our findings showed that PNE repressed the Bcl10/p-p65 development pathway of CD4+SP cells by triggering autophagy, and illuminated the developmental origin mechanism of programmed immune diseases in PNE offspring.


Assuntos
Substâncias Perigosas/toxicidade , Nicotina/toxicidade , Timócitos/fisiologia , Animais , Autofagia/efeitos dos fármacos , Proteína 10 de Linfoma CCL de Células B , Proteína Beclina-1 , Feminino , Feto , Ativação Linfocitária , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Timócitos/efeitos dos fármacos , Timócitos/imunologia , Vitaminas
16.
Chemosphere ; 263: 128017, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32841881

RESUMO

Phthalic acid esters (PAEs), as typical hormone pollutants, do harms to human health after enrichment over a long term exposure, causing the loss of oxygen-carrying function of red blood cells (RBCs). This study has investigated the mechanism for the toxicity of dimethyl phthalate (DMP) on the oxygen-carrying function of RBCs by measuring the iron release content of hemoglobin (Hb) in vivo and in vitro. The hematologic examination showed that the high dose of DMP at 1000 mg/kg significantly reduced the Hb content and increased the granulocyte content, whereas such toxicity was not relatively observed at a low (50 mg/kg) or a medium (250 mg/kg) dose of DMP. The in vitro experiments showed that DMP, incubated with RBCs, increased the iron release content as a function of DMP concentration. Interestingly, such a phenomenon was not observed when DMP was incubated with Hb alone, indicating that the release of hemoglobin iron could not directly caused by the combination of DMP and hemoglobin. The in vivo experiments indicated that DMP induced iron release and oxidative stress for rat RBCs. Moreover, vitamin C and E was found to reduce the level of iron release by recovering erythrocytes from the oxidative stress induced by DMP. This work has revealed that the oxidative stress induced by DMP, causing the release of Hb iron from RBCs, is the reason for the toxicity of DMP to the oxygen-carrying function.


Assuntos
Substâncias Perigosas/toxicidade , Ácidos Ftálicos/toxicidade , Animais , Poluentes Ambientais , Eritrócitos , Hemoglobinas , Humanos , Ferro , Estresse Oxidativo , Oxigênio , Ratos
17.
Chemosphere ; 263: 127990, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32846288

RESUMO

The clinical manifestations of methylmercury toxicity do not differ greatly according to the acute and/or chronic methylmercury overexposure.


Assuntos
Exposição Ambiental/estatística & dados numéricos , Substâncias Perigosas/toxicidade , Mercúrio/toxicidade , Animais , Humanos , Mamíferos , Mercúrio/análise , Compostos de Metilmercúrio/toxicidade
18.
Ann Agric Environ Med ; 27(4): 491-504, 2020 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-33356052

RESUMO

The occupational bioaerosols containing viruses, bacteria, fungi, microbial toxins and plant or animal particles, may evoke infectious, allergic or immunotoxic diseases which may co-exist as comorbidities with COVID-19 and exacerbate the course of disease. They include hypersensitivity pneumonitis (HP) caused mostly by bacteria, fungi, and particles containing animal proteins, and immunotoxic diseases such as organic dust toxic syndrome (ODTS) and byssinosis, caused mostly by bacterial and fungal toxins. The two most probable scenarios of possible interrelations between these three comorbidities (CM) and COVID-19 are: 1) 'Triggering' - when infection with SARS-CoV-2 triggers severe CM after bioaerosol exposure; 2) 'Reverse triggering' when exposure to bioaerosol exacerbates a symptomless or mild course of COVID-19, and evokes a severe disease. The occupations mostly endangered by COVID-19 as the result of exposure to SARS-CoV-2 bioaerosol, or to other bioaerosols which may exacerbate this disease, include: health care workers, social workers, breeders of fur animals, slaughterhouse workers, workers engaged in the processing and selling of seafood, and probably also agricultural workers, mainly in the developing countries. The authors present a hypothesis for the origin of the present pandemic. It assumes that a mild form of the present SARS-CoV-2 that is supposedly circulating among the Chinese population in the eastern part of the country, mutated under the influence of as yet unknown factor(s) present in the Chinese seafood markets, probably component(s) of bioaerosols, into the virulent and highly contagious form, known as the present SARS-CoV-2, under a scenario similar to that the authors have named 'Reverse triggering'.


Assuntos
/etiologia , Substâncias Perigosas/efeitos adversos , Exposição Ocupacional/efeitos adversos , Aerossóis , Alveolite Alérgica Extrínseca/etiologia , Animais , Bissinose/etiologia , Comorbidade , Indústria de Processamento de Alimentos , Pessoal de Saúde , Humanos
20.
Toxicol Lett ; 335: 51-63, 2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-33091563

RESUMO

Electronic cigarettes (e-cigarettes) and tobacco heating products (THPs) have reduced yields of toxicants and have recently emerged as a potentially safer alternative to combustible cigarettes. To understand if reduced toxicant exposure is associated with reductions in biological responses, there is a need for high-quality pre-clinical in vitro studies. Here, we investigated the cytotoxic response of human umbilical vein endothelial cells to conventional cigarette aqueous aerosol extracts (AqE) and highly concentrated AqEs from e-cigarettes (two generations of atomisers) and THPs (two variants). All AqE samples were generated by a standardized methodology and characterized for nicotine, propylene glycol and vegetable glycerol. The cigarette AqE caused a maximum 100 ± 0.00 % reduction in cell viability at 35 % dose (2.80 puffs) as opposed to 96.63 ± 2.73 % at 50 % (20 puffs) and 99.85 ± 0.23 % at 75 % (30 puffs) for the two THP variants (glo Bright Tobacco, glo Rich Tobacco), and 99.07 ± 1.61 % at the neat ePen2.0 e-cigarette (200 puffs). The AqE of the remaining e-cigarettes either resulted in an incomplete dose-response or did not elicit any response. The methods utilized were suitably sensitive to not only differentiate between cigarette, THP and e-cigarette aerosols but also to distinguish between products within each product category.


Assuntos
Sistemas Eletrônicos de Liberação de Nicotina , Substâncias Perigosas/toxicidade , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Fumaça/efeitos adversos , Produtos do Tabaco/toxicidade , Aerossóis , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Calefação , Células Endoteliais da Veia Umbilical Humana/patologia , Humanos
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