Search

Circular RNAs (circRNAs), is a novel type of endogenous non-coding RNAs (ncRNAs) participated in the pathogenesis of many diseases. Beryllium is one of the carcinogenesis elements. However, the mechanism and function of circRNAs in human bronchial epithelial cells (16HBE) induced by beryllium sulfate (BeSO4) was rarely reported. Therefore, the high-throughput RNA sequencing analysis was performed to detect the circRNA profiles between control groups and BeSO4-induced groups. Furthermore, circRNA-miRNA-mRNA network, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, and PPI network analysis were used for bioinformatics analysis. CircRNA sequencing analysis revealed that 36 circRNAs were up-regulated and 35 circRNAs were down-regulated in the BeSO4-exposed groups. The selected circRNAs were verified by real-time fluorescent quantitative PCR (qRT-PCR). Hsa_circ_0004214 and hsa_circ_0003586 were validated to be up-regulated, hsa_circ_0047958, hsa_circ_0001944, and hsa_circ_0008982 were down-regulated. The circRNA-miRNA-mRNA network annotated the key signaling pathway including cellular senescence, TNF signaling pathway, NF-kappa B signaling pathway, HIF-1 signaling pathway, and Hippo signaling pathway. The PPI network indicated the most circRNAs might participate in the BeSO4 toxicity by acting as a sponge for the miR-663b through JAK–STAT signaling pathway. In summary, our study suggests that circRNAs may play roles in the mechanism of beryllium toxicity.

Background Permethrin is one of the pyrethroid insecticides, which is widely used in agriculture and public health. Although acute toxicity of the insecticide has been studied, the chronic toxicity upon the long-term exposure has not been clear yet. The purpose of the current study is to investigate the organ toxicities of permethrin following its long-term low-dose exposure. Methods Male Wistar rats were daily administrated orally with permethrin (75 mg/kg body weight/day, gavage) for 90 days, and then the samples of biofluids (blood and urine) and organs including liver and kidney were collected. The serum and urine samples were measured by biochemical assay and the tissues of kidney and liver were examined and analyzed by histopathological method. Results The results showed that no change was found in serum and urine biochemical parameters for the toxicity; however, significant changes including hyperchromatic nuclei swollen in the hepatic parenchymal cells and the swelling proximal tubules in the kidneys were observed in the tissue structures of liver and kidneys in the histopathological sections. Conclusion These results indicate that low-dose long-term exposure of permethrin can cause chronic toxicity with slight liver and kidney damage.

Background This study aims to establish an in vitro monitoring approach to evaluate the pesticide exposures. We studied the in vitro cytotoxicity of three different body fluids of rats to the respective corresponding tissue-derived cells. Methods Wistar rats were orally administrated daily with three different doses of chlorpyrifos (1.30, 3.26, and 8.15 mg/kg body weight/day, which is equal to the doses of 1/125, 1/50, and 1/20 LD50, respectively) for consecutive 90 days. Blood samples as well as 24-hour urine and fecal samples were collected and processed. Then, urine, serum, and feces samples were used to treat the correspondent cell lines, i.e., T24 bladder cancer cells, Jurkat lymphocytes, and HT-29 colon cancer cells respectively, which derived from the correspondent tissues that could interact with the respective corresponding body fluids in organism. Cell viability was determined by using MTT or trypan blue staining. Results The results showed that urine, serum, and feces extract of the rats exposed to chlorpyrifos displayed concentration- and time-dependent cytotoxicity to the cell lines. Furthermore, we found that the cytotoxicity of body fluids from the exposed animals was mainly due to the presence of 3, 4, 5-trichloropyrindinol, the major toxic metabolite of chlorpyrifos. Conclusions These findings indicated that urine, serum, and feces extraction, especially urine, combining with the corresponding tissue-derived cell lines as the in vitro cell models could be used to evaluate the animal exposure to pesticides even at the low dose with no apparent toxicological signs in the animals. Thus, this in vitro approach could be served as complementary methodology to the existing toolbox of biological monitoring of long-term and low-dose exposure to environmental pesticide residues in practice.

To screen the differentially expressed proteins (DEPs) in human bronchial epithelial cells (HBE) treated with atmospheric fine particulate matter (PMHBE cells were treated with PMOverall, 67 DEPs were screened in the Shenzhen sample-treated group, of which 46 were upregulated and 21 were downregulated. In total, 252 DEPs were screened in the Taiyuan sample-treated group, of which 134 were upregulated and 118 were downregulated. KEGG analysis demonstrated that DEPs were mainly enriched in ubiquitin-mediated proteolysis and HIF-1 signal pathways in Shenzhen PMOur findings provide a valuable basis for further evaluation of PM

Motivation Both β-value and M-value have been used as metrics to measure methylation levels. The M-value is more statistically valid for the differential analysis of methylation levels. However, the β-value is much more biologically interpretable and needs to be reported when M-value method is used for conducting differential methylation analysis. There is an urgent need to know how to interpret the degree of differential methylation from the M-value. In M-value linear regression model, differential methylation M-value ΔM can be easily obtained from the coefficient estimate, but it is not straightforward to get the differential methylation β-value, Δβ since it cannot be obtained from the coefficient alone. Results To fill the gap, we have built a bridge to connect the statistically sound M-value linear regression model and the biologically interpretable Δβ. In this article, three methods were proposed to calculate differential methylation values, Δβ from M-value linear regression model and compared with the Δβ directly obtained from β-value linear regression model. We showed that under the condition that M-value linear regression model is correct, the method M-model-coef is the best among the four methods. M-model-M-mean method works very well too. If the coefficients α0, α2,…αp are not given (as ‘MethLAB’ package), the M-model-M-mean method should be used. The Δβ directly obtained from β-value linear regression model can give very biased results, especially when M-values are not in (−2, 2) or β-values are not in (0.2, 0.8). Availability and implementation The dataset for example is available at the National Center for Biotechnology Information Gene Expression Omnibus repository, GSE104778. Supplementary information Supplementary data are available at Bioinformatics online.

Carbamates and pyrethroids are widely used pesticides. However, their joint toxicity at low doses with long-term exposure remains unknown. Therefore, we investigated the subchronic joint hepatotoxicity of the two representative pesticides within these two classes, i.e., propoxur (PR) and permethrin (PE) in rats. The male Wistar rats were orally treated with three different doses of PR, PE and their mixtures for 90 consecutive days. Liver weight, serum clinical chemistry parameters and histopathological changes were measured to access the hepatotoxicity. In addition, oxidative stress markers in liver were measured using biochemical assays. The results showed that PR reduced liver weight and lead to prominent liver histological changes. Moreover, PR dose-dependently induced lipid peroxidation and reduced superoxide dismutase activity. In contrast, PE induced a relatively mild hepatotoxicity. Intriguingly, the mixture of PR and PE did not reduce liver weight or increase serum aspartate transaminase activity. In addition, the mixture did not reduce the antioxidant enzyme activity as PR did. Thus, these results showed that PR induced prominent hepatotoxicity with subchronic exposure, and there is a potential antagonistic interaction between PR and PE on the oxidative damage in liver of rats.

As a major kind of carbamate insecticide, propoxur plays an important role in agriculture, veterinary medicine, and public health. The acute toxicity of propoxur is mainly neurotoxicity due to the inhibition of cholinesterase. However, little is known regarding the toxicity of propoxur upon long-term exposure at low dose. In this study, Wistar rats were orally administrated with low dose (4.25 mg/kg body weight/day) for consecutive 90 days. And the urine samples in rats treated with propoxur for 30, 60, and 90 days were collected and analyzed by employing 1H NMR-based metabolomics approach. We found that propoxur caused significant changes in the urine metabolites, including taurine, creatinine, citrate, succinate, dimethylamine, and trimethylamine-N-oxide. And the alteration of the metabolites was getting more difference compared with that of the control as the exposure time extending. The present study not only indicated that the changed metabolites could be used as biomarkers of propoxur-induced toxicity but also suggested that the time-course alteration of the urine metabolomic profiles could reflect the progressive development of the toxicity following propoxur exposure.

The environmental pollution associated with electrical discharge machining is not yet clearly understood. Airborne exposure to nanoscale and respirable particles were investigated with regard to the aerosol characteristics of a wire electrical discharge machining (WEDM) workshop. The total number concentration of the aerosol was multimodal, with the highest peak maxima during the working hours of 10:00 am and 3:00 pm. The majority of the released particles were smaller than d = 100 nm, with the maximum amount sized 40 nm. A large quantity of metallic elements, including Fe, Al and Cu, were found in the aerosol particulates coming from WEDM processing. Furthermore, the aerosol particles exhibited higher cellular toxicity and ROS producing ability in human alveolar epithelial cells (16HBE) when compared to the atmospheric background. Our results indicate substantial hazards arising from exposure to polluted atmosphere of a WEDM workshop. Effective exposure controls and protections are thus strongly recommended.

Perfluorooctane sulfonate (PFOS), a new kind of persistent organic pollutant, is widely distributed in the environment and exists in various organisms, where it is also a neurotoxic compound. However, the potential mechanism of its neurotoxicity is still unclear. To examine the role of epigenetics in the neurotoxicity induced by PFOS, SK-N-SH cells were treated with different concentrations of PFOS or control medium (0.1% DMSO) for 48 h. The mRNA levels of DNA methyltransferases (DNMTs) and Brain-derived neurotrophic factor (BDNF), microRNA-16, microRNA-22, and microRNA-30a-5p were detected by Quantitative PCR (QPCR). Enzyme Linked Immunosorbent Assay (ELISA) was used to measure the protein levels of BDNF, and a western blot was applied to analyze the protein levels of DNMTs. Bisulfite sequencing PCR (BSP) was used to detect the methylation status of the BDNF promoter I and IV. Results of MTT assays indicated that treatment with PFOS could lead to a significant decrease of cell viability, and the treated cells became shrunk. In addition, PFOS exposure decreased the expression of BDNF at mRNA and protein levels, increased the expression of microRNA-16, microRNA-22, microRNA-30a-5p, and decreased the expression of DNMT1 at mRNA and protein levels, but increased the expression of DNMT3b at mRNA and protein levels. Our results also demonstrate that PFOS exposure changes the methylation status of BDNF promoter I and IV. The findings of the present study suggest that methylation regulation of BDNF gene promoter and increases of BDNF-related-microRNA might underlie the mechanisms of PFOS-induced neurotoxicity.

Neuropathy target esterase (NTE) is proven to act as a lysophospholipase (LysoPLA) in mice and phospholipase B (PLB) in cultured mammalian cells. In sensitive species, organophosphate (OP)–induced delayed neurotoxicity is initiated when NTE is inhibited by > 70% and then aged. It is hypothesized that homeostasis of phosphatidylcholine (PC) and/or lysophosphatidylcholine (LPC) in mice might be disrupted by the OPs since NTE and other phospholipases could be inhibited. To test this hypothesis, we treated mice using tri-o-cresyl phosphate (TOCP), which can inhibit and age NTE. Phenylmethylsulfonyl fluoride (PMSF), which inhibits NTE but cannot age, was used as a negative control. Effects on activity of NTE, LysoPLA, and PLB, the levels of PC, LPC, and glycerophosphocholine (GPC), and the aging of NTE in the brain, spinal cord, and sciatic nerve were examined. The results showed that the activities of NTE, NTELysoPLA, LysoPLA, NTE-PLB, and PLB were significantly inhibited in both TOCP- and PMSF-treated mice, and the inhibition of NTE and NTE-LysoPLA or NTE-PLB showed a high correlation coefficient. The NTE inhibited by TOCP was of the aged type, while nearly all NTE inhibited by PMSF was of the unaged type. Although the GPC level was remarkedly decreased, no significant change of PC and LPC levels was observed. However, the inhibition of these enzymes in mice by TOCP exhibited different characteristics from the TOCP-treated hens that we previously reported, which indicates that these enzymes were inhibited and then recovered more rapidly in mice than in hens. All results suggest that PC and LPC homeostasis was not disrupted in mice after exposure to TOCP. Differences in inhibition of NTE, LysoPLA, and PLB activities by TOCP between mice and hens may elucidate why these two species display different signs after exposure to the same neuropathic OPs.

Patatin-domain containing proteins constitute a large family of enzymes including known lipases that hydrolyze triglycerides, diglycerides, and phospholipids, some of which still remain to be characterized. One of those is NTE-related esterase (NRE), which exhibits sequence and domain homology to neuropathy target esterase (NTE). A splice variant of the catalytic domain of mouse NRE (mNRECV) was identified in multiple adult tissues, including brain, kidney, liver and testis. Genomic organization showed that mNRECV gene lacked the 22nd exon of mouse NRE and the 14th exon termination site of mNRECV was behind of 5 bp with the comparison of the 34th exon of mNRE gene. Over-expression of mNREC and mNRECV in mammalian cells showed that they had similar phenyl valerate esterase activities, but different from human NTE esterase domain. Subcellular distribution of an enhanced green fluorescent protein-mNRECV fusion protein was mainly observed to colocalize with endoplasmic reticulum in the juxtanuclear area and a little in cytoplasm. Moreover, autophagy/lysosome pathway was found to be involved in the degradation of mNRECV protein by inhibition and induction of autophagy, as well as co-location of mNRECV-EGFP with lysosomes. The high identity between mNRECV and mNREC suggested that mouse NRE has similar characteristics.

Concerns have arisen about the health and environmental impacts of the increasing commercial use of silver nanoparticles (AgNPs). However, the toxic mechanisms and target tissues of AgNPs have not been fully defined. In this paper, we investigated the tissue toxicity of mice after intravenous administration of AgNPs at a single-dose of 0.2, 2 or 5 mg per kg (body weight), respectively. Biodistribution, endoplasmic reticulum stress, and oxidative stress were examined in mouse organs at eight hours after exposure. Stress markers, e.g. HSP70, BIP, p-IRE1, p-PERK, chop and xbp-1s proteins/genes, were significantly upregulated in a dose-dependent manner. In the liver, spleen, lung and kidney, high stress accompanied by apoptosis occurred. Low stress levels were observed in the heart and brain. Thus, it is proposed that the liver, spleen, lung and kidney are dominant target tissues of AgNP exposure. The lower stress and toxicity in the heart and brain were in agreement with lower AgNP accumulation. The present results demonstrated that AgNP exposure eventually resulted in permanent toxic damage by gradually imposing stress impacts on target organs. These findings highlight the potent applications of stress markers in future risk evaluation of silver nanoparticle toxicity.

Silver nanoparticles (AgNPs) attract considerable public attention both for their antimicrobial properties and their potential adverse effects. In the present study, endoplasmic reticulum (ER) stress was used as a sensitive and early biomarker to evaluate the toxic potential of AgNPs in three different human cell lines in vitro and in vivo in mice. In 16HBE cells, the activation of ER stress signaling pathway was observed by upregulated expression including xbp-1s, chop/DDIT3, TRIB3, ADM2, BIP, Caspase-12, ASNS and HERP at either the mRNA and/or protein levels. However, these changes were not observed in HUVECs or HepG2 cells. Furthermore, mice experiments showed that different tissues had various sensitivities to AgNPs following intratracheal instillation exposure. The lung, liver and kidney showed significant ER stress responses, however, only the lung and kidney exhibited apoptosis by TUNEL assay. The artery and tracheal tissues had lower ER stress and apoptosis after exposure. The lowest observable effect concentrations (LOEC) were proposed based on evaluation of AgNP induced ER stress response in cell and mouse models. In summary, preliminary evaluation of AgNP toxicity by monitoring the ER stress signaling pathway provides new insights toward the understanding the biological impacts of AgNPs. The adverse effects of exposure to AgNPs may be avoided by rational use within the safe dose.

Type I and II pyrethroid insecticides display different neurotoxicity. To investigate the long-term (60 days exposure) metabolic effect of the two types of pyrethroid insecticides deltamethrin and permethrin, 1 H nuclear magnetic resonance (NMR) spectroscopy-based metabonomics was used to analyze the biochemical composition of urine and serum samples from rats administrated daily with deltamethrin or permethrin for 60 consecutive days, and principal component analysis used to visualize similarities and differences in the resultant biochemical profiles. Rats treated with either deltamethrin or permethrin displayed increased levels of urinary acetate, dimethylamine, dimethylglycine, trimethylamine and serum free amino acids, and decreased urinary 2-oxoglutarate, all of which are indicative of kidney lesions and nephrotoxicity. The reduced excretion of tricarboxylic acid cycle intermediates, together with increased 3-D-hydroxybutyrate, acetate, and lactate in treated rats could suggest disturbance of the energy metabolism, including an increased rate of anaerobic glycolysis, enhanced fatty acid β -oxidation and ketogenesis. These results show that these two types of insecticides have similarities in the urine and serum spectra, indicating that similar metabolic pathways are perturbed by the insecticides, which induced hepatotoxicity and nephrotoxicity. This approach may lead to the discovery of novel biomarkers of pyrethroids toxicity and thereby provide new insights into the toxicological mechanisms of pesticides pyrethroids.

Metabonomic analysis, clinical chemical analysis and histopathology were used to investigate the toxic effects of subchronic exposure to dichlorvos, deltamethrin, and a combination of these two pesticides, in rats. Weight loss, hind limb weakness and histopathological changes in kidney tissue were only observed in rats exposed to high doses of deltamethrin, or a combination of deltamethrin and dichlorvos. Urinary metabonomic analysis indicated that exposure to a mixture of dichlorvos and deltamethrin was followed by increases in urinary lactate, dimethylamine, N-glycoprotein (NAC) and glycine similar to those observed in rats treated with either dichlorvos or deltamethrin alone. Serum metabonomic analysis suggests that dichlorvos induced an increase in lactate and alanine and a decrease in dimethylglycine (DMG), NAC and very low- and low-density lipoprotein (VLDL/LDL). High levels of lactate and low levels of NAC and VLDL/LDL were observed in the deltamethrin treatment group. Treating rats with a mixture of dichlorvos and deltamethrin caused an increase in serum lactate, trimethylamine-N-oxide (TMAO), choline and alanine, with the highest levels of these metabolites observed in those that received the highest dose. Exposure to a mixture of dichlorvos and deltamethrin also resulted in a decrease in serum acetone, DMG, NAC, and VLDL/LDL. Changes in serum TMAO, alanine, choline and acetone in this treatment group were higher than in rats treated with either dichlorvos or deltamethrin. These results suggest that exposing rats to subchronic doses of dichlorvos, deltamethrin, or a combination of these pesticides, disrupted the energy metabolism of the liver and reduced kidney function.

NTE-related esterase (NRE) is an insulin-regulated lysophospholipase with homology to neuropathy target esterase (NTE), which plays a role in energy metabolism. Here, we reported two alternative splicing variants of the murine NRE (mNRE) gene, termed mNREV1 and mNREV2. Genomic organization analysis indicated that 5' splice site of mNRE intron 33 was changed in both mNREV1 and mNREV2, and mNRE exon 21 was deleted in mNREV2. mNREV1 had the same protein domains with mNRE, while mNREV2 lacked the patatin domain in the C-terminal catalytic region. Green fluorescent protein-mNREV1 or mNREV2 fusion proteins localized to the endoplasmic reticulum. mNREV1 and mNRE exhibited equal hydrolytic activity to the substrate phenyl valerate, whereas mNREV2 did not have any catalytic activity. The expression profiles of mNRE and its splicing isoforms in white adipose tissue, cardiac muscle, skeletal muscle, and testis tissues were further analyzed by real time quantitative-PCR in fed and fasted states, which indicated that the major isoform of mNRE mRNA generated switched from mNREV2 to mNREV1 during fasting. Thus there was a nutritional regulation of mNRE expression at the mRNA levels via alternative splicing.

Neuropathy target esterase (NTE) was proposed as the initial target during the process of organophosphate-induced delayed neuropathy (OPIDN) and adult hens are the animal model of OPIDN. However, little has been known about the sequence and characteristics of chicken NTE. Here, we firstly identified the full length cDNA of chicken NTE (cNTE), which contained an open reading frame of 3966 nucleotides encoding 1321 amino acids. Chicken NTE had two distinct regions, one was the regulatory domain (cNTER) and the other was the catalytic domain (cNEST). Over-expression of cNTER in mammalian cells did not show any NTE activity, whereas cNEST had NTE activity. Cells expressing cNTER tagged with green fluorescent protein (GFP) showed accumulation of cNTER-GFP in an endoplasmic reticulum-like localization pattern. In addition, macroautophagy and the proteasome pathways were found to be involved in the degradation of cNTER, but not cNEST. These results first showed that cNTE was an ER-anchored protein and degraded by macroautophagy as well as the proteasome.