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High expression of HIF-1α alleviates benzene-induced hematopoietic toxicity and immunosuppression in mice
2022
Huang, Jiawei | Pu, Yunqiu | Xu, Kai | Ding, Qin | Sun, Rongli | Yin, Lihong | Zhang, Juan | Pu, Yuepu
Benzene exposure can cause pancytopenia and immunosuppression, leading to serious diseases such as aplastic anemia (AA) or acute myeloid leukemia (AML), but the underlying mechanism has not been fully elucidated. Hypoxia-inducible factor 1 (HIF-1) is an important transcription factor that regulates many downstream target genes. In this study, we reported a novel mechanism by which high expression of HIF-1α alleviated benzene toxicity. Mice with high expression of HIF-1α (HIF-1α⁺) were obtained by the Tet-on system and doxycycline induction, and they and wild-type (WT) mice were exposed to 150 mg/kg benzene for 0, 1, 3, 7, 10, 14, and 28 days. Dynamic changes in hematopoietic and immune-related indicators and the role of HIF-1α were explored. The level of white blood cells in mice reached the highest level on the third day, and immunity was activated and then suppressed within 10 days. Significant pancytopenia and immunosuppression occurred at 14 days and were more pronounced at 28 days. The levels of HIF-1α, EPO, VEGF, RORγt, and IL-17 in WT mice gradually decreased with increasing benzene exposure days, while the levels of Foxp3 and IL-10 increased. These changes were alleviated in HIF-1α⁺ mice. High expression of HIF-1α increased the levels of EPO and VEGF, which helped to maintain the stability of the hematopoietic microenvironment. Simultaneously, it attenuated benzene-induced immunosuppression by alleviating the Th17/Treg imbalance. HIF-1α is expected to be a new target for benzene-induced diseases such as AA and AML.
显示更多 [+] 显示较少 [-]Alternatives of perfluoroalkyl acids and hepatitis B virus surface antibody in adults: Isomers of C8 Health Project in China
2020
Zeng, Xiao-Wen | Li, Qing-Qing | Chu, Chu | Ye, Wan-Lin | Yu, Shu | Ma, Huimin | Zeng, Xiao-Yun | Zhou, Yang | Yu, Hong-Yao | Hu, Liwen | Yang, Bo-Yi | Dong, Guang-Hui
Previous epidemiological and experimental studies have shown that legacy perfluoroalkyl acids (PFAAs) are immunotoxic. However, whether the immunosuppressive effects in PFAA alternatives which recently have been widely detected in the environment are unknown. To address this knowledge gap, we investigated the relationship of serum legacy PFAAs and PFAA alternatives with the antibody of hepatitis B virus in adults. We recruited 605 participants from a cross-sectional study, the Isomer of C8 Health Project in China. We measured two representative legacy PFAAs (perfluorooctane sulfonate, PFOS and perfluorooctanoic acid, PFOA), and three PFAA alternatives (two chlorinated polyfluorinated ether sulfonic acids, Cl-PFESAs and perfluorobutanoic acid, PFBA) in serum using ultra-performance liquid chromatograph-tandem mass spectrometry (UPLC-MS/MS). We applied linear and logistic regression models to analyze associations between serum PFAAs and hepatitis B surface antibody (HBsAb) with multivariable adjustments. We found negative associations between serum PFAAs concentrations and HBsAb. Lower serum HBsAb levels (log mIU/mL) were observed for each log-unit increase in linear PFOS (β = −0.31, 95% confidential interval: 0.84, −0.18), 6:2 PFESA (β = −0.81, 95% CI: 1.20, −0.42), 8:2 PFESA (β = −0.29, 95% CI: 0.43, −0.14) and PFBA (β = −0.18, 95% CI: 0.28, −0.08). The association between PFAAs and HBsAb seronegative seemed to be higher for 6:2 PFESA (odds ratio = 3.32, 95% CI: 2.16, 5.10) than its predecessors, linear PFOS (OR = 1.96, 95% CI: 1.37, 2.81) and branched PFOS isomers (OR = 1.64, 95% CI: 1.05, 2.56). We report new evidence that exposure to PFAA alternatives are associated with lower HBsAb in adults. This association seems to be stronger in 6:2 PFESA than PFOS. Our results suggest that more studies are needed to clarify the potential toxicity of PFAA alternatives in human which will facilitate better chemical regulations for PFAAs.
显示更多 [+] 显示较少 [-]Evidence of immunocompetence reduction induced by cadmium exposure in honey bees (Apis mellifera)
2016
Polykretis, P. | Delfino, G. | Petrocelli, I. | Cervo, R. | Tanteri, G. | Montori, G. | Perito, B. | Branca, J.J.V. | Morucci, G. | Gulisano, M.
In the last decades a dramatic loss of Apis mellifera hives has been reported in both Europe and USA. Research in this field is oriented towards identifying a synergy of contributing factors, i.e. pathogens, pesticides, habitat loss and pollution to the weakening of the hive. Cadmium (Cd) is a hazardous anthropogenic pollutant whose effects are proving to be increasingly lethal. Among the multiple damages related to Cd contamination, some studies report that it causes immunosuppression in various animal species. The aim of this paper is to determine whether contamination by Cd, may have a similar effect on the honey bees’ immunocompetence. Our results, obtained by immune challenge experiments and confirmed by structural and ultrastructural observations show that such metal causes a reduction in immunocompetence in 3 days Cd exposed bees. As further evidence of honey bee response to Cd treatment, Energy Dispersive X-ray Spectroscopy (X-EDS) has revealed the presence of zinc (Zn) in peculiar electron-dense granules in fat body cells. Zn is a characteristic component of metallothioneins (MTs), which are usually synthesized as anti-oxidant and scavenger tools against Cd contamination. Our findings suggest that honey bee colonies may have a weakened immune system in Cd polluted areas, resulting in a decreased ability in dealing with pathogens.
显示更多 [+] 显示较少 [-]Environmental exposure to cadmium reduces the primary antibody-mediated response of wood mice (Apodemus sylvaticus) from differentially polluted locations in the Netherlands
2021
García-Mendoza, Diego | van den Berg, Hans J.H.J. | Brink, Nico W. van den
The Wood mouse (Apodemus sylvaticus) is a widespread mammalian species that acts as a reservoir host for multiple infections, including zoonotic diseases. Exposure to immunotoxins, like for instance trace metals, may reduce the ability of the host to mount proper responses to pathogens, potentially increasing the transmission and prevalence of infections. Antibody-mediated responses are crucial in preventing and limiting infections, and the quantification of the primary antibody response is considered a sensitive predictor of immunosuppression. The current study aims to investigate effects of cadmium exposure on the antibody-mediated responses of wood mice inhabiting polluted and non-polluted areas in the Netherlands. Wood mice were captured alive at different locations and immunized to sheep red blood cells (SRBC) to induce a primary antibody response. SRBC-specific antibody-producing cells, or plaque forming cells (PFC), were quantified and related to kidney cadmium levels. Differential circulating main leukocyte populations were also characterised. Cadmium concentrations in mice kidneys differed between mice captured at different locations, and increased with individual body mass, likely associated with age-related time of exposure. Effect of cadmium was apparent on the percentages of B cell counts in blood. Because of potential natural immune heterogeneity between wild rodent populations, mice immune responses were analysed and compared grouped by captured locations. Capture location had significant effect on the total counts of white blood cells. Increasing cadmium exposure in wood mice captured from polluted sites was associated with a decrease of splenic PFC counts. This field research shows that wood mice antibody responses can be impaired by cadmium exposure, even at low environmental levels, by affecting B cell functioning mainly. Impaired B cell function can make exposed mice more susceptible to infections, potentially increasing the reservoir function of their populations. It also shows that immunomodulatory effects in the field should be assessed site specifically.
显示更多 [+] 显示较少 [-]Grass carps co-exposed to environmentally relevant concentrations of cypermethrin and sulfamethoxazole bear immunodeficiency and are vulnerable to subsequent Aeromonas hydrophila infection
2020
Zhao, Hongjing | Wang, Yu | Guo, Menghao | Mu, Mengyao | Yu, Hongxian | Xing, Mingwei
The aquatic ecosystem is seriously damaged because of the heavy use of pesticides and antibiotics. Fish is the indispensable link between environmental pollution and human health. However, the toxic effects of environment-related concentrations of pesticides and antibiotics in fish have not been thoroughly studied. In this study, grass carps exposed to cypermethrin (CMN, 0.651 μg/L) or/and sulfamethoxazole (SMZ, 0.3 μg/L) for 42 days caused oxidative stress, apoptosis and immunodeficiency in the spleen of grass carps. CMN or/and SMZ exposure led to oxidative damage (consumption of antioxidant enzymes (superoxide dismutase and catalase)) and lipid peroxidation (accumulation of malondialdehyde), induced apoptosis (increases in TUNEL index, Bax/bcl-2, p53, puma and Caspase family expression). In addition, the levels of immunoglobulin M (IgM), complement 3 (C3) were significantly decreased in all treatment groups, which trend was also found in C-reactive protein in CMN and MIX group, and lysozyme in MIX group. Transcription of almost all genes involved in the Toll-like receptors (TLR) signaling pathway was up-regulated under CMN or/and SMZ exposure. However, when subsequently attacked by Aeromonas hydrophila for 2 days, the TLR pathway was inhibited in spleens of all treatment groups accompanied by higher mortality. Overall, the environmentally relevant concentration of CMN and SMZ damages the immune system, triggering oxidative stress and apoptosis in carps. And by affecting the conduction of TLR signaling pathway, CMN or/and SMZ exposure inhibits the innate immune response of fish and reducing their disease resistance. This study highlights the importance of rational and regulated use of these pesticides and antibiotics.
显示更多 [+] 显示较少 [-]Predicting the effects of polychlorinated biphenyls on cetacean populations through impacts on immunity and calf survival
2018
Hall, Ailsa J. | McConnell, Bernie J. | Schwacke, Lori H. | Ylitalo, Gina M. | Williams, Rob | Rowles, Teri K.
The potential impact of exposure to polychlorinated biphenyls (PCBs) on the health and survival of cetaceans continues to be an issue for conservation and management, yet few quantitative approaches for estimating population level effects have been developed. An individual based model (IBM) for assessing effects on both calf survival and immunity was developed and tested. Three case study species (bottlenose dolphin, humpback whale and killer whale) in four populations were taken as examples and the impact of varying levels of PCB uptake on achievable population growth was assessed. The unique aspect of the model is its ability to evaluate likely effects of immunosuppression in addition to calf survival, enabling consequences of PCB exposure on immune function on all age-classes to be explored. By incorporating quantitative tissue concentration-response functions from laboratory animal model species into an IBM framework, population trajectories were generated. Model outputs included estimated concentrations of PCBs in the blubber of females by age, which were then compared to published empirical data. Achievable population growth rates were more affected by the inclusion of effects of PCBs on immunity than on calf survival, but the magnitude depended on the virulence of any subsequent encounter with a pathogen and the proportion of the population exposed. Since the starting population parameters were from historic studies, which may already be impacted by PCBs, the results should be interpreted on a relative rather than an absolute basis. The framework will assist in providing quantitative risk assessments for populations of concern.
显示更多 [+] 显示较少 [-]Delayed effects of chlorpyrifos across metamorphosis on dispersal-related traits in a poleward moving damselfly
2016
Dinh, Khuong Van | Janssens, Lizanne | Therry, Lieven | Bervoets, Lieven | Bonte, Dries | Stoks, Robby
How exposure to contaminants may interfere with the widespread poleward range expansions under global warming is largely unknown. Pesticide exposure may negatively affect traits shaping the speed of range expansion, including traits related to population growth rate and dispersal-related traits. Moreover, rapid evolution of growth rates during poleward range expansions may come at a cost of a reduced investment in detoxification and repair thereby increasing the vulnerability to contaminants at expanding range fronts. We tested effects of a sublethal concentration of the widespread pesticide chlorpyrifos on traits related to range expansion in replicated edge and core populations of the poleward moving damselfly Coenagrion scitulum reared at low and high food levels in a common garden experiment. Food limitation in the larval stage had strong negative effects both in the larval stage and across metamorphosis in the adult stage. Exposure to chlorpyrifos during the larval stage did not affect larval traits but caused delayed effects across metamorphosis by increasing the incidence of wing malformations during metamorphosis and by reducing a key component of the adult immune response. There was some support for an evolutionary trade-off scenario as the faster growing edge larvae suffered a higher mortality during metamorphosis. Instead, there was no clear support for the faster growing edge larvae being more vulnerable to chlorpyrifos. Our data indicate that sublethal delayed effects of pesticide exposure, partly in association with the rapid evolution of faster growth rates, may slow down range expansions.
显示更多 [+] 显示较少 [-]Health risks of phthalates: A review of immunotoxicity
2022
Zhang, Ying | Lyu, Liang | Tao, Yue | Ju, Hanxun | Chen, Jie
Phthalates (PAEs) are known environmental endocrine disruptors that have been widely detected in several environments, and many studies have reported the immunotoxic effects of these compounds. Here, we reviewed relevant published studies, summarized the occurrence and major metabolic pathways of six typical PAEs (DMP, DEP, DBP, BBP, DEHP, and DOP) in water, soil, and the atmosphere, degradation and metabolic pathways under aerobic and anaerobic conditions, and explored the molecular mechanisms of the toxic effects of eleven PAEs (DEHP, DPP, DPrP, DHP, DEP, DBP, MBP, MBzP, BBP, DiNP, and DMP) on the immune system of different organisms at the gene, protein, and cellular levels. A comprehensive understanding of the mechanisms by which PAEs affect immune system function through regulation of immune gene expression and enzymes, increased ROS, immune signaling pathways, specific and non-specific immunosuppression, and interference with the complement system. By summarizing the effects of these compounds on typical model organisms, this review provides insights into the mechanisms by which PAEs affect the immune system, thus supplementing human immune experiments. Finally, we discuss the future direction of PAEs immunotoxicity research, thus providing a framework for the analysis of other environmental pollutants, as well as a basis for PAEs management and safe use.
显示更多 [+] 显示较少 [-]Systematic multi-omics reveals the overactivation of T cell receptor signaling in immune system following bisphenol A exposure
2022
Park, Yoo-Jin | Rahman, Md. Saidur | Pang, Won-Ki | Ryu, Do-Yeal | Jung, Min-Ji | Amjad, Shehreen | Kim, Jun-Mo | Pang, Myung-Geol
Bisphenol A (BPA) is pervasive in the environment, and exposure to BPA may increase the incidence of noncommunicable diseases like autoimmune diseases and cancer. Although BPA causes immunological problems at the cellular level, no system-level research has been conducted on this. Hence, in this study, we aimed to gain a better understanding of the biological response to BPA exposure and its association with immunological disorders. For that, we explored the transcriptome and the proteomic modifications at the systems and cellular levels following BPA exposure. Our integrated multi-omics data showed the alteration of the T cell receptor (TCR) signaling pathway at both levels. The proportion of enlarged T cells increased with upregulation of CD69, a surface marker of early T cell activation, even though the number of T cells reduced after BPA exposure. Additionally, on BPA exposure, the levels of pLCK and pSRC increased in T cells, while that of pLAT decreased. Following BPA exposure, we investigated cytokine profiles and discovered that chitinase 3 Like 1 and matrix metalloproteinase 9 were enriched in T cells. These results indicated that T cells were hyperactivated by CD69 stimulation, and phosphorylation of SRC accelerated on BPA exposure. Hence, alteration in the TCR signaling pathway during development and differentiation due to BPA exposure could lead to insufficient and hasty activation of TCR signaling in T cells, which could modify cytokine profiles, leading to increased environmental susceptibility to chronic inflammation or diseases, increasing the chance of autoimmune diseases and cancer. This study enhances our understanding of the effects of environmental perturbations on immunosuppression at molecular, cellular, and systematic levels following pubertal BPA exposure, and may help develop better predictive, preventative, and therapeutic techniques.
显示更多 [+] 显示较少 [-]Zearalenone and deoxynivalenol reduced Th1-mediated cellular immune response after Listeria monocytogenes infection by inhibiting CD4+ T cell activation and differentiation
2021
Cai, Guodong | Xia, Sugan | Zhong, Fang | Liu, Shuangshuang | Gu, Jianhong | Yuan, Yan | Zhu, Guoqiang | Zou, Hui | Liu, Zongping | Bian, Jianchun
Based on the fact that mycotoxins and the food-borne bacteria coexist in the natural environment and pose a significant health hazard to humans and animals, it is important to investigate the immunosuppressive mechanism of ZEA (zearalenone), DON (deoxynivalenol), and their combination in bacterial infections. In this study, we established a mouse model of mycotoxin low-dose exposure combined with Listeria monocytogenes infection and investigated the effects of ZEA, DON and their combination on Th1-mediated anti-intracellular bacterial infection based on CD4⁺ T cell activation and differentiation using both in vitro and in vivo analyses. The present study showed that both ZEA and DON aggravated Listeria monocytogenes infection in mice and affected the activation of CD4⁺ T cells and Th1 differentiation, including the effects on costimulatory molecules CD28 and CD152 and on cross-linking of IL-12 and IL-12R, by inhibiting T cell receptor (TCR) signaling. When compared with ZEA, DON was found to have a greater impact on many related indicators. Surprisingly, the combined effects of ZEA and DON did not appear to enhance toxicity compared to treatment with the individual mycotoxins. Our findings more clearly revealed that exposure to low-dose ZEA and DON caused immunosuppression in the body by mechanisms including inhibition of CD4⁺ T cells activation and reduction of Th1 cell differentiation, thus exacerbating infection of animals by Listeria monocytogenes.
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