Nickel is associated with reproductive toxicity. However, the reproductive toxicity of nickel nanoparticles (Ni NPs) is unclear. Our goal was to determine the association between nickel nanoparticle exposure and reproductive toxicity. According to the one-generation reproductive toxicity standard, rats were exposed to nickel nanoparticles by gavage and we selected indicators including sex hormone levels, sperm motility, histopathology, and reproductive outcome etc. Experimental results showed nickel nanoparticles increased follicle stimulating hormone (FSH) and luteinizing hormone (LH), and lowered etradiol (E2) serum levels at a dose of 15 and 45 mg/kg in female rats. Ovarian lymphocytosis, vascular dilatation and congestion, inflammatory cell infiltration, and increase in apoptotic cells were found in ovary tissues in exposure groups. For male rats, the weights decreased gradually, the ratio of epididymis weight over body weight increased, the motility of rat sperm changed, and the levels of FSH and testosterone (T) diminished. Pathological results showed the shedding of epithelial cells of raw seminiferous tubule, disordered arrangement of cells in the tube, and the appearance of cell apoptosis and death in the exposure group. At the same time, Ni NPs resulted in a change of the reproductive index and the offspring development of rats. Further research is needed to elucidate exposure to human populations and mechanism of actions.
The potential immune effects of titanium dioxide nanoparticles (nano-TiO?) are raising concern. Our previous study verified that nano-TiO? induce local immune response in lung tissue followed by intratracheal instillation administration. In this study, we aim to evaluate the systemic immune effects of nano-TiO?. Sprague Dawley rats were treated by intratracheal instillation with nano-TiO? at doses of 0.5, 4, and 32 mg/kg body weight, micro-TiO? with 32 mg/kg body weight and 0.9% NaCl, respectively. The exposure was conducted twice a week, for four consecutive weeks. Histopathological immune organs from exposed animals showed slight congestion in spleen, generally brown particulate deposition in cervical and axillary lymph node. Furthermore, immune function response was characterized by increased proliferation of T cells and B cells following mitogen stimulation and enhanced natural killer (NK) cell killing activity in spleen, accompanying by increased number of B cells in blood. No significant changes of Th1-type cytokines (IL-2 and INF-?) and Th2-type cytokines (TNF-? and IL-6) were observed. Intratracheal exposure to nano-TiO? may be one of triggers to be responsible for the systemic immune response. Further study is needed to confirm long-lasting lymphocyte responses and the potential mechanisms.
Microcystin-LR (MC-LR) and microcystin-RR (MC-RR) produced by harmful cyanobacterial blooms (HCBs) pose substantial threats to the ecosystem and public health due to their potential hepatotoxicity. Degradation of microcystins (MCs) by indigenous bacteria represents a promising method for removing MCs from fresh water without harming the aquatic environment, but only a few microcystin (MC)-degrading bacteria have been isolated and had their mechanisms reported. This study aimed to isolate indigenous bacteria from Lake Taihu, and investigate the capability and mechanism of MC degradation by these bacteria. During a Microcystis bloom, an indigenous MC-degrading bacterium designated MC-LTH2 was successfully isolated from Lake Taihu, and identified as Stenotrophomonas acidaminiphila based on phylogenetic analysis. In the presence of MC-LR together with MC-RR, the strain MC-LTH2 was capable of totally degrading both simultaneously in 8 days, at rates of 3.0 mg/(L?d) and 5.6 mg/(L?d), respectively. The degradation rates of MCs were dependent on temperature, pH, and initial MC concentration. Adda (3-amino-9-methoxy-2, 6, 8-trimethyl-10-phenyldeca-4, 6-dienoic acid) was detected as an intermediate degradation product of MCs using high performance liquid chromatography coupled with time-of-flight mass spectrometry (HPLC-TOF-MS). To the best of our knowledge, this is the first report of Stenotrophomonas acidaminiphila capable of degrading two MC analogues and other compounds containing Adda residue completely under various conditions, although the mlrA gene in the strain was not detected. These results indicate the Stenotrophomonas acidaminiphila strain MC-LTH2 possesses a significant potential to be used in bioremediation of water bodies contaminated by MC-LR and MC-RR, and is potentially involved in the degradation of MCs during the disappearance of the HCBs in Lake Taihu.
This study aimed to isolate and characterize an indigenous algicidal bacterium named LTH-1 and its algae-lysing compounds active against three Microcystis aeruginosa strains (toxic TH1, nontoxic TH2 and standard FACHB 905). The LTH-1 isolated from Lake Taihu, near Wuxi City in China, was identified as Aeromonas sp. based on its morphological characteristic features and phylogenetic analysis by sequencing of 16S rDNA. Extracellular compounds produced by LTH-1 showed strong algaelysing activity, and they were water-soluble and heat-tolerant, with a molecular mass lower than 2 kDa. Two algae-lysing compounds were isolated and purified from extracellular filtrate using silica gel column chromatography. One of these was identified as phenylalanine (C9H11NO2, m/z 166.0862) and the other (C8H16N2O3, m/z 189.1232) was unidentified by hybrid ion trap/time-of-flight mass spectrometry coupled with a high-performance liquid chromatography (LC/MS-IT-TOF) system. The half maximal effective concentration (EC50) of phenylalanine produced by LTH-1 against FACHB 905 was 68.2 +/- 8.2 microg mL(-1) in 48h. These results suggest that the algicidal Aeromonas sp. LTH-1 could play a role in controlling Microcystis blooms, and its extracellular compounds are also potentially useful for regulating blooms of the harmful M. aeruginosa.
The risk of lung cancer among night-shift workers is unknown. Over 20 years of follow-up (1988-2008), we documented 1,455 incident lung cancers among 78,612 women in the Nurses Health Study. To examine the relationship between rotating night-shift work and lung cancer risk, we used multivariate Cox proportional hazard models adjusted for detailed smoking characteristics and other risk factors. We observed a 28% increased risk of lung cancer among women with 15 or more years spent working rotating night shifts (multivariate relative risk (RR) = 1.28, 95% confidence interval (CI): 1.07, 1.53; Ptrend = 0.03) compared with women who did not work any night shifts. This association was strongest for small-cell lung carcinomas (multivariate RR = 1.56, 95% CI: 0.99, 2.47; Ptrend = 0.03) and was not observed for adenocarcinomas of the lung (multivariate RR = 0.91, 95% CI: 0.67, 1.24; Ptrend = 0.40). Further, the increased risk associated with 15 or more years of rotating night-shift work was limited to current smokers (RR = 1.61, 95% CI: 1.21, 2.13; Ptrend < 0.001), with no association seen in nonsmokers (Pinteraction = 0.03). These results suggest that there are modestly increased risks of lung cancer associated with extended periods of night-shift work among smokers but not among nonsmokers. Though it is possible that this observation was residually confounded by smoking, our findings could also provide evidence of circadian disruption as a "second hit" in the etiology of smoking-related lung tumors.
To determine the relevance of O-6-methylguanine-DNA methyltransferase (MGMT), human mutS homolog 2 (hMSH2), and human mutL homolog 1 (hMLH1) in TP53 mutations in esophageal squamous cell carcinoma, we employed methylation-sensitive high-resolution melting technology and methylation-specific polymerase chain reaction (PCR) to analyze promoter hypermethylation of MGMT, hMSH2, and hMLH1, respectively, in 51 paired tumors and their adjacent normal tissues. The protein expression of the three proteins was also evaluated by Western blot analysis, and the PCR products of TP53, from exon 5 to exon 8, were directly sequenced to measure the mutation spectrum. Esophageal tumor tissues embraced statistically higher MGMT and hMSH2 promoter methylation level than normal tissue. The promoter methylation status of MGMT and hMSH2 corresponds positively with the protein expression level of MGMT and hMSH2. However, such relevance was not found for hMLH1. Furthermore, TP53 mutation status was well associated with MGMT and hMSH2 promoter methylation status, indicating that silencing of the two genes could lead to TP53 mutation in ESCC.
The abnormal function of O(6)-methylguanine-DNA methyltransferase (MGMT) is reported to be associated with the occurrence of various tumors and malignant tumor progression. However, little evidence is available to describe its role in esophageal carcinogenesis. To address this issue, we constructed a stable MGMT-silenced esophageal cancer cell line by RNA interference, and exposed the cells to N-methyl-N-nitro-N-nitrosoguanidine (MNNG) to investigate the role that MGMT plays in toxicity. During this time, we also observed the malignant behavior of cells in vitro and in vivo. In addition, two-dimensional electrophoresis and mass spectrometry were used to detect and confirm the proteins that were differentially expressed in the MGMT-deficient and MGMT-proficient cells, which might be responsible for the malignant alteration of cells. Results showed that the IC(50) of MGMT-deficient and MGMT-proficient cells exposed to MNNG was 30 ?M and 65 ?M, respectively, and MGMT-deficient cells had more aggressive motility and invasive abilities compared with MGMT-proficient cells. Nineteen differentially expressed proteins were detected between the MGMT-deficient and MGMT-proficient cells, 14 of which were identified, including the membrane-cytoskeleton linker protein, Ezrin, which was confirmed by both mass spectrometry and western blot analysis. The correlation between MGMT, Ezrin expression, and the malignant behavior of one normal epithelial esophageal cell line and seven esophageal cancer lines is discussed. In conclusion, loss of MGMT expression leads EC109 esophageal cancer cells to have increased malignant behavior, which may correlate with its high Ezrin protein expression.
Cytochrome P450 2E1 (CYP2E1) is an important metabolizing enzyme involved in oxidative stress responses to benzene, a chemical associated with bone marrow toxicity and leukemia. We aimed to identify the CYP2E1 genetic biomarkers of susceptibility to benzene toxicity in support of environmental and occupational exposure prevention, and to test whether a model using immortal human lymphocytes might be an efficient tool for detecting genetic biomarkers.
Small-sized titanium dioxide (TiO2) nanoparticles (< 10 nm) are widely used in both industry and daily life due to their enhanced thermomagnetic and photocatalytic properties and surface activity. However, their increasing use increases the health risk of people exposed to these particles, either occupationally or environmentally. This study was performed to evaluate the effect of small-sized TiO2 nanoparticles on the immune function of rat pulmonary alveolar macrophages in vivo. Forty-two rats were intra-tracheally instilled with 0.5, 5 or 50 mg/kg of NP-1 and F-1 TiO2 primary particles with a median size of 5 nm and 200 nm, respectively. Rat pulmonary alveolar macrophages were obtained from lung lavage fluids using a closed chest technique. Cells were assessed for morphology, phagocytic ability and chemotactic ability, Fc receptor expression, MHC-class II molecule expression, and expression of nitric oxide (NO) and tumor necrosis factor-alpha (TNF-alpha). The result showed that the inhalation of NP-1 TiO2 particles induced the membrane and ultrastructure damage of PAMs. The phagocytic ability of the macrophages increased when they were exposed to low dose of NP-1 TiO2 and decreased when they were exposed to high dose of NP-1 TiO2. Exposure to NP-1 TiO2 also decreased the chemotactic ability of the macrophages as well as decreasing the expression of Fc receptors and MHC-class II on the cell surface. The mechanism responsible for these changes was mediated via altering NO and TNF-alpha expression by the PAMs. The amount of NO and TNF-alpha secreted by macrophages gradually increased as the dosage of TiO2 nanoparticles increased. Small-sized TiO2 nanoparticles (but not the fine counterpart) elicited stronger NO and TNF-alpha production. The present study suggests that both damage to the cell structure and pulmonary alveolar macrophage dysfunction may occur, leading to a reduction in both non-specific and specific immune responses in individuals exposed to small-sized TiO2 nanoparticles.
The functional modification of the outer surface of carbon nanotubes (CNTs) is likely to improve their biocompatibility. Therefore, CNTs have attracted great attention not only in electrical, optical and mechanical applications but also in biological and pharmaceutical applications. Thus, it is important to examine the biodistribution and kinetics of the carbon-based nanotubes when they are introduced into living systems. Here, we synthesized and characterized tyrosine-functionalized carbon nanotubes (CNTs-Tyr), and assessed the biodistribution profile of CNTs-Tyr in mice, following three different administrations by the 125I radioisotope tracer method. CNTs-Tyr was delivered quickly around the entire body, and different absorbtion and biodistribution profiles of CNTs-Tyr were observed with different routes of administration. Following intravenous injection, CNTs-Tyr accumulated within 24 h mainly in the lungs and slightly in the spleen and liver, and may be eliminated primarily through the kidneys. After administration via gavage, most of the CNTs-Tyr were eliminated through the intestine, and rarely delivered into the organs. After intraperitoneal injection, CNTs-Tyr accumulated in the spleen and were rapidly eliminated from the other organs within 24 h. The blood circulation half-life of CNTs-Tyr was about 4.4 h. The behavior of CNTs-Tyr in mice is somewhat different from the results reported previously. This suggests that the functionalized group may affect the affinity of carbon nanotubes for particular organs. The results provide basic biological information for the biomedical application and risk assessment of CNTs.
Single-nucleotide polymorphisms (SNP) in genes coding metabolizing enzymes modulate gene functions and cellular toxicity in response to chemicals. Quinone oxidoreductase 1 (NQO1) is an important detoxification enzyme involved in the catabolism of 1,4-benzoquinone (1,4-BQ), a benzene metabolite believed to be associated with bone-marrow toxicity and leukemia. Gene function was evaluated in immortalized human B lymphocytes derived from a Chinese Han population with independent genotypes at 2 NQO1 SNP sites. 1,4-Benzoquinone was incubated with these immortalized lymphocytes of differing genotypes. Among the genotypes of 2 SNP examined, cell lines with rs1800566CC showed a higher NQO1 enzymic activity after a 48 h of treatment with 10 muM 1,4-BQ, and a lower comet rate compared with cells of CT/TT genotypes. Data suggested that NQO1 rs1800566 might serve as a functional genetic marker for benzene toxicity in the Chinese Han population. The immortalized B lymphocytes derived from different populations might thus be used as a biomarker to detect functional genetic markers related to exposure to environmental chemicals.
Glutathione S-transferases (GST) belong to a superfamily of phase II enzymes believed to be associated with enhanced frequency of esophageal carcinoma. This study was performed to evaluate whether the GST family was associated with susceptibility to esophageal carcinoma in China. Ninety-seven patients with newly diagnosed, untreated esophageal squamous-cell carcinoma (ESCC) and 97 healthy controls matched in age, gender, and residence were recruited in this community-based case-control study. Null genotypes of GSTM1 and GSTT1 were determined by multiplex polymerase chain reaction (PCR) technique. Ile105Val polymorphism in the fifth exon, mRNA level, CpG island hypermethylation of promoter, and protein levels of GSTP1 gene were measured with peripheral blood mononuclear cell (PBMC) by PCR-restriction fragment length polymorphism (PCR-RFLP) techniques, quantitative real-time reverse transcription PCR, methylation-specific PCR (MSP), and Western blotting, respectively. The results showed that GSTM1 null genotype and GSTT1 null genotype were significantly associated with increased risk for esophageal cancer in Chinese population. Compared with the control, the relative expression levels of mRNA were significantly reduced in ESCC patients. The conditional logistic regression analysis demonstrated that increased risk for esophageal cancer was associated with CpG island hypermethylation of promoter of GSTP1 gene. GSTP1 protein levels also showed significant decrease in ESCC when adjusted for age, gender, smoking status, and alcohol use. An individual with GSTM1 or GSTT1 null genotype may thus be more susceptible to esophageal cancer development. Reduced expression in mRNA and protein levels were the main manifestations noted in aberrant function of GSTP1 gene. Data thus suggest that the CpG island hypermethylation of promoter gene may serve as a useful biomarker for early diagnosis of esophageal carcinoma development.
Carbon nanotubes have attracted attention not only due to electrical, optical, and mechanical applications but also due to their presence in biological and pharmaceutical products. In this study, modified multi-walled carbon nanotubes (MWCNT) were used as a model to evaluate potential subchronic effects of carbon nanotubes on mice. ICR mice were treated with phosphorylcholine-grafted multi-walled carbon nanotubes (MWCNT-PC) daily for 28 d at 10, 50, or 250 mg/kg by the intraperitoneal (ip) route. Subchronic exposure to MWCNT-PC did not produce any apparent systemic effects in mice. The body weight of the high-dose group was significantly lower than control in male mice, whereas tissue to body weight ratios of liver, spleen, and lung rose significantly with increase of dose of MWCNT-PC. There were significant differences between high-dose exposure and control groups. Accumulation of carbon nanotubes and inflammation response in liver, spleen, and lung were observed in the high-dose exposure group. No systemic toxicity and histopathological changes were found in 10-mg/kg exposure groups. Data in the present study support the view that MWCNT in vivo do not exert apparent marked effects in mice and that MWCNT products are relatively safe for human consumption.
As titanium dioxide (TiO(2)) nanoparticles are widely used commercially, the potential effects of TiO(2) nanoparticles on humans are a concern. To evaluate the effects of TiO(2) nanoparticles on hepatic and renal functions and correlate changes to oxidative stress, Sprague-Dawley rats were treated with TiO(2) particles of two different specific surface areas (TiO(2-S50): 50 m(2)/g, and TiO(2-S210): 210 m(2)/g) at 0.5, 5, or 50 mg/kg body weight by intratracheal instillation. After 7 d, TiO(2) nanoparticles produced no obvious acute toxicity on hepatic and renal functions. However, superoxide dismutase (SOD) activity of plasma and glutathione peroxidase (GSH-PX) activity of kidney in the low-dose TiO(2-S210) group were significantly decreased. After TiO(2-S210) exposure, malondialdehyde (MDA) levels of liver and kidney in intermediate and high-dose groups were significantly increased. This change only appeared in liver after TiO(2-S50) exposure. Furthermore, SOD activity in liver and kidney and GSH-PX activity in kidney with low TiO(2-S210) exposure group were significantly less than with low TiO(2-S50). No apparent pathological changes in liver and kidney were observed. Intratracheal exposure to TiO(2) nanoparticles may induce oxidative stress in liver and kidney, but does not influence hepatic or renal functions. There was no apparent evidence that TiO(2-S210) was more toxic than TiO(2-S50). In general, intratracheal exposure to TiO(2) did not markedly affect extrapulmonary tissue functions.
Recent reports have shown that vitamin D status was inversely associated with the risk of various cancers. However, few studies examined the association between vitamin D levels and risk of skin cancer.
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