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PCB52 exposure alters the neurotransmission ligand-receptors in male offspring and contributes to sex-specific neurodevelopmental toxicity
2020
Zhao, Dong | Wang, Qi | Zhou, Wen-Tao | Wang, Li-Bin | Yu, Hao | Zhang, Kai-Kai | Chen, Li-Jian | Xie, Xiao-Li
Polychlorinated biphenyls (PCBs) in the air are predominantly the less chlorinated congeners. Non-dioxin-like (NDL) low-chlorinated PCBs are more neurotoxic, and cause neurodevelopmental and neurobehavioral alterations in humans. However, the underlying mechanisms for this neurodevelopmental toxicity remain unknown. In the present study, Wistar rats were treated by gavage with PCB52 (1 mg/kg body weight) or corn oil from gestational day 7 to postnatal day 21. Both the body lengths and weights of the suckling rats at birth were significantly decreased by PCB52 treatment, suggesting developmental toxicity. Although no obvious histopathological changes were observed in the brain, using RNA-sequencing, 208 differentially expressed genes (DEGs) were identified in the striatum of PCB52-treated male offspring, while just 13 DEGs were identified in female offspring, suggesting sex-specific effects. Furthermore, using Gene Ontology enrichment analysis, neurodevelopmental processes, neurobehavioral alterations, and neurotransmission changes were enriched from the 208 DEGs in male offspring. Similarly, using Kyoto Encyclopedia of Genes and Genomes enrichment analysis, neuroactive ligand receptor interactions and multiple synapse pathways were enriched in male offspring, implying dysfunction of the neurotransmission system. Reductions in the protein expressions of these ligand receptors were also identified in the striatum, cerebral cortex, and hippocampus using western blotting methods. Taken together, our findings indicate that PCB52 exposure during gestation and lactation results in the abnormal expression of neurotransmission ligand-receptors in male offspring with a sex bias, and that this may contribute to neurodevelopmental toxicity.
Mostrar más [+] Menos [-]Monobutyl phthalate (MBP) can dysregulate the antioxidant system and induce apoptosis of zebrafish liver
2020
Jiao, Yaqi | Tao, Yue | Yang, Yang | Diogene, Tuyiringire | Yu, Hui | He, Ziqing | Han, Wei | Chen, Zhaobo | Wu, Pan | Zhang, Ying
In this paper, the acute toxicity of monobutyl phthalate (MBP), the main hydrolysis product of dibutyl phthalate, on adult zebrafish liver antioxidant system was studied. Compared the toxicity effect of MBP and DBP by histopathology and apoptosis experiments, we speculated that the toxic effects of DBP on animals may be caused by its metabolite MBP. The results indicated that the antioxidant Nrf2-Keap1 pathway was insufficient to resist MBP-induced hepatotoxicity and led to an imbalance of membrane ion homeostasis and liver damage. Decreased cell viability, significant tissue lesions and early hepatocyte apoptosis were observed in the zebrafish liver in MBP exposure at high concentration (10 mg/L). The activities of antioxidant enzymes and ATPases in zebrafish liver were inhibited with increased malondialdehyde (MDA) content and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities. Integrated biomarker response (IBR) calculation results indicated that MBP mainly inhibited catalase (CAT) activity. Simultaneously, the expression of antioxidant-related genes (SOD, CAT, GPx, Nrf2, HO-1) was down-regulated, while apoptosis-related genes (p53, bax, cas3) were significantly up-regulated.
Mostrar más [+] Menos [-]Tris(4-hydroxyphenyl)ethane (THPE), a trisphenol compound, is antiestrogenic and can retard uterine development in CD-1 mice
2020
Xiao, Han | Wang, Yue | Jia, Xiaojing | Yang, Lei | Wang, Xiaoning | Guo, Xuan | Zhang, Zhaobin
Tris (4-hydroxyphenyl)ethane (THPE), a trisphenol compound widely used as a branching agent and raw material in plastics, adhesives, and coatings is rarely regarded with concern. However, inspection of in vitro data suggests that THPE is an antagonist of estrogen receptors (ERs). Accordingly, we aimed to evaluate the antiestrogenicity of THPE in vivo and tested its effect via oral gavage on pubertal development in female CD-1 mice. Using uterotrophic assays, we found that THPE either singly, or combined with 17β-estradiol (E₂) (400 μg/kg bw/day) suppressed the uterine weights at low doses (0.1, 0.3, and 1 mg/kg bw/day) in 3-day treatment of weaning mice. When mice were treated with THPE during adolescence (for 10 days beginning on postnatal day 24), their uterine development was significantly retarded at doses of at least 0.1 mg/kg bw/day, manifest as decreased uterine weight, atrophic endometrial stromal cells and thinner columnar epithelial cells. Transcriptome analyses of uteri demonstrated that estrogen-responsive genes were significantly downregulated by THPE. Molecular docking shows that THPE fits well into the antagonist pocket of human ERα. These results indicate that THPE possesses strong antiestrogenicity in vivo and can disrupt normal female development in mice at very low dosages.
Mostrar más [+] Menos [-]Effects of ketoprofen on rice seedlings: Insights from photosynthesis, antioxidative stress, gene expression patterns, and integrated biomarker response analysis
2020
Wang, Huan | Jin, Mingkang | Xu, Linglin | Xi, Hao | Wang, Binhui | Du, Shaoting | Liu, Huijun | Wen, Yuezhong
Pharmacologically active compounds found in reclaimed wastewater irrigation or animal manure fertilizers pose potential risks for agriculture. The mechanism underlying the effects of ketoprofen on rice (Oryza sativa L.) seedlings was investigated. The results showed that low concentrations (0.5 mg L⁻¹) of ketoprofen slightly stimulate growth of rice seedlings, while high concentrations can significantly inhibit growth by reducing biomass and causing damage to roots. Ketoprofen affects photosynthetic pigment content (Chla, Chlb, and carotenoids) and chlorophyll synthesis gene (HEMA, HEMG, CHLD, CHLG, CHLM, and CAO) expression. Fluorescence parameters such as minimum fluorescence (F₀), maximum fluorescence (Fₘ), variable fluorescence (Fᵥ), potential photosynthetic capacity (Fᵥ/F₀), maximum quantum efficiency of PSII photochemistry (Fᵥ/Fₘ), electron transfer rate (ETR), and Y(II), Y(NPQ), Y(NO) values were affected, showing photosynthetic electron transfer was blocked. Active oxygen radical (O₂•−and H₂O₂), malondialdehyde and proline content increased. Superoxide dismutase, catalase and ascorbate peroxidase activities, glutathione content and antioxidant-related gene (FSD1, MSD1, CSD1, CSD2, CAT1, CAT2, CAT3, APX1, APX2) expression were induced. Higher integrated biomarker response values of eight oxidative stress response indexes were obtained at higher ketoprofen concentrations. Ultrastructure observation showed that ketoprofen causes cell structure damage, chloroplast swelling, increase in starch granules, and reduction in organelles. This study provides some suggested toxicological mechanisms and biological response indicators in rice due to stress from pharmacologically active compounds.
Mostrar más [+] Menos [-]Transcriptome alterations in female Daphnia (Daphnia magna) exposed to 17β-estradiol
2020
Zheng, Yao | Yuan, Julin | Gu, Zhimin | Yang, Guang | Li, Tian | Chen, Jiazhang
The molecular mechanism of evaluating 17β-estradiol (E₂)-induced toxicity in female Daphnia magna has not been determined. In this study, the transcriptome of D. magna was analyzed after exposure to three different concentrations (0, 10, and 100 ng L⁻¹) of E₂ at 3, 6, and 12 h. The results showed 351–17,221 significantly up-regulated and 505–10,282 significantly down-regulated genes (P < 0.05). Overall, the selected largest 10,282 (10 ng L⁻¹vs control at 12 h) down-regulated and 17,221 (100 vs 10 ng L⁻¹) up-regulated genes were identified; following annotation, pathways in cancer and RNA transport were found to be enriched according to the interaction network. Among all completed comparisons, KEGG pathways related to the immune system, cancer, disease infection, and active compound metabolism were identified by short time series expression miner analysis. A different set of genes fluctuated in a “U”-shaped pattern over time and at different concentrations of E₂, whereas some genes associated with disintoxication showed a reverse “U”-shaped response as E₂ administration was increased. These results suggest that E₂ exposure caused transcriptional changes in the immune system, disintoxication, disease prevention, and the protein degradation pathway.
Mostrar más [+] Menos [-]Genotoxicity and DNA damage signaling in response to complex mixtures of PAHs in biomass burning particulate matter from cashew nut roasting
2020
Approximately 3 billion people world-wide are exposed to air pollution from biomass burning. Herein, particulate matter (PM) emitted from artisanal cashew nut roasting, an important economic activity worldwide, was investigated. This study focused on: i) chemical characterization of polycyclic aromatic hydrocarbons (PAHs) and oxygenated (oxy-) PAHs; ii) intracellular levels of reactive oxygen species (ROS); iii) genotoxic effects and time- and dose-dependent activation of DNA damage signaling, and iv) differential expression of genes involved in xenobiotic metabolism, inflammation, cell cycle arrest and DNA repair, using A549 lung cells. Among the PAHs, chrysene, benzo[a]pyrene (B[a]P), benzo[b]fluoranthene, and benz[a]anthracene showed the highest concentrations (7.8–10 ng/m³), while benzanthrone and 9,10-anthraquinone were the most abundant oxy-PAHs. Testing of PM extracts was based on B[a]P equivalent doses (B[a]Pₑq). IC₅₀ values for viability were 5.7 and 3.0 nM B[a]Pₑq at 24 h and 48 h, respectively. At these low doses, we observed a time- and dose-dependent increase in intracellular levels of ROS, genotoxicity (DNA strand breaks) and DNA damage signaling (phosphorylation of the protein checkpoint kinase 1 – Chk1). In comparison, effects of B[a]P alone was observed at micromolar range. To our knowledge, no previous study has demonstrated an activation of pChk1, a biomarker used to estimate the carcinogenic potency of PAHs in vitro, in lung cells exposed to cashew nut roasting extracts. Sustained induction of expression of several important stress response mediators of xenobiotic metabolism (CYP1A1, CYP1B1), ROS and pro-inflammatory response (IL-8, TNF-α, IL-2, COX2), and DNA damage response (CDKN1A and DDB2) was also identified. In conclusion, our data show high potency of cashew nut roasting PM to induce cellular stress including genotoxicity, and more potently when compared to B[a]P alone. Our study provides new data that will help elucidate the toxic effects of low-levels of PAH mixtures from air PM generated by cashew nut roasting.
Mostrar más [+] Menos [-]Environmental co-exposure to TBT and Cd caused neurotoxicity and thyroid endocrine disruption in zebrafish, a three-generation study in a simulated environment
2020
Li, Ping | Li, Zhi-Hua
Although the coexistence of heavy metals and environmental hormones always occur in aquatic environment, the information of the combined impacts remains unclear. To explore the multi-generational toxicity of cadmium (Cd) and tributyltin (TBT), adult zebrafish (Danio rerio) (F0) were exposed to different treated groups (100 ng/l Cd, 100 ng/l TBT and their mixture) for 90 d, with their offspring (F1 and F2) subsequently reared in the same exposure solutions corresponding to their parents. Both developmental neurotoxicity and thyroid disturbances were examined in the three (F0, F1, and F2) generations. Our results showed that co-exposure to Cd and TBT induced the developmental neurotoxicity in F1 and F2 generations, reflected by the significant lower levels of neurotransmitters (dopamine and serotonin) and the inhibited acetylcholinesterase (AChE) activities. And the thyroid endocrine disruption were observed in the two-generations larval offspring by parental exposure to Cd and/or TBT, including the significantly decreasing levels of thyroid hormones and the down-regulated the expression of genes involved in the hypothalamus-pituitary-thyroid axis, compared to the control. Additional, the embryonic toxicity and growth inhibition were also determined in the fish larvae. Overall, this study examined the impacts of parental co-exposure to Cd and TBT, with regard to developmental inhibition, nervous system damage and endocrine disruption, which highlighted that co-exposure influences are complicated and need to be considered for accurate environmental risk assessment.
Mostrar más [+] Menos [-]A multi-omics approach reveals molecular mechanisms by which phthalates induce cardiac defects in zebrafish (Danio rerio)
2020
Mu, Xiyan | Chen, Xiaofeng | Liu, Jia | Yuan, Lilai | Wang, Donghui | Qian, Le | Qian, Yu | Shen, Gongming | Huang, Ying | Li, Xuxing | Li, Yingren | Lin, Xiangming
The potential risks of phthalates affecting human and animal health as well as the environment are emerging as serious concerns worldwide. However, the mechanism by which phthalates induce developmental effects is under debate. Herein, we found that embryonic exposure of zebrafish to di-(2-ethylhexyl) phthalate (DEHP) and di-butyl phthalate (DBP) increased the rate of heart defects including abnormal heart rate and pericardial edema. Changes in the transcriptional profile demonstrated that genes involved in the development of the heart, such as tbx5b, nppa, ctnt, my17, cmlc1, were significantly altered by DEHP and DBP at 50 μg/L, which agreed with the abnormal cardiac outcomes. Methylated DNA immunoprecipitation sequencing (MeDIP-Seq) further showed that significant hypomethylation of nppa and ctnt was identified after DEHP and DBP exposure, which was consistent with the up-regulation of these genes. Notably, hypermethylation on the promoter region (<1 kb) of tbx5b was found after DEHP and DBP exposure, which might be responsible for its decrease in transcription. In conclusion, phthalates have the potential to induce cardiac birth defects, which might be associated with the transcriptional regulation of the involved developmental factors such as tbx5b. These findings would contribute to understand the molecular pathways that mediated the cardiac defects caused by phthalates.
Mostrar más [+] Menos [-]Transcriptome analysis in Parhyale hawaiensis reveal sex-specific responses to AgNP and AgCl exposure
2020
Artal, Mariana Coletty | Pereira, Karina Danielle | Luchessi, Augusto Ducati | Okura, Vagner Katsumi | Henry, Theodore Burdick | Marques-Souza, Henrique | de Aragão Umbuzeiro, Gisela
Analysis of the transcriptome of organisms exposed to toxicants offers new insights for ecotoxicology, but further research is needed to enhance interpretation of results and effectively incorporate them into useful environmental risk assessments. Factors that must be clarified to improve use of transcriptomics include assessment of the effect of organism sex within the context of toxicant exposure. Amphipods are well recognized as model organisms for toxicity evaluation because of their sensitivity and amenability to laboratory conditions. To investigate whether response to metals in crustaceans differs according to sex we analyzed the amphipod Parhyale hawaiensis after exposure to AgCl and Ag nanoparticles (AgNP) via contaminated food. Gene specific analysis and whole genome transcriptional profile of male and female organisms were performed by both RT-qPCR and RNA-seq. We observed that expression of transcripts of genes glutathione transferase (GST) did not differ among AgCl and AgNP treatments. Significant differences between males and females were observed after exposure to AgCl and AgNP. Males presented twice the number of differentially expressed genes in comparison to females, and more differentially expressed were observed after exposure to AgNP than AgCl treatments in both sexes. The genes that had the greatest change in expression relative to control were those genes related to peptidase and catalytic activity and chitin and carbohydrate metabolic processes. Our study is the first to demonstrate sex specific differences in the transcriptomes of amphipods upon exposure to toxicants and emphasizes the importance of considering gender in ecotoxicology.
Mostrar más [+] Menos [-]Proteomic analysis revealed gender-specific responses of mussels (Mytilus galloprovincialis) to trichloropropyl phosphate (TCPP) exposure
2020
Zhong, Mingyu | Wu, Huifeng | Li, Fei | Shan, Xiujuan | Ji, Chenglong
Trichloropropyl phosphate (TCPP) is a halogenated organophosphate ester that is widely used as flame retardants and plasticizers. In this study, gender-specific accumulation and responses in mussel Mytilus galloprovincialis to TCPP exposure were focused and highlighted. After TCPP (100 nmol L⁻¹) exposure for 42 days, male mussels showed similar average bioaccumulation (37.14 ± 6.09 nmol g⁻¹ fat weight (fw)) of TCPP with that in female mussels (32.28 ± 4.49 nmol g⁻¹ fw). Proteomic analysis identified 219 differentially expressed proteins (DEPs) between male and female mussels in control group. There were 52 and 54 DEPs induced by TCPP in male and female mussels, respectively. Interestingly, gender-specific DEPs included 37 and 41 DEPs induced by TCPP in male and female mussels, respectively. The proteomic differences between male and female mussels were related to protein synthesis and degradation, energy metabolism, and functions of cytoskeleton and motor proteins. TCPP influenced protein synthesis, energy metabolism, cytoskeleton functions, immunity, and reproduction in both male and female mussels. Protein-protein interaction (PPI) networks indicated that protein synthesis and energy metabolism were the main biological processes influenced by TCPP. However, DEPs involved in these processes and their interaction patterns were quite different between male and female mussels. Basically, twelve ribosome DEPs which directly or indirectly interacted were found in protein synthesis in TCPP-exposed male mussels, while only 3 ribosome DEPs (not interacted) in TCPP-exposed female mussels. In energy metabolism, only 4 DEPs (with the relatively simple interaction pattern) mainly resided in fatty acid metabolism, butanoate/propanoate metabolism and glucose metabolism were discovered in TCPP-exposed male mussels, and more DEPs (with multiple interactions) functioned in TCA cycle and pyruvate/glyoxylate/dicarboxylate metabolism were found in TCCP-exposed female mussels. Taken together, TCPP induced gender-specific toxicological effects in mussels, which may shed new lights on further understanding the toxicological mechanisms of TCPP in aquatic organisms.
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