Fenitrothion induces glucose metabolism disorders in rat liver BRL cells by inhibiting AMPKα and IRS1/PI3K/AKT signaling pathway.

Fenitrothion (FNT) is a common organophosphorus pesticide that is widely used in both agricultural and domestic pest control. FNT has been frequently detected in various environmental media, including the human body, and is a notable contaminant. Epidemiological investigations have recently shown the implications of exposure to FNT in the incidence of various metabolic diseases, such as diabetes mellitus in humans, indicating that FNT may be a potential endocrine disruptor. However, the effects of FNT exposure on glucose homeostasis and their underlying mechanisms in model organisms remain largely unknown, which may limit our understanding of the health risks of FNT. In this study, FNT (4 5, 90, 180, and 4 50 µM) exposure model of rat hepatocytes (Buffalo Rat Liver, BRL cells) was established to investigate the effects and potential mechanisms of its toxicity on glucose metabolism. Several key processes of glucose metabolism were detected in this study. The results showed significantly increased glucose levels in the culture medium and decreased glycogen content in the FNT-exposed BRL cells. The results of quantitative real-time PCR and enzymology showed the abnormal expression of genes and activity/content of glucose metabolic enzymes involved in glucose metabolism, which might promote gluconeogenesis and inhibit glucose uptake, glycolysis, and glycogenesis. Furthermore, gluconeogenesis and glycolytic were carried out in the mitochondrial membrane. The abnormal of mitochondrial membrane potential may be a potential mechanism underlying FNT-induced glucose metabolism disorder. In addition, the mRNA and protein expression implicated that FNT may disrupt glucose metabolism by inhibiting the AMPKα and IRS1/PI3K/AKT signaling pathways. In conclusion, results provide in vitro evidence that FNT can cause glucose metabolism disorder, which emphasizes the potential health risks of exposure to FNT in inducing diabetes mellitus.

A comprehensive review on recent xanthine oxidase inhibitors of dietary based bioactive substances for the treatment of hyperuricemia and gout: Molecular mechanisms and perspective.

Hyperuricemia (HUA) has attained a considerable global health concern, related to the development of other metabolic syndromes. Xanthine oxidase (XO), the main enzyme that catalyzes xanthine and hypoxanthine into uric acid (UA), is a key target for drug development against HUA and gout. Available XO inhibitors are effective, but they come with side effects. Recent, research has identified new XO inhibitors from dietary sources such as flavonoids, phenolic acids, stilbenes, alkaloids, polysaccharides, and polypeptides, effectively reducing UA levels. Structural activity studies revealed that -OH groups and their substitutions on the benzene ring of flavonoids, polyphenols, and stilbenes, cyclic rings in alkaloids, and the helical structure of polysaccharides are crucial for XO inhibition. Polypeptide molecular weight, amino acid sequence, hydrophobicity, and binding mode, also play a significant role in XO inhibition. Molecular docking studies show these bioactive components prevent UA formation by interacting with XO substrates via hydrophobic, hydrogen bonds, and π-π interactions. This review explores the potential bioactive substances from dietary resources with XO inhibitory, and UA lowering potentials detailing the molecular mechanisms involved. It also discusses strategies for designing XO inhibitors and assisting pharmaceutical companies in developing safe and effective treatments for HUA and gout.

Overview of deltamethrin residues and toxic effects in the global environment.

Pyrethroids are synthetic organic insecticides. Deltamethrin, as one of the pyrethroids, has high insecticidal activity against pests and parasites and is less toxic to mammals, and is widely used in cities and urban areas worldwide. After entering the natural environment, deltamethrin circulates between solid, liquid and gas phases and enters organisms through the food chain, posing significant health risks. Increasing evidence has shown that deltamethrin has varying degrees of toxicity to a variety of organisms. This review summarized worldwide studies of deltamethrin residues in different media and found that deltamethrin is widely detected in a range of environments (including soil, water, sediment, and air) and organisms. In addition, the metabolism of deltamethrin, including metabolites and enzymes, was discussed. This review shed the mechanism of toxicity of deltamethrin and its metabolites, including neurotoxicity, immunotoxicity, endocrine disruption toxicity, reproductive toxicity, hepatorenal toxicity. This review is aim to provide reference for the ecological security and human health risk assessment of deltamethrin.

Effects of Freeze-Thaw Pretreatment Combined with Hot Air on Snake Gourd (Trichosanthes anguina L.).

Snake gourd is a seasonal vegetable with a high water content and medicinal value, but the short harvest period limits the large-scale application of snake gourd. Therefore, the effects of freeze-thaw pretreatment (FT) combined with hot air (HD) on the drying characteristics, active ingredients and bioactivities of snake gourd were investigated. The results showed that FT pretreatment reduced browning and shortened the drying time by 44%; the Page model was the best fit for describing the drying process. The polysaccharide contents (21.70% in alcoholic extract (TG1) and 44.34% in water extract (TG2)) and total phenol contents (1.81% in TG1 and 0.88% in TG2) of snake gourd pretreated by FT-HD were higher than those of snake gourd pretreated by the corresponding HD treatment. The FT pretreatment decreased the molecular weight of snake gourd polysaccharides and increased the molar ratio of glucose. The extracts pretreated by FT-HD showed greater chemical, cellular antioxidant capacity and α-amylase and α-glucosidase inhibition than those pretreated by HD. FT-HD can be recommended for achieving a short drying time and high quality of snake gourd and can be used for the drying of other fruits and vegetables.

Role of autonomic nervous system in BDE-209 maternal exposure induced immunotoxicity in female offspring.

Decabrominated diphenyl ether (BDE-209) is a typical persistent organic pollutant that can cross the placental barrier, increasing the exposure risk for offspring. Norepinephrine (NE) from nerve terminals and acetylcholine (Ach) can bind to specific receptors on immune cells, inhibit the immune function of the body then cause immunotoxicity. However, whether maternal exposure to BDE-209 could lead to immunotoxicity in the offspring by acting on the sympathetic and parasympathetic nervous systems remains unclear. In view of this, the pregnancy and lactation rat BDE-209 exposure model was established and the results demonstrated that pregnancy and lactation BDE-209 exposure could induce immunotoxicity to female offspring via affecting immunopathology (hematological and biochemical parameters, organ indices, and spleen histopathological), decreasing humoral immunity (serum hemolysin, immunoglobulins, and cytokine productions), damaging cellular immunity (splenic lymphocytes and spleen cytokine productions), and restraining nonspecific immunity. Moreover, a dramatically significant correlation was observed between spleen nerve indices and immunity indices. Additionally, the mechanism revealed that maternal BDE-209 exposure caused offspring immunotoxicity through (1) activating MHC/PKCθ/NF-κB pathway; (2) promoting sympathetic nervous pathway, by upregulating the expression of ß2AR protein, which in turn elevating cAMP, following activate PKA and phosphorylate CREB, ultimately leading to immunotoxicity;(3) activating parasympathetic nerve pathway by reducing the binding with Ach and α7nAchR, upregulating the expression of JAK2 and phosphorylating STAT3, induced immunotoxicity of female offspring.

Association of tetrabromobisphenol A (TBBPA) with micro/nano-plastics: A review of recent findings on ecotoxicological and health impacts.

Despite the diverse research into the environmental impact of plastics, several stones have yet to be unraveled in terms of their ecotoxicological potential. Moreover, their detrimental impacts have become terrifying in recent years as the understanding of their tendency to associate and form cohorts with other emerging contaminants grew. Despite the hypothesis that microplastics may potentially adsorb organic pollutants, sequestering and making them not bioavailable for enhanced toxicity, evidence with pollutants such as Tetrabromobisphenol A (TBBPA) defers this assertion. TBBPA, one of the most widely used brominated flame retardants, has been enlisted as an emerging contaminant of serious environmental and human health concerns. Being also an additive to plasticware, it is not far to suspect that TBBPA could be found in association with micro/nanoplastics in our environment. Several pieces of evidence from recent studies have confirmed the micro/nanoplastics-TBBPA association and have exposed their compounded detrimental impacts on the environment and human health. This study, therefore, presents a comprehensive and up-to-date review of recent findings regarding their occurrence, factors that foster their association, including their sorption kinetics and isotherms, and their impacts on aquatic/agroecosystem and human health. The way forward and prospects for future studies were presented. This research is believed to be of significant interest to the readership due to its relevance to current environmental challenges posed by plastics and TBBPA. The study not only contributes valuable insights into the specific interaction between micro/nanoplastics and TBBPA but also suggests the way forward and prospects for future studies in this field.

Differential susceptibility of BRL cells with/without insulin resistance and the role of endoplasmic reticulum stress signaling pathway in response to acrylamide-exposure toxicity effects in vitro.

Acrylamide (ACR) is an endogenous food contaminant, high levels of ACR have been detected in a large number of foods, causing widespread concern. Since different organism states respond differently to the toxic effects of pollutants, this study establishes an insulin-resistant BRL cell model to explore the differential susceptibility of BRL cells with/without insulin resistance in response to acrylamide-exposure (0.0002, 0.02, or 1 mM) toxicity effects and its mechanism. The results showed that ACR exposure decreased glucose uptake and increased intracellular lipid levels by promoting the expression of fatty acid synthesis, transport, and gluconeogenesis genes and inhibiting the expression of fatty acid metabolism genes, thereby further exacerbating disorders of gluconeogenesis and lipid metabolism in insulin-resistant BRL cells. Simultaneously, its exposure also exacerbated BRL cells with/without insulin-resistant damage. Meanwhile, insulin resistance significantly raised susceptibility to BRL cell response to ACR-induced toxicity. Furthermore, ACR exposure further activated the endoplasmic reticulum stress (ERS) signaling pathway (promoting phosphorylation of PERK, eIF-2α, and IRE-1α) and the apoptosis signaling pathway (activating Caspase-3 and increasing the Bax/Bcl-2 ratio) in BRL cells with insulin-resistant, which were also attenuated after ROS scavenging or ERS signaling pathway blockade. Overall results suggested that ACR evokes a severer toxicity effect on BRL cells with insulin resistance through the overactivation of the ERS signaling pathway.

Acrylamide-Aggravated Liver Injury by Activating Endoplasmic Reticulum Stress in Female Mice with Diabetes.

Acrylamide (ACR) is a common industrial contaminant with endocrine-disrupting toxicity. Numerous studies have indicated that females and diabetics are more sensitive to environmental contaminants. However, it remains unknown whether female diabetics are susceptible to ACR-induced toxicity and its potential mechanisms. Thus, the female ACR-exposure diabetic Balb/c mice model was established to address these issues. Results showed that ACR could induce liver injury in normal mice and cause more serious inflammatory cell infiltration, hepatocyte volume increase, and fusion in diabetic mice liver. Meanwhile, ACR could lead to exacerbation of diabetic symptoms in diabetic mice by disturbing the glucose and lipid metabolism in the liver, which mainly manifests as the accumulation of liver glycogen and liver lipids, the reduction of the activity/content of glycolytic and metabolizing enzyme as well as pentose phosphatase, upregulation of the gene expression in fatty acid transporter and gluconeogenesis, and downregulation of the gene expression in fatty acid synthesis and metabolism. Moreover, ACR exposure could induce oxidative stress, inflammation, and endoplasmic reticulum stress in the liver by a decrease in hepatic antioxidant enzyme activity and antioxidant content, an increase in inflammatory factor levels, and a change in the related protein expression of endoplasmic reticulum stress (ERS) and apoptosis-related pathways in diabetic mice. Statistical analysis results revealed that ACR-induced liver injury was highly correlated with inflammation and oxidative stress, and ERS and diabetic mice had a higher risk of liver injury than normal mice. Overall results suggested that female diabetic mice easily suffer from ACR-induced toxicity, and the reason was that ACR could induce further damage to the liver by worsening the condition of inflammation, oxidative stress, and ERS in the liver.

Neurodevelopmental toxicity and molecular mechanism of environmental concentration of tetrabromobisphenol A bis (2- hydroxyethyl) ether exposure to sexually developing male SD rats.

Tetrabromobisphenol A bis (2- hydroxyethyl) ether (TBBPA-DHEE), as one of the main derivatives of Tetrabromobisphenol A, been attracted attention for its health risks. In this study, the neurotoxicity, mechanism, and susceptivity of TBBPA-DHEE exposure to sexually developing male rats were systematically studied. Neurobehavioral research showed that TBBPA-DHEE exposure could significantly affect the behavior, learning,and memory abilities of male-developing rats, and aggravate their depression. TBBPA-DHEE exposure could inhibit the secretion of neurotransmitters. Transcriptomics studies show that TBBPA-DHEE can significantly affect gene expression, and a total of 334 differentially expressed genes are enriched. GO function enrichment analysis shows that TBBPA-DHEE exposure can significantly affect the expression of genes related to synapses and cell components. KEGG function enrichment analysis shows that TBBPA-DHEE exposure can significantly affect the expression of signal pathways related to nerves, nerve development, and signal transduction. Susceptibility analysis showed that female rats were more susceptible to TBBPA-DHEE exposure than male rats. Therefore, TBBPA-DHEE exposure has neurodevelopmental toxicity to male developmental rats, and female developmental rats are more susceptible than male developmental rats. Its possible molecular mechanism is that TBBPA-DHEE may inhibit the secretion of neurotransmitters and affect signal pathways related to neurodevelopment and signal transduction.

Protective Effect of Protocatechuic Acid on Oxidative Damage and Cognitive Impairment in Pb-Induced Rats.

Protocatechuic acid (PCA), a class of water-soluble phenolic acid abundant in the human diet, has been shown to be of great nutritional interest and to have medicinal value. However, the protective effects against lead (Pb)-induced body injury have not been elucidated. In this study, we explored the protective effect of PCA on Pb-induced oxidative damage and cognitive impairment in rats. The results showed that PCA could reduce the Pb content in rat bodies (blood, bone, brain, liver, and kidney) after Pb exposure. Moreover, PCA may inhibit Pb-induced oxidative damage by increasing the activity of antioxidant enzymes such as superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) and decreasing the level of malondialdehyde (MDA) in the brain, liver, and kidney. In addition, PCA may alleviate Pb-induced learning and memory impairment by upregulating neurotransmitter levels; maintaining the normal function of N-methyl-D-aspartate receptors (NMDARs); and promoting Ca2+ influx, thus activating signaling molecules, related protein kinases, and transcription factors in the cAMP-PKA-CREB pathway. In general, PCA could reduce oxidative stress and ameliorate the learning and memory deficits in Pb-treated rats, indicating that PCA may be an effective preventive agent and treatment or plumbism.

RNA-Seq analysis offers insight into the TBBPA-DHEE-induced endocrine-disrupting effect and neurotoxicity in juvenile zebrafish (Danio rerio).

Tetrabromobisphenol A bis(2-hydroxyethyl) ether (TBBPA-DHEE) is the major TBBPA derivative. It has been detected in different environmental samples. Previous studies show that TBBPA-DHEE caused neurotoxicity in rats. In this study, juvenile zebrafish were exposed to various concentrations of TBBPA-DHEE to ascertain the potential neurotoxicity of TBBPA-DHEE, the chemical, and its possible molecular mechanism of action. Behavioral analysis revealed that TBBPA-DHEE could significantly increase the swimming distance and speed in the 1.5 mg/L group compared to the control. In contrast, the swimming distance and speed were significantly reduced in the 0.05 and 0.3 mg/L groups, affecting learning, memory, and neurodevelopment. Similarly, TBBPA-DHEE exposure caused a concentration-dependent significant increase in the levels of excitatory neurotransmitters, namely, dopamine, norepinephrine, and epinephrine, which could be attributed to the change observed in zebrafish behavior. This demonstrates the neurotoxicity of TBBPA-DHEE on juvenile zebrafish. The concentration-dependent increase in the IBR value revealed by the IBR index reveals the noticeable neurotoxic effect of TBBPA-DHEE. Transcriptomic analysis shows that TBBPA-DHEE exposure activated the PPAR signaling pathways, resulting in a disturbance of fatty acid (FA) metabolism and changes in the transcript levels of genes involved in these pathways, which could lead to lipotoxicity and hepatotoxicity. Our findings demonstrate a distinct endocrine-disrupting response to TBBPA-DHEE exposure, possibly contributing to abnormal behavioral alterations. This study provides novel insights into underlying the mechanisms and effects of TBBPA-DHEE on aquatic organisms, which may be helpful forenvironmental/human health risk assessments of the emerging pollutant.

A review of cumulative toxic effects of environmental endocrine disruptors on the zebrafish immune system: Characterization methods, toxic effects and mechanisms.

Environmental endocrine disrupting chemicals (EDCs), are a type of exogenous organic pollutants, are ubiquitous in natural aquatic environments. Currently, in addition to neurological, endocrine, developmental and reproductive toxicity, ecotoxicology studies on immunotoxicity are receiving increasing attention. In this review, the composition of immune system of zebrafish, the common indicators of immunotoxicity, the immunotoxicity of EDCs and their molecular mechanism were summarized. We reviewed the immunotoxicity of EDCs on zebrafish mainly in terms of immune organs, immunocytes, immune molecules and immune functions, meanwhile, the possible molecular mechanisms driving these effects were elucidated in terms of endocrine disruption, dysregulation of signaling pathways, and oxidative damage. Hopefully, this review will provide a reference for further investigation of the immunotoxicity of EDCs.

A review of heavy metal risks around e-waste sites and comparable municipal dumpsites in major African cities: Recommendations and future perspectives.

In Africa, the effects of informal e-waste recycling on the environment are escalating. It is regularly transported from developed to developing nations, where it is disassembled informally in search of precious metals, thus increasing human exposure to harmful compounds. Africa has a serious problem with e-waste, as there are significant facilities in Ghana and Nigeria where imported e-waste is unsafely dismantled. however, because they are in high demand and less expensive than new ones, old electronic and electrical items are imported in large quantities, just like in many developing nations. After that, these objects are frequently scavenged to recover important metals through heating, burning, incubation in acids, and other techniques. Serious health hazards are associated with these activities for workers and individuals close to recycling plants. At e-waste sites in Africa, there have been documented instances of elevated concentrations of hazardous elements, persistent organic pollutants, and heavy metals in dust, soils, and vegetation, including plants consumed as food. Individuals who handle and dispose of e-waste are exposed to highly hazardous chemical substances. This paper examines heavy metal risks around e-waste sites and comparable municipal dumpsites in major African cities. Elevated concentrations of these heavy metals metal in downstream aquatic and marine habitats have resulted in additional environmental impacts. These effects have been associated with unfavourable outcomes in marine ecosystems, such as reduced fish stocks characterized by smaller sizes, increased susceptibility to illness, and decreased population densities. The evidence from the examined studies shows how much e-waste affects human health and the environment in Africa. Sub-Saharan African nations require a regulatory framework that includes specialized laws, facilities, and procedures for the safe recycling and disposal of e-waste.

Persistent immune injury induced by short-term decabromodiphenyl ether (BDE-209) exposure to female middle-aged Balb/c mice.

Decabromodiphenyl ether (BDE-209), widely used in various industries for its excellent flame-retardant performance, could be enriched in humans and is closely associated with immune impairment. In addition, immune system is gradually declined and becoming more sensitive to environmental pollutants in the ageing process. Therefore, the immunotoxicity of BDE-209 (4, 40, and 400 mg/kg/day) to middle-aged mice and its recovery and susceptibility was first to be comprehensively investigated in this study. The results showed that BDE-209 exposure could lead to oxidative injury to immune organs (spleen, thymus, and liver), impair humoral (immunoglobulins), cellular (lymphopoiesis), and non-specific immunity, and disturb the expressions of the genes related to Th1/Th2 balance (T helper cells) in the middle-aged mice. In addition, Integrated Biomarker Response (IBR) indicated that BDE-209-induced immune impairment was challenging to self-regulated, and even exacerbated after 21 days of recovery and oxidative injury in immune organs could be the main reason. Furthermore, factorial analysis showed that middle-aged mice exposed to BDE-209 suffered from greater immune impairment than adult mice, and the immune impairment in aged mice is more difficult to be self-repaired than that in adult mice. It can be seen that the aged tend to suffer from BDE-209-induced persistent immune impairment and health threats.

A Se-enriched Grifola frondosa polysaccharide induces macrophage activation by TLR4-mediated MAPK signaling pathway.

Se-polysaccharide (Se-GFP-22) from Se-enriched Grifola frondosa has double and cooperative activities of polysaccharide and Se. To delineate the underlying mechanism and signaling cascade involved in immune-stimulatory property of Se-GFP-22, the production of cellular mediators and key proteins in signaling pathway was examined. Results showed that Se-GFP-22 exhibited no cytotoxic and had a high capacity to promote macrophage phagocytosis, up-regulate interleukin-2 (IL-2), tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), and nitric oxide (NO) productions, as well as the relative messenger RNA (mRNA) expressions. In Se-GFP-22-induced macrophages, intracellular superoxide dismutase (SOD) activity was significantly increased to protect cells from oxidative injury. However, Se-GFP-22 induced macrophage activation was suppressed when the toll-like receptor 4 (TLR4) signaling pathway was blocked by a specific TLR4 inhibitor. According to the western blot analysis and the use of specific inhibitors against the mitogen-activated protein kinases (MAPK) signaling pathway, we speculated that Se-GFP-22 activated RAW264.7 macrophages through the TLR4-mediated MAPK signaling pathway. This study provides a molecular basis for the potential of Se-GFP-22 as a novel immune-stimulatory agent.

The neurotoxicity and mechanism of TBBPA-DHEE exposure in mature zebrafish (Danio rerio).

Tetrabromobisphenol A-bis (2-hydroxyethyl) ether (TBBPA-DHEE) has been detected in various environmental media and organisms, and its ecological risks and health hazards have attracted great attention, but sufficient toxicological data have not proved the toxic effects of TBBPA-DHEE exposure on aquatic organism. In this study, the neurotoxicity and mechanism of zebrafish (3-month-old) exposed to TBBPA-DHEE (0.86 µg/L, 12.9 µg/L, 193.5 µg/L) were studied. Furthermore, the neurotoxicity susceptibility of different sexes of zebrafish was revealed. Behavioral studies revealed that TBBPA-DHEE exposure has significant differences in average speed, duration of mania, the distance between objects, and ATP content between male and female zebrafish. Slight damage in brain tissue of male zebrafish was found. The transcriptome analysis revealed that the molecular mechanism of neurotoxicity in mature female and male zebrafish is different. For mature female zebrafish, TBBPA-DHEE significantly affected the expression of genes related to behavior and development, and its mechanism may be that it can produce neurotoxicity by affecting related genes in the hormone, synapse, and Ca2+ signaling pathway. For mature male zebrafish, TBBPA-DHEE can significantly affect their behavior and expression of nerve-related genes. Results from the transcriptomic analysis suggests that the possible molecular mechanism may be through the inhibition of Ca2+ signal transmission and produce neurotoxicity by affecting the expression of related genes in neural synapses, Ca2+ signal, and MAPK signal in brain tissue of zebrafish. The results suggested that exposure to low-dose TBBPA-DHEE could induce neurotoxicity in zebrafish, and female and male zebrafish showed different toxic effects and molecular mechanisms.

Transcriptomic profiling reveals the neuroendocrine-disrupting effect and toxicity mechanism of TBBPA-DHEE exposure in zebrafish (Danio rerio) during sexual development.

TBBPA bis(2-hydroxyethyl) ether (TBBPA-DHEE) pollution in the environment has raised serious public health concerns due to its potential neuroendocrine-disrupting effects. The neuroendocrine-disrupting effects of TBBPA-DHEE on marine spices, on the other hand, have received little attention. The behavioral, neuroendocrine-disrupting, and possible reproductive toxicity of TBBPA-DHEE were assessed in sexual developing zebrafish treated for 40 days by examining locomotor activity, Gonadotrophin releasing hormone (GnRH), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) levels, and quantifying gene expression. In addition, transcriptome profiling was carried out to explore the possible mechanisms. According to our findings, TBBPA-DHEE treated zebrafish showed altered locomotor activity, a potential neuroendocrine-disrupting effect via the toxic effect on the hypothalamus and pituitary gland, which is evident in decreased levels of GnRH, FSH, and LH, according to our findings. The transcriptomic profiling reveals that a total of 216 DEGs were detected (5 upregulated and 211 down-regulated). Transcriptomic analysis shows that TBBPA-DHEE exposure caused decreased transcript levels of genes (cyp11a1, ccna1, ccnb2, ccnb1, cpeb1b, wee2) involved in cell cycle oocyte meiosis, progesterone mediated oocyte maturation, and ovarian steroidogenesis, which are known reproduction-related pathways. Overall, these findings add to our understanding of the impact of TBBPA-DHEE and biomonitoring in the maritime environment.

The potential mechanisms of TBBPA bis(2-hydroxyethyl) ether induced developmental neurotoxicity in juvenile zebrafish (Danio rerio).

TBBPA bis(2-hydroxyethyl) ether (TBBPA-DHEE), one of the main derivatives of TBBPA, has been widely detected in environmental samples and been discovered to be potential neurotoxic. In this study, the juvenile zebrafish were selected as the research subject to explore the neurotoxicity and its mechanism of low-dose TBBPA-DHEE exposure, and to reveal the neurotoxicity susceptibility in different sexes. Behavioral studies revealed that TBBPA-DHEE could significantly reduce the swimming velocity, maximum acceleration and cumulative duration of high-speed mobility, significantly increasing the cumulative duration of low-speed mobility and average social distance. It significantly reduced the contents of ATP, glutamate and Ca2+ in the whole brain. The histopathological study demonstrated that TBBPA-DHEE could cause brain tissue damage in female and male juvenile zebrafish. The comprehensive data analysis indicated that female zebrafish were more susceptible to TBBPA-DHEE exposure than male zebrafish. Transcriptomic analysis showed that TBBPA-DHEE could significantly affect the expressions of behavioral and development-related genes. Furthermore, female and male juvenile zebrafish have different molecular mechanisms of neurotoxicity. For female juvenile zebrafish, the potential mechanism of neurotoxicity could be that it interfered with the feedback regulation of nerves by affecting the related genes expressions in the signaling pathways such as Ca2+ signaling, Wnt signaling and synapses. For male juvenile zebrafish, the potential mechanism of neurotoxicity may be through affecting the expression of related genes in hormones and neuro-related genes. This research could reveal the potential neurotoxicity of TBBPA-DHEE to aquatic organisms, which will be helpful to reveal the health effects of the emerging environmental pollutants.

A transcriptomic-based analysis predicts the neuroendocrine disrupting effect on adult male and female zebrafish (Danio rerio) following long-term exposure to tetrabromobisphenol A bis(2-hydroxyethyl) ether.

Endocrine-disrupting chemicals (EDCs) are now ubiquitously distributed in the environment. Tetrabromobisphenol A bis(2-hydroxyethyl) ether (TBBPA-DHEE) pollution in environment media poses a significant threat to humans and aquatic organisms as a result of its potential neurotoxicity and endocrine-disrupting effect. The endocrine-disrupting effects of TBBPA-DHEE on aquatic organisms, however, have received limited attention. In this study, the neurotoxicity and reproductive endocrine-disruptive effect of TBBPA-DHEE was evaluated by observing the neurobehavioral changes, vitellogenin (VTG), testosterone, 17ß-estradiol and gene expression levels in adult male and female zebrafish exposed to TBBPA-DHEE (0.05, 0.2 and 0.3 mg/L) for 100 days. Furthermore, transcriptomic analysis was conducted to unravel other potential neuroendocrine-disrupting mechanism. Our result showed TBBPA-DHEE significantly (p < 0.05) altered the locomotor behavior and motor coordination abilities in both sexes. Steroid hormone and VTG levels were also altered indicating the neuroendocrine-disrupting effect of TBBPA-DHEE on the hypothalamic-pituitary-gonadal-axis. A total of 1568 genes were upregulated and 542 genes downregulated in males, whereas, 1265 upregulated and 535 downregulated genes were observed in females. The KEGG enrichment analysis showed that cell cycle and p55 signaling pathways were significantly enriched due to TBBPA-DHEE exposure. These pathways and its component genes are potential target of EDCs. The significant upregulation of genes in these pathways could partly explain the neuroendocrine disrupting effect of TBBPA-DHEE. The observed toxic effects of TBBPA-DHEE observed in this study is confirmation of the endocrine-disrupting toxicity of this chemical which would be valuable in biosafety evaluation and biomonitoring of TBBPA-DHEE for public health purposes.

Transcriptomic sequencing reveals the potential molecular mechanism by which Tetrabromobisphenol A bis (2-hydroxyethyl ether) exposure exerts developmental neurotoxicity in developing zebrafish (Danio rerio).

Tetrabromobisphenol A bis (2-hydroxyethyl ether) (TBBPA-DHEE) is a derivative of Tetrabromobisphenol A (TBBPA) used as an intermediate flame retardant in engineering polymers. The mechanism of neurodevelopmental toxicity of TBBPA-DHEE remains unclear due to limited toxicological data. We performed behavioral and transcriptomic analyses to assess the neurodevelopmental effects of TBBPA-DHEE on developing zebrafish and potential toxicity mechanisms. Our result shows that exposure to TBBPA-DHEE significantly increased mortality, deformity rate, and reduction in hatch rate, hatchability, and body length relative to the DMSO control. The behavior analysis indicates that TBBPA-DHEE significantly reduced the spontaneous movement of larva compared to the control. The TSH and GH levels were significantly reduced in all the exposure groups in a concentration-dependent manner relative to the DMSO control. TBBPA-DHEE exhibited a significant reduction in locomotor activity across all the exposure groups in the light/dark locomotion test. The transcriptomic analysis result shows that 579 genes were differentially expressed. KEGG analysis shows the enrichment of complement cascade, JAK-STAT signaling pathway, cytokine-cytokine interaction, and phototransduction pathway resulting in a change in mRNA expression of their genes. These observed changes in developmental endpoints, hormonal level, and alteration in mRNA expression of component genes involved in neurodevelopmental pathways could be part of the possible mechanism of the observed toxic effects of TBBPA-DHEE exposure on zebrafish. This study could reveal the possible neurodevelopmental toxicity of TBBPA-DHEE to aquatic species, which could help uncover the health implications of emerging environmental contaminants.