Combined Exposure Group Research Articles

Effects of acute exposure to Al2O3-NPs (α and γ) and white noise and their combination on cochlea structure and function in Wistar rats.

Hearing loss induced by noise and combinations of factors is a common occupational disease among workers. This study aimed to investigate the impact of acute exposure to white noise and Al2O3 NPs, alone and in combination, on changes in the hearing and structural functions of the cochlea in rats. Thirty-six rats were randomly assigned to one of six groups: Control, acute exposure to white noise, exposure to γ-Al2O3 NPs, exposure to noise plus γ-Al2O3 NPs, exposure to α-Al2O3 NPs, and exposure to the combination of noise plus α-Al2O3 NPs. TTS and PTS were examined using DPOAE, while oxidative index (MDA, GSH-Px), gene expression (NOX3, TGF-ß, CYP1A1), protein expression (ß-Tubulin, Myosin VII), and histopathological changes were examined in the cochlea. The morphology of Al2O3 NPs was examined by TEM. The results of the DPOAE test showed a significant increase in TTS in all groups and an increase in PTS in the groups exposed to noise, γ-Al2O3 NPs, and a combination of noise plus Al2O3 NPs (P < 0.05). In the group exposed to white noise plus Al2O3 NPs, the MDA levels increased, the level of GSH-Px decreased, and the expression percentage of ß-Tubulin and Myosin VII decreased, while the expression of NOX3, TGF-ß, and CYP1A1 (except for the α-Al2O3 NPs group) significantly increased (P < 0.05). Histopathological changes of the cochlea indicated damage to hair and ganglion cells, which was more severe in the combined exposure group. The combined and independent exposure to white noise and Al2O3 NPs damaged hair and ganglion cells for high-frequency perception, affecting the function and structure of the cochlea and leading to TTS and PTS.

Synergetic effects of polyethylene microplastic and abamectin pesticides on the eyes of zebrafish larvae and adults through activation of apoptosis signaling pathways

Although the toxicity of microplastics (MPs) and pesticides has recently been described, the possible effects of combining these pollutants are poorly understood. Thus, we evaluated the potential impact of exposure to polyethylene MP (PE-MP) and abamectin (ABM) (alone and combined) in zebrafish. After five days, the combined exposure to MP and ABM decreased the survival rate compared to exposures to individual pollutants. A significant increase in reactive oxygen species (ROS), lipid peroxidation, apoptosis, and impairment in antioxidant response was observed in zebrafish larvae. Morphological changes in the eyes of zebrafish significantly increased in the combined exposure group than in the individual exposure. Furthermore, the bax and p53 expression (specific apoptotic genes) was significantly upregulated after the combined exposure to PE-MP and ABM. So, the synergetic effect of MP and ABM cannot be ignored, and further research on other higher models is required to confirm its consequences.

Micro-polystyrene plastic and benzo[α]pyrene exposure affects the endocrine system and causes physiological stress in Carassius auratus

Microplastics, owing to their hydrophobic properties and the various chemicals used in their production, can act as carriers of persistent organic pollutants, such as polycyclic aromatic hydrocarbons (PAHs). In this study, we exposed the goldfish Carassius auratus to benzo[α]pyrene (BaP, 10 μg/L), a representative PAH, and micro-polystyrene plastic (MP; 10 and 100 beads/L), of size 1.0 μm, as a single or complex environmental stressor, and evaluated the stress response and the resulting DNA damage. The expression of CRH and ACTH mRNA in the pituitary gland and hypothalamus, of the hypothalamus–pituitary–interrenal (HPI) axis, increased significantly after 6 h of exposure. Plasma cortisol levels showed a similar trend to the expression of stress-regulating genes along the HPI axis, and a significant increase was observed in the combined exposure groups (BaP + LMP [low-concentration MP] and BaP + HMP [high-concentration MP]) compared to those in the single exposure group. H2O2 concentration and CYP1A1 and MT mRNA expression levels in the liver were significantly higher in the combined exposure groups compared with in the single exposure groups. In situ hybridization revealed a similar pattern of MT mRNA expression, and many signals were observed in the BaP + HMP group. Furthermore, the BaP + HMP group showed more DNA damage, and the degree of DNA damage increased with exposure time for all experimental groups, except for the control group. Therefore, exposure to BaP and MP alone can induce stress in goldfish; however, when a combination of both substances is provided, their synergistic effect leads to increased stress and DNA damage. MP was confirmed to be a more serious stress-inducing factor in goldfish than BaP, based on the expression levels of stress-regulating genes along the HPI axis.

Preliminary study on the role of aryl hydrocarbon receptor in the neurotoxicity of three typical bisphenol compounds (BPA, BPS and TBBPA) at environmentally relevant concentrations to adult zebrafish (Danio rerio)

ObjectiveThis study was aimed to explore the role of AhR in the neurotoxicity of adult zebrafish induced by three typical bisphenol compounds (BPA, BPS, TBBPA) at environmentally relevant doses. MethodsThe adult zebrafish were randomly divided into solvent control group (DMSO) and AhR inhibitor CH223191 (CH) group (0.05 μmol/L), bisphenol exposure groups (10, 100, 1000 nmol/L) and combined exposure groups (0.05 μmol/L CH and 1000 nmol/L bisphenol compounds). Each tank contained 8 fish (4 male and 4 female), and two parallel tanks were set synchronously. After 30 days of exposure, zebrafish were put on ice plate for anesthesia, weighed and measured for body length, and dissected for brain tissue. The gene expression was detected by RT-qPCR, and the activities of antioxidant enzymes were detected by commercial kits. SPSS 26.0 was used to analyze the data. Additionally, GO, KEGG and principal component analysis (PCA) were carried out. ResultsCompared with the solvent control group, there were no significant differences in body weight and length among the exposed groups. In general, exposure to bisphenol compounds could affect the expression of Ahr2 and AhR target genes (cyp1a1, cyp1a2, and cyp1c1), key genes of neural function (elavl3, gfap, mbp, syn2a, gap43, Zn5, shha, and ache), oxidative stress related genes (nrf2, gpx1a, gstp1/gstp1.2, gstp2/gstp1.1, sod1, sod2, and cat), and the activities of antioxidant enzymes (SOD, CAT and GSH-Px/GPX) in zebrafish brain tissue to some extent. Compared with the groups exposed to bisphenols alone, CH could antagonize the above interference effects caused by bisphenols to some extent. Therefore, the toxic effects of BPA, BPS and TBBPA might be produced through similar mechanisms. ConclusionEnvironmentally related doses of bisphenols (BPA, BPS, TBBPA) could disturb the expression of key molecules of oxidative stress and neural function through activating the AhR signaling pathway, and ultimately lead to neurotoxicity.

Interactive effects of polystyrene nanoplastics and 6:2 chlorinated polyfluorinated ether sulfonates on the histomorphology, oxidative stress and gut microbiota in Hainan Medaka (Oryzias curvinotus)

Nanoplastics adsorb surrounding organic contaminants in the environment, which alters the physicochemical properties of contaminants and affects associated ecotoxicological effects on aquatic life. The current work aims to explore the individual and combined toxicological implications of polystyrene nanoplastics (80 nm) and 6:2 chlorinated polyfluorinated ether sulfonate (Cl-PFAES, trade name: F-53B) in an emerging freshwater fish model Hainan Medaka (Oryzias curvinotus). Therefore, O. curvinotus were exposed to 200 μg/L of PS-NPs or 500 μg/L of F-53B in the single or mixture exposure for 7 days to investigate the effects on fluorescence accumulation, tissue damage, antioxidant capacity and intestinal flora. The PS-NPs fluorescence intensity was significantly higher in the single exposure treatment than it in combined exposure treatment (p < 0.01). Histopathological results showed that exposure to PS-NPs or F-53B inflicted varying degree of damages to the gill, liver, and intestine, and these damage were also present in the corresponding tissues of the combined treatment group, illustrating a stronger extent of destruction of these tissues by the combined treatment. Compared to the control group, combined exposure group elevated the malondialdehyde (MDA) content, superoxide dismutase (SOD) and catalase (CAT) activities except in the gill. In addition, the adverse contribution of PS-NPs and F-53B on the enteric flora in the single and combined exposure groups was mainly characterised in the form of reductions in the number of probiotic bacteria (Firmicutes) and this reduction was aggravated by the combined exposure group. Collectively, our results indicated that the toxicological effects of PS-NPs and F-53B on pathology, antioxidant capacity and microbiomics of medaka may be modulated by the interaction of two contaminants with mutually interactive effects. And our work offers fresh information on the combined toxicity of PS-NPs and F-53B to aquatic creatures along with a molecular foundation for the environmental toxicological mechanism.

Combined effects of EMP and RF field on emotional behavior in mice.

Recently, concerns about the combined effects of electromagnetic field (EMF) in daily living and occupational environment are rapidly growing. In this study, we investigated the combined effects of 1-week exposure to electromagnetic pulse (EMP) at 650 kV/m for 1,000 pulses and 4.9 GHz radiofrequency (RF) at 50 W/m2 for 1 h/d in male mice. Open field test, tail suspension test and Y-maze were applied to evaluate anxiety, depression-like behaviors and spatial memory ability, respectively. It was found that compared with Sham group, combined exposure to EMP and RF induced anxiety-like behavior, increased the level of serum S100B and decreased the level of serum 5-HT. The results of quantitative proteomic and KEGG analysis showed that the differentially expressed proteins in hippocampus were enriched in Glutamatergic and GABAergic synapse after combined exposure group, which were verified by western blot. In addition, an obvious histological alteration and autophagy-associated cell death were observed in amygdala instead of hippocampus after combined exposure to EMP and 4.9 GHz RF. Combined exposure to EMP and 4.9 GHz RF could induce emotional behavior alteration, which might be associated with Glutamatergic and GABAergic synapse system of hippocampus and autophagy in amygdala.

Granulocyte-colony stimulating factor does not prevent in vitro cisplatin-induced germ cell reduction in immature human and mouse testis

BackgroundCurrently there are no established fertility preservation options for pre-pubertal boys facing cancer treatment. Granulocyte-colony stimulating factor (G-CSF) treatment has been proposed to be chemoprotective against spermatogonial cell loss in an alkylating chemotherapy model of busulfan treated adult mice. Having previously shown that exposure to the alkylating-like chemotherapy cisplatin resulted in a reduction in germ cell numbers in immature human testicular tissues, we here investigate whether G-CSF would prevent cisplatin-induced germ cell loss in immature human and mouse (fetal and pre-pubertal) testicular tissues.MethodsOrganotypic in vitro culture systems were utilised to determine the effects of clinically-relevant concentrations of G-CSF in cisplatin-exposed immature testicular tissues. Human fetal (n = 14 fetuses) and mouse pre-pubertal (n = 4 litters) testicular tissue pieces were cultured and exposed to cisplatin or vehicle control for 24 hrs and analysed at 72 and 240 hrs post-exposure. Combined G-CSF and cisplatin exposure groups explored varying concentrations and duration of G-CSF supplementation to the culture medium (including groups receiving G-CSF before, during and after cisplatin exposure). In addition, effects of G-CSF supplementation alone were investigated. Survival of total germ cell and sub-populations were identified by expression of AP2γ and MAGE-A4 for human gonocytes and (pre)spermatogonia, respectively, and MVH and PLZF, for mouse germ cells and putative spermatogonial stem cells (SSCs) respectively, were quantified.ResultsExposure to cisplatin resulted in a reduced germ cell number in human fetal and mouse pre-pubertal testicular tissues at 240 hrs post-exposure. Germ cell number was not preserved by combined exposure with G-CSF using any of the exposure regimens (prior to, during or after cisplatin exposure). Continuous supplementation with G-CSF alone for 14 days did not change the germ cell composition in either human or mouse immature testicular tissues.ConclusionsThis study demonstrates that exposure to G-CSF does not prevent cisplatin-induced germ cell loss in immature human and mouse testicular tissues in an in vitro system.

Influence of Agaricus bisporus Mushroom on Pb Toxicokinetic in Pregnant Rats.

(Pb) is a toxic metal, responsible for several damages to human health. Agaricus bisporus (Ab) is a mushroom with promising antioxidant properties to be used as an alternative chelator in Pb intoxication. The aim was to understand the Pb toxicokinetic and the potential of Ab as a protective agent. A total of 20 female Wistar rats were distributed into 4 groups (n = 5/group): Control (receiving water); Group Ab 100 mg/kg (gavage); Group Pb 100 mg/L in water; and Group Ab + Pb-100 mg/kg + 100 mg/L (gavage and water). Pb administration occurred daily until the 19th day of pregnancy. On day 19 of gestation, the rats were euthanized, and the blood and tissues were collected for Pb measurement, using an inductively coupled plasma mass spectrometer. The results showed that the levels of Pb in the blood, placenta, and liver of the mothers, and in the brain of the fetuses increased significantly in the Pb group. On the other hand, the combined exposure to Pb + Ab showed a significant decrease in the metal concentration in relation to the Pb group, returning to normal levels. Kidney and bone lead levels also increased significantly in the Pb group. However, in the combined exposure group, levels did not return to the control amounts; there was protection, but the Pb concentration was still significantly higher than in the control. In the brain, no significant differences were observed. In conclusion, we suggest A. bisporus is a natural chelator, because the co-administration of the mushroom was able to interact with Pb ions, minimizing the Pb absorption and distribution. These effects are suggested since A. bisporus have antioxidants and beta glucan that interact with Pb, chelating it and, thus, reducing its toxic effects.

Combined Protective Effects of Quercetin, Rutin, and Gallic Acid against Cadmium-Induced Testicular Damages in Young-Adult Rats

Cadmium (Cd) is a toxic metal that damages several tissues of animals and humans including the testis. The ameliorative effects of quercetin (QUE), rutin (RUT), and gallic acid (GAL) at 20 mg kg-1 body weight alone or in combination against testicular injury induced by Cd (24 mg kg-1 body weight) in male Wistar rats were evaluated in this study. Forty-two (42) rats were randomly grouped into six (6) groups: (1) vehicle control group, (2) Cd group, (3) RUT+Cd group, (4) GAL+Cd group, (5) QUE+Cd group, and (6) RUT+GAL+QUE+Cd group. At the end of the oral gavage of the tested chemicals, the rats were sacrificed, blood samples were collected, and testes were harvested and processed for biochemical assays. Cd exposure damaged the testis (smaller epithelium thickness and spermatogenesis index and sloughing of the epithelium); increased lipid peroxidation, glutathione S-transferase activity, and DNA fragmentation; and diminished glutathione reductase activity and serum testosterone level 40 days posttreatment. Treatment with the phenolics separately or in combination attenuated the effect of Cd on serum testosterone, glutathione reductase and glutathione S-transferase activities, lipid peroxidation, and percent fragmented DNA. The increased nitric oxide concentration in the QUE+Cd group was attenuated to control values in the combined (RUT+GAL+QUE+Cd) exposure group. Coadministration of the phenolics appears to have more substantial protective effects than their single effects against Cd-induced testicular DNA damage, glutathione S-transferase activity, and the recovery of testosterone levels and spermatogenesis index. Overall, the tested phenolics can reduce testicular damage more efficiently in their combined form than individual administration.

Combined exposure to di(2-ethylhexyl) phthalate and polystyrene microplastics induced renal autophagy through the ROS/AMPK/ULK1 pathway.

Di(2-ethylhexyl) phthalate (DEHP) and polystyrene microplastics (PS-MPs) are new environmental pollutants that attracted increased attention. At present, the effects and underlying mechanisms of action of combined exposure of DEHP and PS-MPs on the kidney have not been elucidated. To investigate the renal toxicity of DEHP and PS-MPs exposure, we established single and combined DEHP and PS-MPs exposure models in mice and HEK293cells, respectively. Hematoxylin and eosin staining, transmission electron microscopy, monodansylcadaverine staining, immunofluorescence, real-time quantitative PCR, Western blot analysis and other methods were used to detect relevant indicators. The results showed that the expression levels of ROS/AMPK/ULK1 and Ppargc1α/Mfn2 signaling pathway-related genes were significantly increased in the DEHP and PS-MPs exposure models. The mRNA and protein expression levels of autophagy markers were also upregulated. In addition, we found that the expression levels of mRNAs and proteins in the combined exposure group were more significantly increased than those in the single exposure group. In conclusion, combined exposure to DEHP and PS-MPs caused oxidative stress and activated the AMPK/ULK1 pathway, thereby inducing renal autophagy. Our results enhance the field of nephrotoxicity studies of plasticizers and microplastics and provide new light on combined toxicity studies of DEHP and PS-MPs.

Combined negative effects of microplastics and plasticizer DEHP: The increased release of Nets delays wound healing in mice

Environmental harmful pollutants microplastics (MPs) and di (2-ethyl) hexyl phthalate (DEHP) are widely residual in the environment, which may cause lesion to multiple apparatus by inducing oxidative stress, threatening the health of human and animals. Neutrophil extracellular traps (Nets) are involved in skin wound healing. Most studies focused on the individual effects of different poisons on animals and ecosystems, but there are few studies on the accumulation and interaction of multiple poisons. The purpose of this study is to explore the effect of DEHP and MPs co-exposure on skin wound healing and the formation of Nets. For this purpose, we detected this hypothesis by replicating the DEHP and MPs-exposed skin wound model in mice, as well as the co-culture system of neutrophil and fibroblast. The results displayed that MPs and DEHP exposure delayed skin healing, which was more pronounced in the combined exposure group. In vitro and in vivo experiments confirmed that compared with the DEHP or MPs group, the DEHP+MPs group had more significant oxidative stress, increased Nets release and inflammatory factors, and inhibited the Wnt/β-catenin pathway and fibrosis-related factors. N-acetylcysteine (NAC) attenuated these phenomena. Through the co-culture system, we confirmed that the overproduction of Nets induced fibroblasts to exacerbate inflammatory responses and inhibit Wnt pathway and fibrosis. Overall, DEHP and MPs can produce synergistic toxic injury in mice skin wounds, and the excessive activation of ROS/Nets can aggravate inflammatory and inhibit fibrosis, resulting in delayed wound healing.

Combined Reproductive Effects of Imidacloprid, Acetochlor and Tebuconazole on Zebrafish (Danio rerio)

Pesticides usually occur as mixtures of multiple chemicals in the natural aquatic ecosystem, so research based on the toxicity data of a single compound on aquatic organisms is not enough to accurately assess the actual toxicity risk of pesticides. There is still a gap in the research on the reproductive toxicity of combined insecticides, herbicides and fungicides on zebrafish (Danio rerio). In this study, zebrafish were used to systematically investigate the separate and combined reproductive toxicity of imidacloprid (IMI), acetochlor (ACT) and tebuconazole (TBZ), which are commonly used in rice fields. Adult zebrafish were exposed to the three pesticides individually and in combination for 28 days, and the number, heartbeat, deformation rate, body length, and swim bladder development of F1 offspring embryos were observed and the reproductive hormones testosterone (T), estradiol (E2), and vitellogenin (VTG) contents and the expressions of nine reproductive genes (ar, esr2a, vtg1, gr, star, fshr, hmgcrb, 3βhsd and vasa) in the testes of the male and the ovaries of the female F0 zebrafish adults were measured to evaluate the individual and combined effects. The results showed that exposure to the mixtures of IMI, ACT and TBZ resulted in a decrease in heartbeat, body length and swim bladder development and an increase in the deformity rate of F1 offspring embryos compared to the individual exposure groups. In the combined exposure group, the content of T decreased significantly and the content of VTG increased significantly in the testes of the males; the content of T significantly increased, while the content of E2 and VTG significantly decreased in the ovaries of the females, indicating that combined exposure showed a more obvious endocrine-disrupting effect compared to the individual exposures. In addition, the expression of nine reproductive genes was significantly altered compared to the individual exposure groups. Therefore, our results indicated that the mixture of IMI, ACT and TBZ caused fewer number of F1 embryos, higher developmental defects of F1, greater disruption in the content of reproductive hormones and the expression of reproductive genes compared to the individual pesticides at the corresponding doses. Therefore, the presence of pesticides in mixtures in the real water environment is likely to increase the toxic reproductive effects on zebrafish and cause more serious impacts on aquatic ecosystems.

Toxic effects of combined exposure of tritiated water and genistein on the growth and development of zebrafish and its mechanism

Water pollution and control are important issues of our lasting concern. Environmental media often contains a variety of compounds. Tritium is widely present in nature due to human activities. As an endocrine disruptor, genistein is widely found in water body. Will it cause damage when combined with tritiated water and genistein? In this study, Zebrafish embryos were randomly divided into 4 groups: blank control group (simple E3 medium), tritiated water exposure group (tritiated water with a final concentration of 3.7*102Bq/mL in the medium), and genistein exposure group (the final concentration of 1.4 mg/L genistein in the medium) and the combined exposure group of tritiated water and genistein (3.7*102 Bq/mL tritium water +1.4 mg/L genistein). The results show that tritiated water with 3.7*102 Bq/ml exposure alone did not affect the development of zebrafish embryos. However, the survival rate, hatching rate and heart rate of zebrafish larvae decreased combined exposure with genistein, and the abnormality rate and apoptotic cells in the embryos and the level of oxidative stress increased. The results of RNA sequencing showed that the combined exposure of tritiated water and genistein affected the gene expression of zebrafish embryos. Differential genes were mainly enriched in many pathways, such as p53 signaling pathway, steroid hormone biosynthesis, PPAR signaling pathway, metabolism of xenobiotics by cytochrome P450. The results of qRT-PCR and gene knockout experiment showed that cyp19a1b gene may plays an important role in the toxic effects of combined exposure.

Polystyrene nanoplastics aggravates lipopolysaccharide-induced apoptosis in mouse kidney cells by regulating IRE1/XBP1 endoplasmic reticulum stress pathway via oxidative stress.

Nanoplastics (NPs) pollution poses a huge threat to the ecosystem and has become one of the environmental pollutants that have attracted much attention. There is increasing evidence that both oxidative stress and endoplasmic reticulum stress(ERS) are associated with polystyrene nanoplastics (PS-NPs) exposure. Lipopolysaccharide (LPS) has been shown to induce apoptotic damage in various tissues, but whether PS-NPs can aggravate LPS-induced apoptosis in mouse kidneys through oxidative stress-regulated inositol-requiring enzyme 1 (IRE1)/X-box binding protein 1 (XBP1) ERS pathway remains unclear. In this study, based on the establishment of in vitro and in vivo PS-NPs and LPS exposure models alone and in combination in mice and HEK293 cells, the effects and mechanisms of PS-NPs on LPS-induced renal cell apoptosis were investigated. The results showed that PS-NPs could aggravate LPS-induced apoptosis. PS-NPs/LPS can induce ERS through oxidative stress, activate the IRE1/XBP1 pathway, and promote the expression of apoptosis markers (Caspase-3 and Caspase-12). Kidney oxidative stress, ERS, and apoptosis in PS-NPs + LPS combined exposure group were more severe than those in the single exposure group. Interestingly, 4-phenylbutyric acid-treated HEK293 cells inhibited the expression of theIRE1/XBP1 ERS pathway and apoptotic factors in the PS-NPs + LPS combined exposure group. N-acetyl-L-cysteineeffectively blocked the activation of the IRE1/XBP1 ERS pathway, suggesting that PS-NPs-inducedoxidative stress is an early event that triggers ERS. Collectively, these results confirmed that PS-NPs aggravated LPS-induced apoptosis through the oxidative stress-induced IRE1/XBP1 ERS pathway. Our study provides new insights into the health threats of PS-NPs exposed to mammals and humans.

The combined effect of titanium dioxide nanoparticles and cypermethrin on male reproductive toxicity in rats.

Titanium nanoparticles and pyrethroid pesticides are now being widely used in industrial, agriculture, and biomedical applications. In recent years, their health safety profiles have aroused concerns among health scientists. This study mainly explored the combined effects of titanium dioxide nanoparticles (TiO2NPs) and cypermethrin (CYP) on reproductive toxicity in male rats by gavage for 90days. Thirty-two male Sprague-Dawley rats were assigned to four groups: the control group, the TiO2NPs group, the CYP group, and the combined titanium dioxide nanoparticles with cypermethrin (TiO2NPs + CYP) group. The results of biochemical analysis on testicular tissue homogenate showed that TiO2NPs and CYP mixtures decreased the activities of glutathione peroxidase (GSH-Px) and catalase (CAT) while increasing the activity of malondialdehyde (MDA) and lactate dehydrogenase (LDH). Meanwhile, the results of two-way factorial analysis of variance (ANOVA) showed a significant effect on GSH-Px, CAT, LDH, testicular cell apoptosis, and sperm quality in rats after exposure. Furthermore, the combined exposure group exhibited apoptosis of testicular cells and DNA damage. The results indicated that exposure to a mixture of TiO2NPs and CYP had adverse effects on the reproductive status of male rats.

Sub-chronic, low dose co-exposure to Aflatoxin B1 and Microcystin-LR in C57BL/6 mice significantly alters the cytokine response in serum and liver

ABSTRACT In this study, we examined the expression of 11 cytokines in liver and serum of C57BL/6 mice upon single or co-exposed to Aflatoxin B1 and Microcystin-LR at low-dose and sub-chronic conditions. The objective is to elucidate the potential combined hepatotoxic effects induced by AFB1+MC-LR, and we aim to provide references for further immune impacts in the liver. Luminex-based cytokine examination was applied, and we found that most of the cytokine expression increased with time. The level of IL-18, GM-CSF, IFN-γ, IL-1β and IL-4 in the liver showed a significant rise. However, some cytokines (IL-13) showed an upward trend after being suppressed during the middle stage of exposure. The level of IFN-γ and IL-12p70 generally represented the immune response in the combined exposure group. Conclusionally, there are many uncertainties due to sub-chronic and low-dose exposure. Therefore, the occurrence of subsequent irreversible liver injury and liver cancer is a probabilistic event.

Acute arsenic exposure exacerbates lipopolysaccharide-induced lung injury possibly by compromising the integrity of the lung epithelial barrier in rats

Inhalation of large amounts of arsenic can damage the respiratory tract and may exacerbate the development of bacterial pneumonia, but the exact mechanism remains unclear. In this study, male Wistar rats were randomly divided into control, arsenic trioxide (16.0 μg/kg ATO), lipopolysaccharide (0.5 mg/kg LPS), and ATO combined with LPS (16.0 μg/kg ATO + 0.5 mg/kg LPS) groups. Blood and lung tissue samples were collected from each group 12 h after exposure. The results showed that exposure to ATO or LPS alone produced different effects on leukocytes and inflammatory factors, while combined exposure significantly increased serum interleukin-6, interleukin-10, lung water content, lung lavage fluid protein, and p38 protein phosphorylation levels. Alveolar interstitial thickening, alveolar membrane edema, alveolar type I and II cell matrix vacuolization, and nuclear pyknosis were observed in rats exposed to either ATO or LPS. More severe ultrastructural changes were found in the combined exposure group, and chromatin splitting was observed in alveolar type I cells. Lanthanum nitrate particles leaked from the alveolar vascular lumen in the ATO-exposed group, whereas in the combined exposure group, Evans Blue levels were increased and lanthanum nitrate particles were present in the lung parenchyma. Claudin-3 protein expression increased and claudin-4 expression decreased after ATO or LPS exposure, while claudin-18 expression was unchanged. The changes in claudin-3 and claudin-4 protein expression were further exacerbated by combined exposure. In conclusion, these results suggest that inhalation of ATO may exacerbate the development of bacterial pneumonia and that common mechanisms may exist to synergistically disrupt epithelial barrier integrity.

Bisphenol A exacerbates selenium deficiency-induced pyroptosis via the NF-κB/NLRP3/Caspase-1 pathway in chicken trachea

Selenium deficiency can lead to multiple tissue and organ damage in the body and could coexist with chronic toxic exposures. Contamination from Bisphenol A (BPA) exposure can induce the occurrence of various injuries including pyroptosis. However, it is not clear whether selenium deficiency and BPA exposure affect tracheal tissue pyroptosis in chickens. To investigate whether selenium deficiency and BPA exposure induce chicken tracheal tissue pyroptosis via the NF-κB/NLRP3/Caspase-1 pathway and the effect of their combined exposure on tissue injury, we developed a model of relevant chicken tracheal injury. Sixty broilers were divided into four groups: the control group (C group), selenium-deficient group (SeD group), BPA-exposed group (BPA group) and combined exposure group (SeD + BPA group). The study examined the expression indicators of markers of pyroptosis (NLRP3&GSDMD), NF-κB pathway-related inflammatory factors (NF-κB, iNOS, TNF-α, COX-2), pyroptosis-related factors (ASC, Caspase-1, IL-1β, IL-18), and some heat shock proteins and interleukins (HSP60, HSP90, IL-6, IL-17) in the samples. The results showed that the expression of the above indicators was significantly upregulated in the different treatment groups (P < 0.05). In addition, the expression levels of the above related indicators were more significantly up-regulated in the combined selenium-deficient and BPA-exposed group compared to the group in which they were individually exposed. It was concluded that selenium deficiency and BPA exposure induced tracheal tissue pyroptosis in chickens through NF-κB/NLRP3/Caspase-1 pathway, and BPA exposure exacerbated selenium deficiency-induced tracheal pyroptosis. The present study provides new ideas into studies related to the co-exposure of organismal micronutrient deficiency and chronic toxicants.

Joint effect of myocardial infarction and obesity on the risk of venous thromboembolism: The Tromsø Study

BackgroundMyocardial infarction (MI) is associated with an increased risk of venous thromboembolism (VTE). Obesity is a recognized risk factor for both MI and VTE. Whether obesity further increases the risk of VTE in MI patients is scarcely investigated. AimTo study the joint effect of MI and obesity on the risk of VTE. MethodsStudy participants (n = 29 410) were recruited from three surveys of the Tromsø Study (conducted in 1994–1995, 2001, and 2007–2008) and followed up through 2014. All incident MI and VTE cases during follow‐up were recorded. Cox regression models with MI as a time‐dependent variable were used to estimate hazard ratios (HRs) of VTE (adjusted for age and sex) by combinations of MI exposure and obesity status. Joint effects were assessed by calculating relative excess risk and attributable proportion (AP) due to interaction. ResultsDuring a median of 19.6 years of follow‐up, 2090 study participants experienced an MI and 784 experienced a VTE. Among those with MI, 55 developed a subsequent VTE, yielding an overall incidence rate (IR) of VTE of 5.3 per 1000 person‐years (95% confidence interval [CI]: 4.1–6.9). In the combined exposure group (MI+/Obesity+), the IR was 11.3 per 1000 person‐years, and the adjusted HR indicated a 3‐fold increased risk of VTE (HR 3.16, 95% CI: 1.99–4.99) compared to the reference group (MI−/Obesity−). The corresponding AP was 0.46 (95% CI: 0.17–0.74). ConclusionsThe combination of MI and obesity yielded a supra‐additive effect on VTE risk of which 46% of the VTE events were attributed to the interaction.

Low-dose florfenicol and copper combined exposure during early life induced health risks by affecting gut microbiota and metabolome in SD rats

The potential health risks associated with simultaneous presence of residues of heavy metals and antibiotics in the environment and food have been of wide concern. However, the adverse health effects of combined heavy metal and antibiotic exposure at low doses remain unclear. In this study, the effects of combined exposure to florfenicol and copper at low doses during early life on toxicity, gut microbiota, drug resistance genes, and the fecal metabolome were investigated in Sprague–Dawley (SD) rats. The results showed that combined exposure induced inflammatory responses and visceral injury as well as faster weight gain compared with florfenicol or copper exposure alone. Alpha and beta diversity indices indicated that the composition of the gut microbiota and the abundance of bacteria related to energy intake and disease in the combined exposure group were significantly altered. The increase in resistance genes (floR, fexA) induced by florfenicol exposure was suppressed under combined exposure to florfenicol and copper. The fecal metabolome also demonstrated that metabolic pathways related to energy intake and liver injury were significantly affected in the combined exposure group. In conclusion, this study shows that combined exposure to florfenicol and copper during early life can pose a nonnegligible health risk even if the exposure concentration of florfenicol or copper is below the safe limit.