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Occupational lead exposure on genome-wide DNA methylation and DNA damage
2022
Meng, Yu | Zhou, Mengyu | Wang, Tuanwei | Zhang, Guanghui | Tu, Yuting | Gong, Shiyang | Zhang, Yunxia | Christiani, David C. | Au, William | Liu, Yun | Xia, Zhao-lin
Lead (Pb) exposure can induce DNA damage and alter DNA methylation but their inter-relationships have not been adequately determined. Our overall aims were to explore such relationships and to evaluate underlying epigenetic mechanisms of Pb-induced genotoxicity in Chinese workers. Blood Pb levels (BLLs) were determined and used as individual's Pb-exposure dose and the Comet assay (i.e., % tail DNA) was conducted to evaluate DNA damage. In the screening assay, 850 K BeadChip sequencing was performed on peripheral blood from 10 controls (BLLs ≤100 μg/L) and 20 exposed workers (i.e., 10 DNA-damaged and 10 DNA-undamaged workers). Using the technique, differentially methylated positions (DMPs) between the controls and the exposed workers were identified. In addition, DMPs were identified between the DNA-undamaged and DNA-damaged workers (% tail DNA >2.14%). In our validation assay, methylation levels of four candidate genes were measured by pyrosequencing in an independent sample set (n = 305), including RRAGC (Ras related GTP binding C), USP1 (Ubiquitin specific protease 1), COPS7B (COP9 signalosome subunit 7 B) and CHEK1 (Checkpoint kinase 1). The result of comparisons between the controls and the Pb-exposed workers show that DMPs were significantly enriched in genes related to nerve conduction and cell cycle. Between DNA-damaged group and DNA-undamaged group, differentially methylated genes were enriched in the pathways related to cell cycle and DNA integrity checkpoints. Additionally, methylation levels of RRAGC and USP1 were negatively associated with BLLs (P < 0.05), and the former mediated 19.40% of the effect of Pb on the % tail DNA. These findings collectively indicated that Pb-induced DNA damage was closely related to methylation of genes in cell cycle regulation, and methylation levels of RRAGC were involved in Pb-induced genotoxicity.
اظهر المزيد [+] اقل [-]Lifelong exposure to pyrethroid insecticide cypermethrin at environmentally relevant doses causes primary ovarian insufficiency in female mice
2022
Ma, Xiaochen | Zhang, Wei | Song, Jingyi | Li, Feixue | Liu, Jing
Pyrethroids are a class of widely used insecticides. Our recent epidemiological study of Chinese women reported that pyrethroid exposure was positively associated with the risk of primary ovarian insufficiency (POI). In this study, we utilized cypermethrin (CP), the most frequently detected pyrethroid in the environment, to recognize how lifelong and low-dose exposure to pyrethroids affects ovarian functions and the underlying mechanism(s). Female mice were exposed to CP at doses of human dietary intake of 6.7 μg/kg/day, an acceptable daily intake (ADI) of 20 μg/kg/day, or the chronic reference dose (RfD) of 60 μg/kg/day, starting from gestational day 0.5 until 44-week-old. We assessed effects on fertility, serum hormone levels, ovarian follicular development and ovarian transcriptomic profiles. Chronic exposure to CP at doses of ADI and RfD caused a significant reduction in the size of the primordial follicle pool on postnatal day (PND) 5 and the number of all types of follicles in 44-week-old mice, lower estrogen and higher gonadotropin levels, as well as decreased fertility. Significant increase in apoptosis and decrease in cell proliferation were observed in CP-exposed ovarian follicles from PND 5 and 44-week-old mice. Ovarian transcriptomic data showed that the pro-apoptotic protein BMF and the cell cycle inhibitor p27 were significantly up-regulated in CP-exposed ovaries. Cyp17a1, Cyp19a1 and Hsd17b1 genes involved in the key steps of steroidogenesis were down-regulated in the ovaries of female mice exposed to CP. This study first reported that lifelong exposure to CP at doses of ADI or RfD caused an ovarian phenotype similar to human POI in female mice and provided a mechanistic explanation. Our findings suggest that lifelong exposure to pyrethroids of low doses, which are recommended as ‘safe’ dosages, may have a significant impact on the ovarian health of female mammals and humans.
اظهر المزيد [+] اقل [-]The inflammation response and risk associated with aflatoxin B1 contamination was minimized by insect peptide CopA3 treatment and act towards the beneficial health outcomes
2021
Dey, Debasish Kumar | Chang, Sukkum Ngullie | Kang, S. C. (Sun Chul)
This study focused on the possible chemo-preventive effects of insect peptide CopA3 on normal human colon cells against the inflammation induced by the toxic environmental pollutant aflatoxin B1 (AFB1). In the study, we used CCD 841 CoN normal human colon cells to investigate the cytotoxic effect induced by AFB1 and elucidated the negative impact of AFB1 exposure on the cell cycle progression. Further, we also carried out the in-vivo experiment, where male BALB/c mice were administrated with AFB1 to induce inflammation associated cancer like phenotype and the dietary effect of CopA3 was evaluated on the early stages of AFB1-induced hepatotoxicity and inflammation in colon tissues. At the initiation stage, CopA3 was given along with water, which significantly decreased the inflammation in the liver and colon of AFB1 exposed mice model. Mice that received CopA3 alone showed enhanced activity of several antioxidant enzymes. In the post treatment stage, the CopA3 dosage remarkably increased the Ki-67 protein expression, indicating the enhancement in cell proliferation event and increased the number of apoptotic cells in colonic crypts, suggesting the capability of CopA3 treatment towards the epithelial cell turnover. Thus, CopA3 treatment shows its potential to inhibit the development of the early stages of AFB1-induced colon inflammation and hepatotoxicity in mice by inhibiting the DNA synthesis of the damaged and inflammatory cell and induced apoptosis for the clearance of damaged cells. Collectively, the results of this study suggest that CopA3 treatment may play a protective role against the mycotoxin induced inflammation.
اظهر المزيد [+] اقل [-]Physarum polycephalum macroplasmodium exhibits countermeasures against TiO2 nanoparticle toxicity: A physiological, biochemical, transcriptional, and metabolic perspective
2021
Zhang, Zhi | Liang, Zhi Cheng | Liang, Xiu Yi | Zhang, Qing Hai | Wang, Ya Jie | Zhang, Jian Hua | De Liu, Shi
Concerns about the environmental and human health implications of TiO₂ nanoparticles (nTiO₂) are growing with their increased use in consumer and industrial products. Investigations of the underlying molecular mechanisms of nTiO₂ tolerance in organisms will assist in countering nTiO₂ toxicity. In this study, the countermeasures exhibited by the slime mold Physarum polycephalum macroplasmodium against nTiO₂ toxicity were investigated from a physiological, transcriptional, and metabolic perspective. The results suggested that the countermeasures against nTiO₂ exposure include gene-associated metabolic rearrangements in cellular pathways involved in amino acid, carbohydrate, and nucleic acid metabolism. Gene-associated nonmetabolic rearrangements involve processes such as DNA repair, DNA replication, and the cell cycle, and occur mainly when macroplasmodia are exposed to inhibitory doses of nTiO₂. Interestingly, the growth of macroplasmodia and mammal cells was significantly restored by supplementation with a combination of responsive metabolites identified by metabolome analysis. Taken together, we report a novel model organism for the study of nTiO₂ tolerance and provide insights into countermeasures taken by macroplasmodia in response to nTiO₂ toxicity. Furthermore, we also present an approach to mitigate the effects of nTiO₂ toxicity in cells by metabolic intervention.
اظهر المزيد [+] اقل [-]Enantioselective residues and toxicity effects of the chiral triazole fungicide hexaconazole in earthworms (Eisenia fetida)
2021
Liu, Tong | Fang, Kuan | Liu, Yalei | Zhang, Xiaolian | Han, Lingxi | Wang, Xiuguo
The enantioselective toxic effect and environmental behavior of chiral pesticides have attracted increasing research attention. In this study, the enantioselective toxicity and residues of hexaconazole (HEX) in earthworms (Eisenia fetida) were investigated. In the present study, significant enantioselective degradation characteristics were observed in artificial soil with the R-enantiomer preferentially degrading (p < 0.05); however, no significant enantioselective bioaccumulation was observed in the earthworms (p > 0.05). The acute toxicity of S-(+)-HEX was higher than that of R-(−)-HEX in earthworms, with 48-h LC₅₀ values of 8.62 and 22.35 μg/cm², respectively. At 25 mg/kg, enantiospecific induction of oxidative stress was observed in earthworms; moreover, S-(+)-HEX had a greater influence on the contents of malonaldehyde, cytochrome P450, and 8-hydroxy-2-deoxyguanosine than R-(−)-HEX. These results were consistent with those of the enrichment analysis of differentially expressed genes. The transcriptome sequencing results showed that S-(+)-HEX had a more significant influence on steroid biosynthesis, arachidonic acid metabolism, and cell cycle processes than R-(−)-HEX, leading to abnormal biological function activities. These results indicate that S-(+)-HEX may pose a higher risk to soil organisms than R-(−)-HEX. This study suggests that the environmental risk of chiral pesticides to nontarget organisms should be assessed at the enantiomeric level.
اظهر المزيد [+] اقل [-]The herbicide dinitramine affects the proliferation of murine testicular cells via endoplasmic reticulum stress-induced calcium dysregulation
2021
Ham, Jiyeon | Park, Sunwoo | Lim, Whasun | Song, Gwonhwa
The hazardous effects of herbicides are well known; however, their effects on the reproductive system remain unclear. In this study, we demonstrated the anti-proliferative effects of dinitramine (DN) on immature murine testicular cell lines (Leydig and Sertoli cells) mediated via endoplasmic reticulum (ER) stress-induced calcium dysregulation in the cytosol and mitochondria. The results demonstrated that the viability and proliferation of DN-treated TM3 and TM4 cells decreased significantly, even in the spheroid state. DN induced the apoptosis of TM3 and TM4 cells and decreased the expression of genes related to cell cycle progression. Treatment with DN increased the cytosolic and intramitochondrial levels of calcium by activating ER stress signals. DN activated the Erk/P38/Jnk Mapk pathway and inactivated the Pi3k/Akt pathway in murine testicular cells. Co-treatment with 2-aminoethoxydiphenyl borate (2-APB) mitigated DN-induced calcium upregulation in both testicular cell lines. Although 2-APB did not antagonize the anti-proliferative effect of DN in TM3 cells, treatment with 2-APB and 1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid restored the proliferation of DN-treated TM4 cells.
اظهر المزيد [+] اقل [-]Cytotoxic effects of wildfire ashes: In-vitro responses of skin cells
2021
Ré, Ana | Rocha, Ana Teresa | Campos, Isabel | Keizer, Jan Jacob | Gonçalves, Fernando J.M. | Silva, Helena Oliveira da | Pereira, Joana Luísa | Abrantes, Nelson
Wildfires are a complex environmental problem worldwide. The ashes produced during the fire bear metals and PAHs with high toxicity and environmental persistence. These are mobilized into downhill waterbodies, where they can impair water quality and human health. In this context, the present study aimed at assessing the toxicity of mimicked wildfire runoff to human skin cells, providing a first view on the human health hazardous potential of such matrices. Human keratinocytes (HaCaT) were exposed to aqueous extracts of ashes (AEA) prepared from ash deposited in the soil after wildfires burned a pine or a eucalypt forest stand. Cytotoxicity (MTT assay) and changes in cell cycle dynamics (flow cytometry) were assessed. Cell viability decreased with increasing concentrations of AEA, regardless of the ash source, the extracts preparation method (filtered or unfiltered to address the dissolved or the total fractions of contaminants, respectively) or the exposure period (24 and 48 h). The cells growth was also negatively affected by the tested AEA matrices, as evidenced by a deceleration of the progress through the cell cycle, namely from phase G0/G1 to G2. The cytotoxicity of AEA could be related to particulate and dissolved metal content, but the particles themselves may directly affect the cell membrane. Eucalypt ash was apparently more cytotoxic than pine ash due to differential ash metal burden and mobility to the water phase. The deceleration of the cell cycle can be explained by the attempt of cells to repair metal-induced DNA damage, while if this checkpoint and repair pathways are not well coordinated by metal interference, genomic instability may occur. Globally, our results trigger public health concerns since the burnt areas frequently stand in slopes of watershed that serve as recreation sites and sources of drinking water, thus promoting human exposure to wildfire-driven contamination.
اظهر المزيد [+] اقل [-]Whole-transcriptome analysis of the toxic effects of zearalenone exposure on ceRNA networks in porcine granulosa cells
2020
Zearalenone (ZEA), an estrogen-like mycotoxin, is commonly detected in animal feeds including improperly stored grains. It has been well demonstrated that ovarian granulosa cells (GCs) perform vital roles during follicular development, however, the competing endogenous RNA (ceRNA) network in GCs after ZEA exposure remains to be well described. Here, for the first time, we adopted whole-transcriptome sequence technology to explore the molecular mechanism of ZEA toxicology on porcine GCs. The results provide evidence that the cell cycle of porcine GCs is arrested in the G2/M phase after exposure to ZEA. Furthermore, bioinformation analysis found that cell cycle arrest related genes were perturbed, including CDK1, CCNB1, CDC25A, and CDC25C, which was consistent with the results of RT-qPCR, immunofluorescence, and Western Blotting. Based on the whole-transcriptome sequence data, by constructing ceRNA networks related to cell cycle arrest, we observed that ZEA exposure arrested cell cycle progression at the G2/M phase in porcine GCs, and non-coding RNAs (ncRNAs) played an important role in this process via regulating the expressions of cell cycle arrest related genes. Taken together, our data here provides strong data to support that the toxicological mechanism regarding the widely distributed toxicant ZEA acts through ceRNA networks in porcine granulosa cells.
اظهر المزيد [+] اقل [-]Environmental six-ring polycyclic aromatic hydrocarbons are potent inducers of the AhR-dependent signaling in human cells
2020
Vondráček, Jan | Pěnčíková, Kateřina | Ciganek, Miroslav | Pivnička, Jakub | Karasová, Martina | Hýžďalová, Martina | Strapáčová, Simona | Pálková, Lenka | Neča, Jiří | Matthews, Jason | Lom, Michal Vojtíšek | Topinka, Jan | Milcová, Alena | Machala, Miroslav
The toxicities of many environmental polycyclic aromatic hydrocarbons (PAHs), in particular those of high-molecular-weight PAHs (with MW higher than 300), remain poorly characterized. The objective of this study was to evaluate the ability of selected environmentally relevant PAHs with MW 302 (MW302 PAHs) to activate the aryl hydrocarbon receptor (AhR), since this represents a major toxic mode of action of PAHs. A large number of the evaluated compounds exhibited strong AhR-mediated activities, in particular in human models. The studied MW302 PAHs also significantly contributed to the overall calculated AhR activities of complex environmental mixtures, including both defined standard reference materials and collected diesel exhaust particles. The high AhR-mediated activities of representative MW302 PAHs, e.g. naphtho[1,2-k]fluoranthene, corresponded with the modulation of expression of relevant AhR target genes in a human lung cell model, or with the AhR-dependent suppression of cell cycle progression/proliferation in estrogen-sensitive cells. This was in a marked contrast with the limited genotoxicity of the same compound(s). Given the substantial levels of the AhR-activating MW302 PAHs in combustion particles, it seems important to continue to investigate the toxic modes of action of this large group of PAHs associated with airborne particulate matter.
اظهر المزيد [+] اقل [-]Toxic effects and mechanisms of three commonly used fungicides on the human colon adenocarcinoma cell line Caco-2
2020
Tao, Huaping | Bao, Zhiwei | Jin, Cuiyuan | Miao, Wenyu | Fu, Zhengwei | Jin, Yuanxiang
Fungicides, usually refer to the chemical agents that can effectively control or kill the pathogenic microorganisms. Here, we revealed the effects of three different fungicides, imazalil (IMZ), chlorothalonil (CTL) and carbendazim (CBZ), which are typical broad-spectrum fungicides that are detected at high levels in the natural environment, on heterogeneous human epithelial colorectal cells (Caco-2 cells). All three fungicides had the potential to induce different degrees of toxicity, cause apoptosis, reactive oxygen species (ROS) and even change the cell cycle in the cells. The half maximal inhibitory concentration (IC50) of CTL is the lowest among these three fungicides, suggesting that it may have the highest exposure risk, followed by IMZ, and CBZ. The results of the real-time PCR, Western blotting, and mitochondrial membrane potential (MMP) assays and the activities of key enzymes suggested that CTL induced apoptosis in Caco-2 cells via a mitochondrial-dependent pathway, as indicated by the upregulation of the expression of the apoptotic p53 and bax genes, the increase of the apoptosis marker cytochrome-c, the decrease of mRNA level of bcl-2 gene, and the decrease in the MMP. Exposure to two other fungicides also upregulated the transcriptional level of bax and the expression of cytochrome-c, but the mRNA level of bcl-2 was increased (IMZ) or unchanged (CBZ), suggesting that other pathways may be involved in the induction of cellular apoptosis by these two fungicides. In addition, all three of the fungicides could induce oxidative stress in Caco-2 cells. Our data showed that the three different kinds of fungicides all caused toxic effects in Caco-2 cells through various pathways.
اظهر المزيد [+] اقل [-]