Comparative Biochemistry and Physiology C-toxicology & Pharmacology最新文献

American alligators (Alligator mississippiensis) are apex predators and sentinel species in the coastal wetland ecosystem along the Gulf of Mexico. There is concern for alligator exposure and susceptibility to chemical contaminants due to their high trophic level and lower metabolic capability. At present, their hepatic biotransformation capacity to metabolize or detoxify contaminants has not been comprehensively determined. In this study, the hepatic biotransformation capability of juvenile American alligators to metabolize two commonly found environmental pharmaceuticals: carbamazepine (CBZ) or nicotine (NCT) was evaluated. The formation of their respective primary metabolites, i.e., carbamazepine-10,11-epoxide (CBZ-E) and cotinine (CTN), was evaluated at 10 μM (within the human therapeutic range). The in vitro S9 and a novel in situ liver perfusion assays were used to characterize and compare metabolic ability in isolated hepatic enzymes vs. whole organ (liver). For CBZ, the perfused livers exhibited only 30% of intrinsic formation clearance (${\mathrm{CL}}_{f,int}$) relative to the S9 assay. The metabolism of NCT was not detectable in the S9 assay and was only observed in the perfused liver assay. Compared to the corresponding rat models (S9 or perfused livers),alligators' ${\mathrm{CL}}_{f,int}$ was 2060% for CBZ and 50% for NCT of rats. Additionally, NCT exposure increased lactate levels in perfused livers indicating metabolic stress. This study provides insight into the hepatic capability of alligators to metabolize CBZ and NCT using an established in vitro (S9) system and a newly developed in situ liver perfusion system.

One of the main clinical manifestations presented by victims of snake bite envenoming are coagulation disorders. Considering that fibrinogen is a key molecule for crosslinked fibrin clot formation, the objective of this work was the quantitative analysis of the fibrinogenolytic activity of snakes of medical importance in Brazil and neutralization by specific antivenom. For this, pools of three genera of medical importance (Bothrops, Crotalus and Lachesis) that are used for the production of antivenom were used, and three pools of species of the genus Bothrops that are not part of the pool for the production of antivenom. The Lachesis pool had the highest fibrinogenolytic activity, even demonstrating partial cleavage (42.9 % consumption) of the fibrinogen gamma chain. The Bothrops genus venom pools have shown subtle variations between them. The Crotalus pool, despite not showing total cleavage of any fibrinogen chain, began cleavage of fibrinogen by the beta chain. The specific antivenoms used were able to delay the cleavage of fibrinogen in all the venoms used, which could be the first step towards implementing previous in vitro tests to analyze the quality of the batches of antivenoms produced, thus potentially reducing the use of animals used in this process.

17α-Ethinylestradiol (EE2) is known for its endocrine-disrupting effects on embryonic and adult fish. However, its impact on juvenile zebrafish has not been well established. In this study, juvenile zebrafish were exposed to EE2 at concentrations of 5 ng/L (low dose, L), 10 ng/L (medium dose, M), and 50 ng/L (high dose, H) from 21 days post-fertilization (dpf) to 49 dpf. We assessed their growth, development, behavior, transcriptome, and metabolome. The findings showed that the survival rate in the EE2-H group was 66.8 %, with all surviving fish displaying stunted growth and swollen, transparent abdomens by 49 dpf. Moreover, severe organ deformities were observed in the gills, kidneys, intestines, and heart of fish in both the EE2-H and EE2-M groups. Co-expression analysis of mRNA and lncRNA revealed that EE2 downregulated the transcription of key genes involved in the cell cycle, DNA replication, and Fanconi anemia signaling pathways. Additionally, metabolomic analysis indicated that EE2 influenced metabolism and development-related signaling pathways. These pathways were also significantly identified based on the genes regulated by lncRNA. Consequently, EE2 induced organ deformities and mortality in juvenile zebrafish by disrupting signaling pathways associated with development and metabolism. The results of this study offer new mechanistic insights into the adverse effects of EE2 on juvenile zebrafish based on multiomics analysis. The juvenile zebrafish are highly sensitive to EE2 exposure, which is not limited to adult and embryonic stages. It is a potential model for studying developmental toxicity.

Diethyl phthalate (DEP), bisphenol A (BPA), and external estradiol 17β-estradiol (E2) all are endocrine disrupting chemicals (EDCs). Our previous study has found that the development of ceratohyal cartilage (CH) in embryos could be disrupted when the maternal generation was exposed with 8.06 μM DEP, 2.86 μM BPA, and 1.11 μM E2. However, it is still unknown how doses of the residual EDCs in eggs cause abnormal CH development in their offspring. Microinjection is used at the 2-cell stage of embryos to mimic the maternal effect and to observe the toxicities of EDCs in embryos. Results shown that the amounts of DEP, BPA, and E2 were 1.3 × 10^-6 ng, 4.7 × 10^-7 ng, and 1.4 × 10^-7 ng, respectively, inducing the CH angles to become bigger than the control. However, related genes to the migratory pathways of neural crest cells (NCCs) were not influenced upon BPA and E2 treatments. Both sox10 and smad3 gene expressions were up-regulated upon DEP treatment. On the other hand, the CH angles were smaller than the control upon 1.3 × 10^-5, 9.4 × 10^-6, and 1.4 × 10^-6 ng of DEP, BPA, and E2 microinjection, respectively. Furthermore, genes related to migratory NCCs were significantly influenced upon 10⁻⁵ ng of BPA, and 10⁻⁴ ng of DEP treatments on embryos. According to the data, we suggested that 10⁻⁵–10⁻⁷ ng of EDCs in eggs could disrupt CH development as well as significantly increase the mortality on their embryos. The present study raises concern that the responses were highly sensitive in embryos through maternal effects.

Polycyclic aromatic hydrocarbons (PAHs), such as phenanthrene (PHE), are common pollutants found in coastal areas where shrimp farming is developed. Even though PAHs can have adverse effects on physiology, shrimp can detoxify and metabolize toxic compounds and neutralize the reactive oxygen species (ROS) produced during this process. This requires the activation of multiple antioxidant enzymes, including peroxiredoxin 6 (Prx6). Prx6 uses glutathione (GSH) to reduce phospholipid hydroperoxides, a function shared with GSH peroxidase 4 (GPx4). Prx6 has been scarcely studied in crustaceans exposed to pollutants. Herein, we report a novel Prx6 from the shrimp Penaeus vannamei that is abundantly expressed in gills and hepatopancreas. To elucidate the involvement of Prx6 in response to PAHs, we analyzed its expression in the hepatopancreas of shrimp sub-lethally exposed to PHE (3.3 μg/L) and acetone (control) for 24, 48, 72, and 96 h, along with GPx4 expression, GSH-dependent peroxidase activity, and lipid peroxidation (indicated by TBARS). We found that GPx4 expression is not affected by PHE, but Prx6 expression and peroxidase activity decreased during the trial. This might contribute to the rise of TBARS found at 48 h of exposure. However, maintaining GPx4 expression could aid to minimize lipid damage during longer periods of exposure to PHE.

Arsenic is a toxic metal-like element widely used in the pesticide, preservative and semiconductor industries. However, accumulation of arsenic through the food chain can cause serious damage to animal and human health. However, the toxic mechanism of arsenic-induced hepatotoxicity in chickens is not clear, and the present study aimed to investigate the potential role of cGAS-STING and NF-κB pathways on inflammatory injury in chicken liver. In this study, 75 white-feathered broilers were divided into a control group, a low-dose arsenic group (4 mg/kg) and a high-dose arsenic group (8 mg/kg) to investigate the toxic effects of arsenic on chicken liver. In this study, we found that pathological changes such as inflammatory cell infiltration and vesicular degeneration occurred in the liver when exposed to ATO. Crucially, exposure to ATO triggered the cGAS-STING pathway and markedly raised the levels of mRNA and protein expression of cGAS, STING, TBK1, and IRF7. The type I interferon response was also triggered. Simultaneously, STING induced the activation of the conventional NF-κB signaling pathway and stimulated the expression of genes associated with inflammation, such as IL-6, TNF-α and IL-1β. In summary, the induction of inflammatory responses via cGAS-STING and NF-κB signaling pathways under high ATO exposure provides new ideas for further studies on the toxicological mechanisms of arsenic.

Various factors may affect the antioxidative system in insects, including xenobiotics. Glycoalkaloids (GAs) are plant secondary metabolites produced mainly by the Solanaceae family (nightshades), such as the food crop tomato Solanum lycopersicum L. These compounds exhibit a wide range of biological activities and have attracted increasing interest in the context of potential insecticide properties. Therefore, the aim of the presented study was to analyze the effects of GAs (solanine, chaconine, tomatine, and extracts of tomato leaves) on lipid peroxidation; the expression levels of genes encoding manganese superoxide dismutase (MnSOD), catalase (CAT), and heat shock protein 70 (HSP70); and the enzymatic activity of SOD and CAT in Tenebrio molitor larvae. This species is amodel organism for toxicological and ecophysiological studies and is also a pest of grain storage. The reported changes depend on the GA concentration, incubation time, and type of insect tissue. We observed that the tested GAs affected MnSOD expression levels, increased SOD activity in the fat body, and reduced enzyme activity in the gut. The results showed that CAT expression was upregulated in the fat body and that the enzymatic activity of CAT in the gut was greater in the treated group than in the control group. Moreover, GAs affected HSP70 expression and malondialdehyde levels in both tested tissues. This research contributes to our knowledge about the effects of GAs on the antioxidative system of T. molitor beetles. As efficient antioxidative system functioning is necessary for survival, the tested components may be targets of potential bioinsecticides.

Antimony (Sb) and its compounds can be harmful to people and are known to cause cancer, so they are a key pollutant to control. This study investigated the influence of antimony on non-enzymatic antioxidants and the blood-brain barrier (BBB) in zebrafish(Danio rerio), a model organism that shares a high degree of genetic similarity with humans. Zebrafish were exposed to different doses of antimony in water for 7, 18, and 30 days. The results indicated that antimony accumulated most in the liver, followed by the gills, flesh, and brain, with the accumulation increasing as the exposure duration extends. Additionally, under identical antimony concentrations, the buildup in the four tissues was positively correlated with the duration of exposure. After 18 days of exposure, the total antioxidant capacity (T-AOC) and endogenous non-enzymatic antioxidants vitamin C (VC) and vitamin E (VE) decreased as a result of antimony ingestion in zebrafish, although cysteine secretion was increased in the liver, gills, and brain. The structural integrity of the BBB was compromised by the elevation of ApoE4 and MMP-9 levels as a result of antimony exposure, which led to the breakdown of the basal lamina, tight junctions, and nerve fibers in the brain. At this injured region, 5-HT and MBP were also able to easily enter and leave the BBB, albeit at variable rates. Additionally, when the antimony exposure level reached 16.58 mg·L⁻¹, antimony penetrated the BBB and bound to erythrocytes, causing their lysis.

The minute wasp Habrobracon hebetor venom (HH venom) is a potent cocktail of toxins that paralyzes the victim's muscles and suppresses humoral and cellular immunity. This study examined the effect of HH venom on specific biochemical, physiological, and ultrastructural characteristics of the thoracic and nervous (CNS) tissues of Drosophila melanogaster under in vitro conditions. Venom treatment modulated the activities of superoxide dismutase (SOD) and catalase (CAT), endogenous Drome-AKH level, and affected the relative viability of the cells. Additionally, it reduced the expression of genes related to the immune system in the CNS, including Keap1, Relish, Nox, Eiger, Gadd45, and Domeless, as well as in the thoracic muscles, except for Nox. Besides, venom treatment led to deteriorative changes in the ultrastructure of muscle cells, particularly affecting the mitochondria. When venom and Drosophila melanogaster-adipokinetic hormone (Drome-AKH) were applied together, the effects of the venom alone were often modulated. The harmful effect of the venom on SOD activity was relatively reduced and the activity returned to a level similar to that of the control. In the CNS, the simultaneous application of venom and hormones abolished the suppression of previously reported immune-related genes (except for Gadd45), whereas in the muscles, this was only true for Eiger. Additionally, Drome-AKH restored cell structure to a level comparable to that of the control and lessened the harmful effects of HH venom on muscle mitochondria. These findings suggest a general body response of D. melanogaster to HH venom and a partial defensive role of Drome-AKH in this process.

In the aquatic farming industry, understanding the factors affecting fish behavior is crucial, particularly in response to infections that compromise welfare and productivity. Swimming performance is a key life history trait critical to their ecology. This study explores the swimming behavior imbalance in Nile tilapia (Oreochromis niloticus, GIFT) post-infection with Streptococcus agalactiae (GBS), a common pathogen responsible for significant losses in aquaculture. We focused on how the microbiota-gut-brain axis influences the behavioral response of tilapia to GBS infection. Behavioral changes were quantified by measuring collision times and swimming speeds, which decreased significantly following infection. This behavioral downturn is mediated by alterations in the microbiota-gut-brain axis, evidenced by increased levels of monoamine neurotransmitters (serotonin, norepinephrine, and dopamine) in the brain and intestinal tissues. The study utilized pharmacological agents, the 5-HT_1A receptor agonist (8-OH-DPAT) and antagonist (WAY-100635), to investigate their efficacy in mitigating these behavioral and biochemical changes. Both agents partially restored normal behavior by adjusting neurotransmitter concentrations disrupted by GBS infection. Additionally, a notable increase in the relative abundance of Streptococcus within the gut microbiota of infected fish highlights the potential role of specific bacterial populations in influencing host behavior. This research provides novel insights into the complex interactions between pathogen-induced gut microbiota changes and Nile tilapia's behavioral outcomes, highlighting potential avenues for improving fish health management through microbiota-targeted interventions.