Comprehensive multi-omics investigation of sub-chronic toxicity induced by Cadmium and Triazophos Co-exposure in hook snout carps (Opsariichthys bidens).

The coexistence of heavy metals and pesticides poses a critical challenge in agricultural ecosystems. Traditional toxicity assessments often focus only on the individual impacts of either pesticides or heavy metals. Here, the untargeted metabolomics and 16 S rRNA sequencing were used to assess the individual and combined effects of cadmium (Cd) and triazophos (TRI) on hook snout carps (Opsariichthys bidens). Cd caused much more serious impacts on hepatic metabolism and gut microbiota than those in TRI. Combined Cd and TRI exposure synergistically affected hepatic metabolism, causing mitochondrial dysfunction and even oxidative damage. Simultaneously, 16 S rRNA sequencing highlighted significant variations in the composition and abundance of gut microbiota. A noteworthy connection emerged between these distinct microbiota profiles and disruptions in energy metabolism, ultimately leading to disorders in metabolites. These findings enhanced the understanding of risks posed by heavy metals and pesticides, providing insights for better environmental risk assessments of aquatic organisms.

Cardioprotective potentials of myricetin on doxorubicin-induced cardiotoxicity based on biochemical and transcriptomic analysis.

Doxorubicin (DOX) is a commonly used anthracycline in cancer chemotherapy. The clinical application of DOX is constrained by its cardiotoxicity. Myricetin (MYR) is a natural flavonoid widely present in many plants with antioxidant and anti-inflammatory properties. However, MYR's beneficial effects and mechanisms in alleviating DOX-induced cardiotoxicity (DIC) remain unknown. C57BL/6 mice were injected with 15 mg/kg of DOX to establish the DIC, and MYR solutions were administrated by gavage to investigate its cardioprotective potentials. Histopathological analysis, physiological indicators assessment, transcriptomics analysis, and RT-qPCR were used to elucidate the potential mechanism of MYR in DIC treatment. MYR reduced cardiac injury produced by DOX, decreased levels of cTnI, AST, LDH, and BNP, and improved myocardial injury and fibrosis. MYR effectively prevented DOX-induced oxidative stress, such as lowered MDA levels and elevated SOD, CAT, and GSH activities. MYR effectively suppressed NLRP3 and ASC gene expression levels to inhibit pyroptosis while regulating Caspase1 and Bax levels to reduce cardiac cell apoptosis. According to the transcriptomic analysis, glucose and fatty acid metabolism were associated with differential gene expression. KEGG pathway analysis revealed differential gene enrichment in PPAR and AMPK pathways, among others. Following validation, MYR was found to alleviate DIC by regulating glycolipid metabolism and AMPK pathway-related genes. Our findings demonstrated that MYR could mitigate DIC by regulating the processes of oxidative stress, apoptosis, and pyroptosis. MYR is critical in improving DOX-induced myocardial energy metabolism abnormalities mediated by the AMPK signaling pathway. In conclusion, MYR holds promise as a therapeutic strategy for DIC.

Polyphenolic Nanoparticle-Modified Probiotics for Microenvironment Remodeling and Targeted Therapy of Inflammatory Bowel Disease.

Inflammatory bowel diseases (IBDs) refer to multifaceted disorders in the intestinal microenvironment and microbiota homeostasis. In view of the broad bioactivity and high compatibility of polyphenols, there is considerable interest in developing a polyphenol-based collaborative platform to remodel the IBD microenvironment and regulate microbiota. Here, we demonstrated the coordination assembly of nanostructured polyphenols to modify probiotics and simultaneously deliver drugs for IBD treatment. Inspired by the distinctive structure of tannic acid (TA), we fabricated nanostructured pBDT-TA by using a self-polymerizable aromatic dithiol (BDT) and TA, which exhibited excellent antioxidant and anti-inflammatory capability in vitro. We thus coated pBDT-TA and sodium alginate (SA) to the surface of Escherichia coli Nissle 1917 layer by layer to construct the collaborative platform EcN@SA-pBDT-TA. The modified probiotics showed improved resistance to oxidative and inflammatory stress, which resulted in superior colon accumulation and retention in IBD model mice. Further, EcN@SA-pBDT-TA could alleviate dextran sulfate sodium (DSS)-induced colitis by controlling the inflammatory response, repairing intestinal barriers, and modulating gut microbiota. Importantly, EcN@SA-pBDT-TA-mediated IBD drug delivery could achieve an improved therapeutic effect in DSS model mice. Given the availability and functionality of polyphenol and prebiotics, we expected that nanostructured polyphenol-modified probiotics provided a solution to develop a collaborative platform for IBD treatment.

Gallic acid attenuates LPS-induced inflammation in Caco-2 cells by suppressing the activation of the NF-κB/MAPK signaling pathway.

Inflammatory bowel disease (IBD) is a chronic inflammatory disease characterized by intestinal barrier dysfunction, inflammatory synergistic effects and excessive tissue injury. Gallic acid (GA) is renowned for its remarkable biological activity, encompassing anti-inflammatory and antioxidant properties. However, the underlying mechanisms by which GA protects against intestinal inflammation have not been fully elucidated. The aim of this study is to investigate the effect of GA on the inflammation of a lipopolysaccharide (LPS)-stimulated human colon carcinoma cell line (Caco-2) and on the intestinal barrier dysfunction, and explore the underlying molecular mechanism involved. Our findings demonstrate that 5 µg/mL GA restores the downregulation of the mRNA and protein levels of Claudin-1, Occludin, and ZO-1 and decreases the expressions of inflammatory factors such as IL-6, IL-1ß and TNF-α induced by LPS. In addition, GA exhibits a protective effect by reducing the LPS-enhanced early and late apoptotic ratios, downregulating the mRNA levels of pro-apoptotic factors ( Bax, Bad, Caspase-3, Caspase-8, and Caspase-9), and upregulating the mRNA levels of anti-apoptotic factor Bcl-2 in Caco-2 cells. GA also reduces the levels of reactive oxygen species increased by LPS and restores the activity of antioxidant enzymes, namely, superoxide dismutase and catalase, as well as the level of glutathione. More importantly, GA exerts its anti-inflammatory effects by inhibiting the LPS-induced phosphorylation of key signaling molecules in the NF-κB/MAPK pathway, including p65, IκB-α, p38, JNK, and ERK, in Caco-2 cells. Overall, our findings show that GA increases the expressions of tight junction proteins, reduces cell apoptosis, relieves oxidative stress and suppresses the activation of the NF-κB/MAPK pathway to reduce LPS-induced intestinal inflammation in Caco-2 cells, indicating that GA has potential as a therapeutic agent for intestinal inflammation.

Impacts of prothioconazole and prothioconazole-desthio on bile acid and glucolipid metabolism: Upregulation of CYP7A1 expression in HepG2 cells.

As an efficient triazole fungicide, prothioconazole (PTC) is widely used for the prevention and control of plant fungal pathogens. It was reported that the residues of PTC and prothioconazole-desthio (PTC-d) have been detected in the environment and crops, and the effects of PTC-d may be higher than that of PTC. Currently, PTC and PTC-d have been proven to induce hepatic metabolic disorders. However, their toxic effects on cellular bile acid (BA) and glucolipid metabolism remain unknown. In this study, HepG2 cells were exposed to 1-500 µM of PTC or PTC-d. High concentrations of PTC and PTC-d were found to induce cytotoxicity; thus, subsequent experimental exposure was conducted at concentrations of 10-50 µM. The expression levels of CYP7A1 and TG synthesis-related genes and levels of TG and total BA were observed to increase in HepG2 cells. Molecular docking analysis revealed direct interactions between PTC or PTC-d and CYP7A1 protein. To further investigate the underlying mechanisms, PTC and PTC-d were treated to HepG2 cells in which CYP7A1 expression was knocked down using siCYP7A1. It was observed that PTC and PTC-d affected the BA metabolism process and regulated the glycolipid metabolism process by promoting the expression of CYP7A1. In summary, we comprehensively analyzed the effects and mechanisms of PTC and PTC-d on cellular metabolism in HepG2 cells, providing theoretical data for evaluating the safety and potential risks associated with these substances.

Co-exposure to sodium hypochlorite and cadmium induced locomotor behavior disorder by influencing neurotransmitter secretion and cardiac function in larval zebrafish.

Sodium hypochlorite (NaClO) and cadmium (Cd) are widely co-occurring in natural aquatic environment; however, no study has been conducted on effects of their combined exposure on aquatic organisms. To assess effects of exposure to NaClO and Cd in zebrafish larvae, we designed six treatment groups, as follows: control group, NaClO group (300 µg/L), 1/100 Cd group (48 µg/L), 1/30 Cd group (160 µg/L), NaClO+1/100 Cd group, and NaClO+1/30 Cd group analyzed behavior, neurological function and cardiac function. Results revealed that exposure to 1/30 Cd and NaClO+1/30 Cd caused abnormal embryonic development in larvae by altering body morphology and physiological indicators. Combined exposure to NaClO and 1/30 Cd affected the free-swimming activity and behavior of larvae in response to light-dark transition stimuli. Moreover, exposure to 1/30 Cd or NaClO+1/30 Cd resulted in a significant increase in tyrosine hydroxylase and acetylcholinesterase activities, as well as significant changes of various neurotransmitters. Lastly, exposure to 1/30 Cd or NaClO+1/30 Cd influenced the transcription of cardiac myosin-related genes and disturbed the myocardial contractile function. Altogether, our results suggested that combined exposure to NaClO and Cd induced oxidative damage in larvae, resulting in detrimental effects on nervous system and cardiac function, thus altering their swimming behavior.

Toxicologic effect and transcriptome analysis for sub-chronic exposure to carbendazim, prochloraz, and their combination on the liver of mice.

Carbendazim (CBZ) and prochloraz (PCZ) are broad-spectrum fungicides used in agricultural peat control. Both fungicides leave large amounts of residues in fruits and are toxic to non-target organisms. However, the combined toxicity of the fungicides to non-target organisms is still unknown. Therefore, we characterized the toxic effects of dietary supplementation with CBZ, PCZ, and their combination for 90 days in 6-week-old male Institute of Cancer Research (ICR) mice. CBZ-H (100 mg/kg day), PCZ-H (10 mg/kg day), and their combination treatments increased the relative liver weights and caused liver injury. The serum total cholesterol (TC), triglyceride (TG), glucose (Glu), pyruvate (PYR), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) levels were reduced, and synergistic toxicity was observed. Hepatic transcriptome revealed that 326 differentially expressed genes (DEGs) of liver were observed in the CBZ treatment group, 149 DEGs in the PCZ treatment group, and 272 DEGs in the combination treatment group. According to KEGG enrichment analysis, the fungicides and their combination affected lipid metabolism, amino acid metabolism, and ferroptosis. In addition, the relative mRNA levels of key genes involved in lipid metabolism were also examined. Compared with individual exposure, combined exposure to CBZ and PCZ caused a more obvious decrease in the expression of some genes related to glycolipid metabolism. Furthermore, the relative mRNA levels of some key genes in the combination treatment group were lower than those in the CBZ and PCZ treated groups. In summary, CBZ, PCZ, and their combination generally caused hepatotoxicity and glycolipid metabolism disorders, which could provide new insights for investigating the combined toxicity of multiple fungicides to animals.

Mitochondria Targeted Nanoparticles Potentiate Tumor Chemo-Phototherapy by Toxic Oxidative Stress Mediated Oxeiptosis.

Insufficient accumulation of drug at the tumor site and the low drug response are the main reason for the unsatisfactory effect of cancer therapy. Delivery drugs exquisitely to subcellular level can be employed to reduce side effects, and expand the therapeutic window. Herein, a triphenylphosphine (TPP) modified lipid nanoparticles is designed which are loaded with the photosensitizer indocyanine green (ICG) and chemotherapeutic paclitaxel (PTX) for mitochondria-targeted chemo-phototherapy. Owing to the movement of majority mitochondria along microtubules in cytoplasm, mitochondrial targeting may enable PTX to act more effectively. Meanwhile, the existence of chemo-drug potentiates the phototherapy to achieve synergistic anti-tumor activity. As expected, mitochondria targeting nanomedicine (M-ICG-PTX NPs) showed improved mitochondria targeted cellular distribution and enhanced cell cytotoxicity in vitro. Also, M-ICG-PTX NPs exhibited higher tumor growth inhibition ability by promoting cell apoptosis and oxeiptosis pathway, and high effective inhibition of primary tumor growth and tumor metastasis. Taken together, M-ICG-PTX NPs may be promising nanoplatforms to achieve potent therapeutic effect for the combination of chemo- and photo-therapy (PTT).

F-53B induces hepatotoxic effects and slows self-healing in ulcerative colitis in mice.

Chlorinated polyfluorinated ether sulfonate (F-53 B) is a distinct substitute for perfluorooctane sulphonate. It has been reported to be biologically toxic to mammals, causing enteric toxicity, liver toxicity and neurotoxicity. However, studies about the effects of F-53 B on patients with gastrointestinal diseases such as inflammatory bowel disease are very limited. In this study, whether the toxic impacts of F-53 B on the gut and liver can be exacerbated in mice with colitis was explored. The sensitivity of mice with acute colitis caused by dextran sulfate sodium salt (DSS) to F-53 B was compared with that of healthy mice. The mice were administered water containing F-53 B at doses of 10 and 100 µg/L sequentially for two weeks, respectively. F-53 B exposure exacerbated DSS-induced colonic inflammation, including inducing shortening of colon length, inflammatory cell infiltration and more severe histopathological symptoms. In addition, F-53 B administration significantly increased the levels of inflammatory cytokines, including interleukin (IL)-1, IL-6 and tumour necrosis factor-α, in the plasma of mice with enteritis compared with control group. F-53 B impaired intestinal integrity of mice with colitis by downregulating Claudin-1 and antimicrobial peptide-related genes while elevating serum lipopolysaccharide levels. In addition, in mice with colitis, F-53 B increased the levels of serum total cholesterol, triglyceride, low-density lipoprotein cholesterol, aspartate aminotransferase, and alanine aminotransferase, resulted in more severe liver inflammation and increased the level of genes related to the Gasdermin D-mediated pyrolysis. Conclusively, our results indicated that F-53 B delayed the self-healing of ulcerative colitis (UC) and caused liver inflammation in mice. This study provided some new insights into the health risks of F-53 B and raises concerns about the health of individuals with UC.

Biology of Peptide Transporter 2 in Mammals: New Insights into Its Function, Structure and Regulation.

Peptide transporter 2 (PepT2) in mammals plays essential roles in the reabsorption and conservation of peptide-bound amino acids in the kidney and in maintaining neuropeptide homeostasis in the brain. It is also of significant medical and pharmacological significance in the absorption and disposing of peptide-like drugs, including angiotensin-converting enzyme inhibitors, ß-lactam antibiotics and antiviral prodrugs. Understanding the structure, function and regulation of PepT2 is of emerging interest in nutrition, medical and pharmacological research. In this review, we provide a comprehensive overview of the structure, substrate preferences and localization of PepT2 in mammals. As PepT2 is expressed in various organs, its function in the liver, kidney, brain, heart, lung and mammary gland has also been addressed. Finally, the regulatory factors that affect the expression and function of PepT2, such as transcriptional activation and posttranslational modification, are also discussed.

Transgenerational effects of co-exposure to cadmium and carbofuran on zebrafish based on biochemical and transcriptomic analyses.

The combined toxicity of heavy metals and pesticides to aquatic organisms is still largely unexplored. In this study, we investigated the combined impacts of cadmium (Cd) and carbofuran (CAR) on female zebrafish (F0 generation) and their following F1 generation. Results showed that mixtures of Cd and CAR induced acute synergistic effects on both zebrafish adults of the F0 generation and embryos of the F1 generation. Combined exposure to Cd and CAR could obviously alter the hepatic VTG level of females, and the individual exposures increased the relative mRNA levels of vtg1 and vtg2. Through maternal transmission, co-exposure of Cd and CAR caused toxicity to 4-day-old larvae of the F1 generation, evidenced by the significant changes in T4 and VTG levels, CYP450 activity, and the relative transcriptional levels of genes related to the hormone, oxidative stress, and apoptosis. These effects were also reflected by the global gene expression pattern to 7-day-old larvae of F1 generation using the transcriptomic analysis, and they could also affect energy metabolism. Our results provided a more comprehensive insight into the transgenerational toxic impacts of heavy metal and pesticide mixtures. These findings highlighted that it was highly necessary to consider transgenerational exposures in the ecological risk assessment of chemical mixtures.

Extracellular vesicles-mediated interaction within intestinal microenvironment in inflammatory bowel disease.

Background: The intestinal tract is a complicated ecosystem with dynamic homeostasis via interaction of intestine and microbiota. Inflammatory bowel disease (IBD) is chronic intestinal inflammation involving dysbiosis of intestinal microenvironment. Extracellular vesicles (EVs), as vital characteristics of cell-cell and cell-organism communication, contribute to homeostasis in intestine. Recently, EVs showed excellent potential for clinical applications in disease diagnoses and therapies. Aim of Review: Our current review discusses the modulatory functions of EVs derived from different sources in intestine, especially their effects and applications in IBD clinical therapy. EV-mediated interaction systems between host intestine and microbiota were established to describe possible mechanisms of IBD pathogenesis and its cure. Key Scientific Concepts of Review: EVs are excellent vehicles for delivering molecules containing genetic information to recipient cells. Multiple pieces of evidence have illustrated that EVs participate the interaction between host and microbiota in intestinal microenvironment. In inflammatory intestine with dysbiosis of microbiota, EVs as regulators target promoting immune response and microbial reconstruction. EVs-based immunotherapy could be a promising therapeutic approach for the treatment of IBD in the near future.

Parental exposure to 3-methylcholanthrene before gestation adversely affected the endocrine system and spermatogenesis in male F1 offspring.

The compound 3-methylcholanthrene (3-MC) is an environmental pollutant belonging to the PAHs, which reportedly have the potential to disrupt the endocrine systems of animals. In the present study, 4-week-old male and female mice were given 3-MC through their diet at a dose of 0.5 mg/kg of chow for 6 weeks before pregnancy. The first filial (F1) generation offspring of exposed or unexposed parental mice were sacrificed at the age of 5 or 10 weeks (F1-5 W or F1-10 W), and the potential effects on the F0 and F1 offspring were evaluated. The results showed that the serum and testicular testosterone (T) levels and the genes involved in T synthesis in F0 males and male F1-5 W individuals born from female mice exposed to 3-MC were significantly decreased. In addition, histological analysis suggested that exposure to 3-MC significantly disrupted testicular morphology in F0 mice and in the offspring of female mice exposed to 3-MC. Further investigation revealed that genes involved in spermatogenesis, such as Phosphoglycerate kinase 2 (Pgk2), Glial cell derived neurotrophic factor (Gdnf), Myeloblastosis oncogene (Myb), DEAD box helicase 4 (Ddx4) and KIT proto-oncogene receptor tyrosine kinase (Kit), were suppressed in these mice. However, the adverse effects of parental 3-MC exposure on the adolescent mice were mitigated when they grew to adulthood, which was verified by studies on F1-10 W mice. Our results suggest that female exposure to 3-MC has the potential to disrupt the endocrine system and spermatogenesis in male offspring; nevertheless, the adverse effects might be mitigated with age.

Catechin from green tea had the potential to decrease the chlorpyrifos induced oxidative stress in larval zebrafish (Danio rerio).

Catechin is a biological compound in green tea (Camellia sinesis), which has anti-oxidant, anti-cancer, anti-apoptotic, anti-inflammatory, and attenuated effects in different experimental models. Chlorpyrifos (CPF), a broad-spectrum organophosphate insecticide, has resulted in oxidative stress, mitochondrial dysfunction, and apoptosis in zebrafish. The goal of this study is to assess whether catechin can alleviate CPF-induced oxidative damage and apoptosis in the early developmental stage of zebrafish. According to the results, we observed that 200 µg/L CPF exposure could induce oxidative stress, ROS production and changing the antioxidant-related enzymes and genes in larval zebrafish. Interestingly, catechin had the potential to reduce the oxidative damage and cell apoptosis caused by CPF exposure in larval zebrafish at different endpoints. Especially, catechin could promote the contents of GSH and activity of GST in zebrafish larvae injured by CPF, suggesting that catechin could repair oxidative damage at a certain degree by regulating the activities and gene transcription of some key enzymes related to GSH pathway in zebrafish. In addition, at transcriptional levels, a high concentration of catechin exposure reduced the expression genes of Mn-SOD, Cat, gst, and GPX induced by CPF in larval zebrafish. These genes mainly reflected the degree of oxidative damage of zebrafish, which was basically consistent with the enzyme activity. Catechin also could reduce the transcription of p53 and bax, which are tightly related to the apoptosis induced by CPF in zebrafish larvae. The expression of genes was consistent with ROS production, which proved that catechin could alleviate the apoptosis induced by CPF. This study discovered that catechin had some antioxidant effects in aquatic animals to reduce the toxicity caused by pesticides and offered the scientific basis for the utilization and development of catechin.

Chlorothalonil induces the intestinal epithelial barrier dysfunction in Caco-2 cell-based in vitro monolayer model by activating MAPK pathway.

The widespread use of chlorothalonil (CTL) has caused environmental residues and food contamination. Although the intestinal epithelial barrier (IEB) is directly involved in the metabolism and transportation of various exogenous compounds, there are few studies on the toxic effects of these compounds on the structure and function of IEB. The disassembly of tight junction (TJ) is a major cause of intestinal barrier dysfunction under exogenous compounds intake, but the precise mechanisms are not well understood. Here, we used Caco-2 cell monolayers as an in vitro model of human IEB to evaluate the toxicity of CTL exposure on the structure and function of IEB. Results showed that CTL exposure increased the paracellular permeability of the monolayers and downregulated mRNA levels of the TJ genes (ZO-1, OCLN, and CLDN1), polarity marker gene (SI), and anti-apoptosis gene (BCL-2) but upregulated the mRNA levels of apoptosis-related genes, including BAD, BAX, CASP3, and CASP8. Western blot analysis and immunofluorescence assay results showed the decreased levels and disrupted distribution of TJ protein network, including ZO-1 and CLDN1 in CTL-exposed IEB. In addition, the accumulation of intracellular reactive oxygen species, decreased mitochondrial membrane potential, and increased active CASP3 expression were observed in treated IEB. The result of TUNEL assay further confirmed the occurrence of cell apoptosis after CTL exposure. In addition, the phosphorylation of mitogen-activated protein kinases, including ERK, JNK and p38, was increased in CTL-exposed IEB. In summary, our results demonstrated that CTL exposure induced IEB dysfunction in Caco-2 cell monolayers by activating the mitogen-activated protein kinase pathway.

Bisphenol A impairs cognitive function and 5-HT metabolism in adult male mice by modulating the microbiota-gut-brain axis.

Bisphenol A (BPA) has been found to promote hepatotoxicity, reproductive toxicity, and developmental toxicity. However, the neurotoxicity and mechanism of BPA on cognitive function are still unclear. To that end, eight-week-old adult male and female C57BL/6J mice were exposed to 0.05, 0.5, 5, and 50 mg/kg BPA by dietary supplementation for 22 weeks. BPA exposure impaired learning and memory in male mice, associated with increased neuroinflammation and damaged blood-brain barrier. BPA exposure reduced the tight junctions in the colon, resulting in dysfunction of the gut barrier. The levels of neurotransmitters in the serum, hippocampus, and colon of male mice, including tryptophan, 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid, were all decreased by BPA, together with reduced expression of tryptophan and 5-HT metabolism-related genes. Cecal microbiota analysis revealed that the diversity and composition of the microbiota in male mice were markedly altered by BPA, leading to functional profile changes in the microbial community. These results suggest that the neurotoxicity of BPA in male mice may be partly regulated by the interactions of the microbiota-gut-brain axis. However, BPA has little effect on the cognitive function in female mice, which might be caused by the microbial differences and the role of estrogen receptors.

Maternal exposure of mice to sodium p-perfluorous nonenoxybenzene sulfonate causes endocrine disruption in both dams and offspring.

The toxicity of certain novel perfluoroalkyl substances (PFCs) has attracted increasing attention. However, the toxic effects of sodium p-perfluorous nonenoxybenzene sulfonate (OBS) on the endocrine system have not been elucidated. In this study, OBS was added to the drinking water during the pregnancy and lactation of the healthy female mice at dietary levels of 0.0 mg/L (CON), 0.5 mg/L (OBS-L), and 5.0 mg/L (OBS-H). OBS exposure during the pregnancy and lactation resulted in the presence of OBS residues in the placenta and fetus. We also analyzed physiological and biochemical parameters and gene expression levels in mice of the F0 and F1 generations after maternal OBS exposure. The total serum cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels were significantly increased in female mice of the F0 generation. The androgen levels in the serum and the ovarian mRNA levels of androgen receptor (AR) also tended to increase after maternal OBS exposure in the F0 generation mice. Moreover, maternal OBS exposure altered the mRNA expression of endocrine-related genes in male mice of F1 generation. Notably, the serum TC and LDL-C levels were significantly increased in 8-weeks-old male mice of the F1 generation, and the serum high-density lipoprotein cholesterol (HDL-C) levels were decreased in 24-week-old male mice of the F1 generation. These results indicated that maternal OBS exposure can interfere with endocrine homeostasis in the F0 and F1 generations. Therefore, exposure to OBS during pregnancy and lactation has the potential toxic effects on the dams and male offspring, which cannot be overlooked.

Combined hepatotoxicity of imidacloprid and microplastics in adult zebrafish: Endpoints at gene transcription.

Microplastics (MPs) and pesticides are two kinds of ubiquitous pollutants that can pose a health risk to aquatic organisms. However, researches about the combined effects of MPs and pesticides are very limited. A simple combined exposure model was established in this study, adult zebrafish were exposed to 100 µg/L imidacloprid (IMI), 20 µg/L polystyrene microplastics (PS), and a combination of PS and IMI (PS + IMI) for 21 days. The results demonstrated that exposure to PS and IMI inhibited the growth of zebrafish and altered the levels of glycolipid metabolism and oxidative stress-related biochemical parameters. While gene expression analysis revealed that, compared with PS or IMI treatment group, combined exposure caused a greater change in gene expression levels involving the process of glycolipid metabolism (Gk, Hk1, Aco, PPar-α, Cpt1, Acc, Fas, PPar-γ, Apo) and inflammatory response (IL-1ß, IL-6, IL-8, TNF-α, IL-10). The results demonstrated that even combined exposure of low concentrations of PS and IMI could cause more severe hepatotoxicity in zebrafish, especially in terms of gene transcription. And more combined toxicity studies are essential for MPs and pesticides risk assessment.

Polystyrene nanoparticles trigger the activation of p38 MAPK and apoptosis via inducing oxidative stress in zebrafish and macrophage cells.

Polystyrene nanoparticles (PS NPs), originated from breakdown of large plastic wastes, have already caused much concern for their environmental risks on health. This current study was aimed to reveal the toxicological mechanism of PS NPs on developing zebrafish and macrophage cells. To fulfill this purpose, 42 nm PS NPs were exposed to the early development stage of zebrafish for 5 days, the decreased heart rate and locomotor activity of zebrafish larvae were observed. The fluorescent PS NPs were used to precisely assess the accumulation of PS NPs in zebrafish larvae, and the results indicated that PS NPs not only accumulated in digestive system, but also infiltrated into the liver. More importantly, the transcriptomic analysis revealed that a total of 356 genes were differentially expressed and the KEGG class map showed significant differences in the MAPK pathway upon PS NPs treatment. Meanwhile, the induction of oxidative stress and inflammation were also observed in zebrafish larvae. Furthermore, PS NPs also induced oxidative damage and inflammatory response in RAW 264.7 cells, which activated p38 MAPK signal pathway and finally induced cell apoptosis. Our study provides a new understanding of MAPK signaling pathway involved in toxicity mechanism.

Effects of chlorothalonil, prochloraz and the combination on intestinal barrier function and glucolipid metabolism in the liver of mice.

Chlorothalonil (CHL) and procymidone (PRO) are fungicides that exhibit low toxicity and are widely used in many countries. And both fungicides are frequently detected in the food chain. However, the health risk posed by these fungicides is still unclear. Here, 8-week-old male C57BL/6 mice were orally treated with CHL (10, 50 mg/kg/day), PRO (20, 100 mg/kg/day) and CHL+PRO (5+10, 25+50 mg/kg/day) by dietary supplementation for 10 weeks. Hepatic pathological analysis showed that exposure to CHL, PRO and CHL+PRO could cause liver injury. The glucose, triglyceride (TG) levels and the related gene expression to glucolipid metabolism changed significantly. The significantly reduced acylcarnitine levels demonstrated that CHL, PRO and CHL+PRO exposure inhibited fatty acids (FAs) ß-oxidation. In addition, CHL and PRO altered the structure of the gut microbiota and destroyed the integrity of the intestinal barrier function. In particular, AF12, Odoribacter, Prevotella and Lactobacillus were highly correlated with carnitine. The results showed that CHL, PRO and CHL+PRO exposure might inhibit FAs ß-oxidation by decreasing cystic fibrosis transmembrane conductance regulator (CFTR)-mediated ion transport, indicating that these fungicides disturbed intestinal barrier function associated with glucolipid metabolism disorder. Here, the data also indicated that there was an additive effect between CHL and PRO in mice.