Echinatin mitigates sevoflurane-induced neurotoxicity through regulation of ferroptosis and iron homeostasis.

Surgery and anesthesia are vital medical interventions, but concerns over their potential cognitive side effects, particularly with the use of inhalational anesthetics like sevoflurane, have surfaced. This study delves into the neuroprotective potential of Echinatin against sevoflurane-induced neurotoxicity and the underlying mechanisms. Echinatin, a natural compound, has exhibited anti-inflammatory, antioxidant, and anticancer properties. Sevoflurane, while a popular anesthetic, is associated with perioperative neurocognitive disorders (PND) and neurotoxicity. Our investigation began with cellular models, where Echinatin demonstrated a significant reduction in sevoflurane-induced apoptosis. Mechanistically, we identified ferroptosis, a novel form of programmed cell death characterized by iron accumulation and lipid peroxidation, as a key player in sevoflurane-induced neuronal injury. Echinatin notably suppressed ferroptosis in sevoflurane-exposed cells, suggesting a pivotal role in neuroprotection. Expanding our research to a murine model, we observed perturbations in iron homeostasis, inflammatory cytokines, and antioxidants due to sevoflurane exposure. Echinatin treatment effectively restored iron balance, mitigated inflammation, and preserved antioxidant levels in vivo. Behavioral assessments using the Morris water maze further confirmed Echinatin's neuroprotective potential, as it ameliorated sevoflurane-induced spatial learning and memory impairments. In conclusion, our study unveils Echinatin as a promising candidate for mitigating sevoflurane-induced neurotoxicity. Through the regulation of ferroptosis, iron homeostasis, and inflammation, Echinatin demonstrates significant neuroprotection both in vitro and in vivo. These findings illuminate the potential for Echinatin to enhance the safety of surgical procedures involving sevoflurane anesthesia, minimizing the risk of cognitive deficits and neurotoxicity.

Beyond the surface: Consequences of methyl tert-butyl ether (MTBE) exposure on oxidative stress, haematology, genotoxicity, and histopathology in rainbow trout.

Concerns have been raised about the possible environmental effects of methyl tert-butyl ether (MTBE), which is widely used as a gasoline additive. This research aimed to look at the consequences of MTBE contamination on rainbow trout (Oncorhynchus mykiss), emphasizing oxidative stress, genotoxicity, and histopathological damage. After determining the LC50-96 h value, the effects of sub-lethal doses of MTBE (0 (control), 90, 180, and 450 ppm) on rainbow trout were investigated. In fish tissues, the levels of oxidative stress indicators such as malondialdehyde (MDA) and superoxide dismutase (SOD) were measured. The comet assay, which measures DNA damage in erythrocytes, was used to determine genotoxicity. Histopathological examinations were done on liver and gill tissues to examine potential structural anomalies. The results of this study show that MTBE exposure caused considerable alterations in rainbow trout. Increased oxidative stress was demonstrated by elevated MDA levels and decreased SOD activity, while the comet assay revealed dose-dependent DNA damage, implying genotoxic effects. Histopathological study revealed liver and gill tissue abnormalities, including cell degeneration, necrosis, and inflammation. Overall, this research highlights the possible sub-lethal effects of MTBE contamination on rainbow trout, stressing the need of resolving this issue. Future research should look at the impacts of chronic MTBE exposure and the possibility of bioaccumulation in fish populations.

Neonatal sevoflurane exposure induces long-term changes in dendritic morphology in juvenile rats and mice.

General anesthetics are potent neurotoxins when given during early development, causing apoptotic deletion of substantial number of neurons and persistent neurocognitive and behavioral deficits in animals and humans. The period of intense synaptogenesis coincides with the peak of susceptibility to deleterious effects of anesthetics, a phenomenon particularly pronounced in vulnerable brain regions such as subiculum. With steadily accumulating evidence confirming that clinical doses and durations of anesthetics may permanently alter the physiological trajectory of brain development, we set out to investigate the long-term consequences on dendritic morphology of subicular pyramidal neurons and expression on genes regulating the complex neural processes such as neuronal connectivity, learning, and memory. Using a well-established model of anesthetic neurotoxicity in rats and mice neonatally exposed to sevoflurane, a volatile general anesthetic commonly used in pediatric anesthesia, we report that a single 6 h of continuous anesthesia administered at postnatal day (PND) 7 resulted in lasting dysregulation in subicular mRNA levels of cAMP responsive element modulator (Crem), cAMP responsive element-binding protein 1 (Creb1), and Protein phosphatase 3 catalytic subunit alpha, a subunit of calcineurin (Ppp3ca) (calcineurin) when examined during juvenile period at PND28. Given the critical role of these genes in synaptic development and neuronal plasticity, we deployed a set of histological measurements to investigate the implications of anesthesia-induced dysregulation of gene expression on morphology and complexity of surviving subicular pyramidal neurons. Our results indicate that neonatal exposure to sevoflurane induced lasting rearrangement of subicular dendrites, resulting in higher orders of complexity and increased branching with no significant effects on the soma of pyramidal neurons. Correspondingly, changes in dendritic complexity were paralleled by the increased spine density on apical dendrites, further highlighting the scope of anesthesia-induced dysregulation of synaptic development. We conclude that neonatal sevoflurane induced persistent genetic and morphological dysregulation in juvenile rodents, which could indicate heightened susceptibility toward cognitive and behavioral disorders we are beginning to recognize as sequelae of early-in-life anesthesia.

Sevoflurane and isoflurane anesthesia induce redox imbalance, but only sevoflurane impairs vascular contraction.

Volatile anesthetics may cause vascular dysfunction; however, underlying effects are unclear. The aim of the present study was to investigate whether sevoflurane and isoflurane affect vascular function, nitric oxide (NO) bioavailability, and biomarkers of oxidative stress and inflammation. Wistar rats were divided into three experimental groups: Not anesthetized (control group) or submitted to anesthesia with isoflurane (Iso group) or sevoflurane (Sevo group). Hemodynamic parameters were monitored during anesthesia, and blood gas values and biochemical determinants were analyzed. Isometric contractions were recorded in aortic rings. Vasoconstriction induced by potassium chloride (KCl) and phenylephrine (Phe) were measured. No differences in hemodynamic parameters and blood gasses variables were observed. Impaired KCl and Phe-induced contractions were observed in endothelium-intact aorta of Sevo compared to Iso and Control groups. Redox imbalance was found in Sevo and Iso groups. Reduced NO bioavailability and increased activity of matrix metalloproteinase 2 (MMP-2) were observed in Sevo, but not in the Iso group. While reduced IL-10 and IL-1ß were observed in Sevo, increases in IL-1ß in the Iso group were found. Sevoflurane, but not isoflurane, anesthesia impairs vasocontraction, and reduced NO and cytokines and increased MMP-2 activity may be involved in vascular dysfunction after sevoflurane anesthesia.

Differential epitranscriptome and proteome modulation in the brain of neonatal mice exposed to isoflurane or sevoflurane.

BACKGROUND: Repeated neonatal exposure to anesthetics may disturb neurodevelopment and cause neuropsychological disorders. The m6A modification participates in the gene regulation of neurodevelopment in mouse fetuses exposed to anesthetics. This study aims to explore the underlying molecular mechanisms of neurotoxicity after early-life anesthesia exposure. METHODS: Mice were exposed to isoflurane (1.5%) or sevoflurane (2.3%) for 2 h daily during postnatal days (PND) 7-9. Sociability, spatial working memory, and anxiety-like behavior were assessed on PND 30-35. Synaptogenesis, epitranscriptome m6A, and the proteome of brain regions were evaluated on PND 21. RESULTS: Both isoflurane and sevoflurane produced abnormal social behaviors at the juvenile age, with different sociality patterns in each group. Synaptogenesis in the hippocampal area CA3 was increased in the sevoflurane-exposed mice. Both anesthetics led to numerous persistent m6A-induced alterations in the brain, associated with critical metabolic, developmental, and immune functions. The proteins altered by isoflurane exposure were mainly associated with epilepsy, ataxia, and brain development. As for sevoflurane, the altered proteins were involved in social behavior. CONCLUSIONS: Social interaction, the modulation patterns of the m6A modification, and protein expression were altered in an isoflurane or sevoflurane-specific way. Possible molecular pathways involved in brain impairment were revealed, as well as the mechanism underlying behavioral deficits following repeated exposure to anesthetics in newborns.

Multiple exposures to sevoflurane across postnatal development may cause cognitive deficits in older age.

BACKGROUND: The aim of the study was to determine the effects of repeated anesthesia exposure across postnatal development. METHODS: Seventy-two newborn Sprague-Dawley rats were randomly divided into Sev group and Con-aged group. Sev groups were exposed to 2.6% sevoflurane for 2 h on postnatal day (P) 7, P14, and P21; the Con groups only received carrier gas for 2 h. Learning and memory were evaluated using the MWM test at P31 (juvenile), P91 (adult), and 18 months postnatally (aged). The relative expression of APP and Mapt mRNA was detected by RT-PCR, while Aß, tau, and P-tau protein levels were analyzed by immunohistochemistry. RESULTS: After repeated inhalation of sevoflurane, MWM test performance was significantly decreased in the Sev-aged group compared to the Con-aged group (P > 0.05). The relative expression of APP and Mapt mRNA was not significantly different between groups in each growth period (P > 0.05). The tau expression in the juvenile hippocampal CA1, CA3, and dentate gyrus regions increased markedly in the Sev group, while P-tau only increased in the hippocampal CA3 region in the Sev-adult group. The expression of tau, P-tau, and Aß in the hippocampal regions was upregulated in the Sev-aged group. CONCLUSIONS: Multiple exposures to sevoflurane across postnatal development can induce or aggravate cognitive impairment in old age. IMPACT: Whether multiple sevoflurane exposures across postnatal development cause cognitive impairment in childhood, adulthood, or old age, as well as the relationship between sevoflurane and the hippocampal Aß, tau, and P-tau proteins, remains unknown. This study's results demonstrate that multiple exposures to sevoflurane across postnatal development do not appear to affect cognitive function in childhood and adulthood; however, multiple exposures may lead to a cognitive function deficit in old age. The underlying mechanism may involve overexpression of the tau, P-tau, and Aß proteins in the hippocampus.

Effects of overexpression of Hsp70 in neural stem cells on neurotoxicity and cognitive dysfunction in neonatal mice under sevoflurane exposure.

As one of the commonly used inhalation anesthetics in clinical practice, sevoflurane is currently widely applied in surgery for children and the elderly due to its safety and efficacy. However, the neurotoxicity and cognitive impairment induced by sevoflurane exposure cannot be ignored. A recombinant adenovirus with green fluorescent protein-labeled heat shock protein 70 (Hsp70) was constructed and used to infect neural stem cells (NSCs) separated from neonatal mice. Quantitative real-time PCR and Western blot assays were used to evaluate the expression of certain genes. 5­Ethynyl­2'­deoxyuridine staining and cell counting kit assay were used to detect the proliferation and differentiation ability of NSCs. The Morris water maze experiment was used to test the cognitive abilities of mice. Adv-Hsp70 induced the overexpression of Hsp70 in mouse NSCs. Upregulation of Hsp70 promoted the proliferation ability and differentiation of mouse NSCs. NSCs that overexpressed Hsp70 attenuated sevoflurane-induced neurotoxicity and protected cognitive dysfunction in mice under sevoflurane exposure. In summary, our findings demonstrate the potential of overexpression of Hsp70 in NSCs against sevoflurane-induced impairments.

Methyl-tert-butyl ether (MTBE): integration of rat and mouse carcinogenicity data with mode of action and human and rodent bioassay dosimetry and toxicokinetics indicates MTBE is not a plausible human carcinogen.

Methyl-tert-butyl ether (MTBE) is a fuel oxygenate used in non-United States geographies. Multiple health reviews conclude that MTBE is not a human-relevant carcinogen, and this review provides updated mode of action (MOA), exposure, dosimetry and risk perspectives supporting those conclusions. MTBE is non-genotoxic and has large margins of exposure between blood concentrations at the overall rat 400 ppm inhalation NOAEL and blood concentrations in typical workplace or general population exposures. Non-cancer and threshold cancer hazard quotients range from a high of 0.046 for fuel-pump gasoline station attendants and are 100-1,000-fold lower for general population exposures. Cancer risks conservatively assuming genotoxicity for these same scenarios are all less than 1 × 10-6. The onset of MTBE nonlinear toxicokinetics (TK) in rats at inhalation exposures less than 3,000 ppm, a dose that is also not practically achievable in fuel-use scenarios, indicates that high-dose specific male rat kidney and testes (3,000 and 8,000 ppm) and female mouse liver tumors (8000 ppm) are not quantitatively relevant to humans. Mode of action analyses also indicate MTBE male rat kidney tumors, and lesser so female mouse liver tumors, are not qualitatively relevant to humans. Thus, an integrated analysis of the toxicology, exposure/dosimetry, TK, and MOA data indicates that MTBE presents minimal human cancer and non-cancer risks.

Differential Effects of Sevoflurane Exposure on Long-Term Fear Memory in Neonatal and Adult Rats.

It remains unclear whether exposure to sevoflurane produces different effects on long-term cognitive function in developing and mature brains. In the present study, Sprague-Dawley neonatal rats at postnatal day (PND) 7 and adult rats (PND 56) were used in all experiments. We performed fear conditioning testing to examine long-term fear memory following 4-h sevoflurane exposure. We assessed hippocampal synapse ultrastructure with a transmission electron microscope. Moreover, we investigated the effect of sevoflurane exposure on the expression of postsynaptic protein 95 (PSD-95) and its binding protein kalirin-7 in the hippocampus. We observed that early exposure to sevoflurane in neonatal rats impairs hippocampus-dependent fear memory, reduces hippocampal synapse density, and dramatically decreases the expressions of PSD-95 and kalirin-7 in the hippocampus of the developing brain. However, sevoflurane exposure in adult rats has no effects on hippocampus-dependent fear memory and hippocampal synapse density, and the expressions of PSD-95 and kalirin-7 in the adult hippocampus are not significantly altered following sevoflurane treatment. Our results indicate that sevoflurane exposure produces differential effects on long-term fear memory in neonatal and adult rats and that PSD-95 signaling may be involved in the molecular mechanism for early sevoflurane exposure-caused long-term fear memory impairment.

The Role of Klotho Protein Against Sevoflurane-Induced Neuronal Injury.

The effects of general anesthetics on the developing brain have aroused much attention in recent years. Sevoflurane, a commonly used inhalation anesthetic especially in pediatric anesthesia, can induce developmental neurotoxicity. In this study, the differentially expressed mRNAs in the hippocampus of newborn rats exposed to 3% sevoflurane for 6 h were detected by RNA-Sequencing. Those data indicated that the mRNA of Klotho was increased after exposure to sevoflurane. Moreover, the protein expression of Klotho was assayed by Western Blot. Besides over-expression and under-expression of Klotho protein, we also detected changes of cell proliferation, ROS, JC-1, and Bcl-2/Bax ratio in PC12 cells exposed to sevoflurane. After exposure to 3% sevoflurane, the expression of Klotho protein increased in the hippocampus of neonatal rats. In PC12 cells, exposure to sevoflurane could increase cellular ROS level, reduce mitochondrial membrane potential and Bcl-2/Bax ratio. While overexpression of Klotho alleviated the above changes, knockdown of Klotho aggravated the injury of sevoflurane. Klotho protein could reduce oxidative stress and mitochondrial injury induced by sevoflurane in the neuron.

DNA polymerase ß may be involved in protecting human bronchial epithelial cells from the toxic effects induced by methyl tert-butyl ether exposure.

Methyl tert-butyl ether (MTBE), a widely used gasoline additive and a ubiquitous environmental pollutant in many countries and regions, can cause various kinds of toxic effects on human health. However, the molecular mechanism underlying its toxic effects remains elusive. The present study aimed to explore the cytotoxicity, DNA damage and oxidative damage effects of MTBE on human bronchial epithelial cells (16HBE) and the possible role of DNA polymerase ß (pol-ß) in this process. RNA interference (RNAi) was used to obtain pol-ß gene knocked-down cells (pol-ß-). CCK-8 assay was adopted to analyze the cell viability. Alkaline single-cell gel electrophoresis (SCGE) was performed to detect the DNA damage effects of MTBE. The enzyme activity of GSH-Px, SOD, CAT and the level of MDA were assessed. The data indicated that when treated with MTBE at the concentration exceeding 50 µmol/L and for the time exceeding 24 h, the pol-ß- exhibited significantly decreased cell viability and increased DNA damage effects, as compared to the control (P < 0.05). Furthermore, there was significant difference in the levels of GSH-pX, SOD, CAT and MDA between the pol-ß- and the control (P < 0.05). Our investigation suggests that MTBE can cause obvious cytotoxicity, DNA damage and oxidative damage effects on 16HBE cells. DNA polymerase ß may be involved in protecting 16HBE cells from the toxic effects induced by MTBE exposure. These findings provide a novel insight into the molecular mechanism underlying the toxic effects of MTBE on human cells.

Anesthesia and the Developing Brain: A Review of Sevoflurane-induced Neurotoxicity in Pediatric Populations.

PURPOSE: For over 150 years of anesthetic practice, it was believed that the effects of general anesthetics were temporary and not adverse. A growing number of studies over the past 2 decades, however, have identified structural and cognitive abnormalities, especially in the developing brain. Despite the growing evidence of anesthetic-induced neurotoxicity in animal studies, the evidence to date in humans has been inconsistent and unclear. Sevoflurane, a commonly used inhalational agent in pediatric anesthesia, is an agent of choice for inhalational induction due to its rapid activity and low blood-gas solubility. With evaluation of the current literature, improved considerations can be made regarding the widespread use of sevoflurane as an anesthetic. METHODS: PubMed database was searched for article published between 1969 through 2020. The reference lists of identified articles were searched manually for additional papers eligible for inclusion. This review addressed the tolerability of sevoflurane in specific populations, particularly pediatrics, and is divided into 3 parts: (1) the history of sevoflurane use in anesthetic practice and the pharmacokinetic properties that make it advantageous in pediatric populations; (2) proposed mechanisms of anesthesia-induced neurotoxicity; and (3) considerations due to potential adverse effects of sevoflurane in both short and long procedures. FINDINGS: There is reason for concern regarding the neurotoxic effects of sevoflurane in both the pediatric and elderly populations, as spatial memory loss, developmental deficits, and an enhanced risk for Alzheimer disease have been linked with the use of this popular inhalational agent. IMPLICATIONS: The duration and dose of sevoflurane may need to be altered, especially in longer procedures in pediatric populations. This may change how sevoflurane is administered, thus indicating a greater demand for an understanding of its limitations as an anesthetic agent.

A Comparative Cancer Risk Evaluation of MTBE and Other Compounds (Including Naturally Occurring Compounds) in Drinking Water in New Hampshire.

Methyl tert-butyl ether (MTBE) was added to gasoline in New Hampshire (NH) between 1995 and 2006 to comply with the oxygenate requirements of the 1990 Amendments to the Clean Air Act. Leaking tanks and spills released MTBE into groundwater, and as a result, MTBE has been detected in drinking water in NH. We conducted a comparative cancer risk assessment and a margin-of-safety (MOS) analysis for several constituents, including MTBE, detected in NH drinking water. Using standard risk assessment methods, we calculated cancer risks from exposure to 12 detected volatile organic compounds (VOCs), including MTBE, and to four naturally occurring compounds (i.e., arsenic, radium-226, radium-228, and radon-222) detected in NH public water supplies. We evaluated exposures to a hypothetical resident ingesting the water, dermally contacting the water while showering, and inhaling compounds volatilizing from water in the home. We then compared risk estimates for MTBE to those of the other 15 compounds. From our analysis, we concluded that the high-end cancer risk from exposure to MTBE in drinking water is lower than the risks from all the other VOCs evaluated and several thousand times lower than the risks from exposure to naturally occurring constituents, including arsenic, radium, and radon. We also conducted an MOS analysis in which we compared toxicological points of departure to the NH maximum contaminant level (MCL) of 13 µg/L. All of the MOSs were greater than or equal to 160,000, indicating a large margin of safety and demonstrating the health-protectiveness of the NH MCL for MTBE.

Acetyl-l-carnitine does not prevent neurodegeneration in a rodent model of prolonged neonatal anesthesia.

Many studies have shown that prolonged or repeated use of general anesthesia early in life can cause an increase in neurodegeneration and lasting changes in behavior. While short periods of general anesthesia appear to be safe, there is a concern about the neurotoxic potential of prolonged or repeated general anesthesia in young children. Unfortunately, the use of general anesthesia in children cannot be avoided. It would be a great benefit to develop a strategy to reduce or reverse anesthesia mitigated neurotoxicity. The mechanisms behind anesthesia related neurotoxicity are unknown, but evidence suggests that mitochondrial dysfunction and abnormal energy utilization are involved. Recent research suggests that a class of compounds known as carnitines may be effective at preventing anesthesia related neurotoxicity by influencing fatty acid metabolism in the mitochondria. However, it is unknown if carnitines can provide protection against changes in behavior associated with early life exposure to anesthesia. Accordingly, we evaluated the neuroprotective potential of acetyl-l-carnitine in 7-day old rats. Rat pups were exposed to 6 h of general anesthesia with sevoflurane or a control condition, with and without acetyl-l-carnitine. The oxygenation level of animals was continuously monitored during sevoflurane exposure, and any animal showing signs of hypoxia was removed from the study. Animals exposed to sevoflurane showed clear signs of neurodegeneration 2 h after sevoflurane exposure. The hippocampus, cortex, thalamus, and caudate putamen all had elevated levels of Fluoro-Jade C staining. Despite the elevated levels of Fluoro-Jade C, few behavioral changes were observed in an independent cohort of animals treated with sevoflurane. Furthermore, acetyl-l-carnitine had little impact on levels of Fluoro-Jade C staining in animals treated with sevoflurane. These data suggest that acetyl-l-carnitine may offer little protection again anesthesia related neurotoxicity in fully oxygenated animals.

PDE-7 Inhibitor BRL-50481 Reduces Neurodegeneration and Long-Term Memory Deficits in Mice Following Sevoflurane Exposure.

Sevoflurane, one of the most commonly used anesthetic agents, has been demonstrated to induce widespread neurodegeneration in the developing brain. We aimed to evaluate the protective effects of a PDE-7 inhibitor (BRL-50481) against the neurotoxic effects of sevoflurane on the developing nervous system. Spatial learning and memory in sevoflurane-treated mice were examined using the Morris water maze test, and neuroprotective effects of PDE-7 inhibitor (BRL-50481) against sevoflurane-induced impairments were evaluated. Our results showed that sevoflurane treatment markedly induced neurodegeneration and impaired long-term memory in neonatal mice. Notably, BRL-50481 coadministration could significantly attenuate sevoflurane-induced learning and memory defects, prevent deterioration of recognition memory, and protect against neuron apoptosis. Mechanistically, BRL-50481 administration suppressed sevoflurane-induced neurodegenerative disorders through restoring cAMP and activating cAMP/CREB signaling in the hippocampus. PDE7 inhibitor may be a potential therapeutic agent for sevoflurane-induced neurodegeneration and long-term memory deficits.

Methyl t-butyl ether-degrading bacteria for bioremediation and biocontrol purposes.

A total of fifteen potential methyl t-butyl ether (MtBE)-degrading bacterial strains were isolated from contaminated soil. They have been identified as belonging to the genera Bacillus, Pseudomonas, Kocuria, Janibacter, Starkeya, Bosea, Mycolicibacterium, and Rhodovarius. Bacillus aryabhattai R1B, S. novella R8b, and M. mucogenicum R8i were able to grow using MtBE as carbon source, exhibiting different growth behavior and contaminant degradation ability. Their biocontrol ability was tested against various fungal pathogens. Both S. novella R8b and B. aryabhattai were effective in reducing the development of necrotic areas on leaves within 48 hours from Botritys cinerea and Alternaria alternata inoculation. Whereas, M. mucogenicum effectively controlled B. cinerea after 72 hours. Similar results were achieved using Pythium ultimum, in which the application of isolated bacteria increased seed germination. Only M. mucogenicum elicited tomato plants resistance against B. cinerea. This is the first report describing the occurrence of bioremediation and biocontrol activities in M. mucogenicum, B. aryabhattai and S. novella species. The production of maculosin and its antibiotic activity against Rhizoctonia solani has been reported for first time from S. novella. Our results highlight the importance of multidisciplinary approaches to achieve a consistent selection of bacterial strains useful for plant protection and bioremediation purposes.

The urinary metabolic profile of diethylene glycol methyl ether and triethylene glycol methyl ether in Sprague-Dawley rats and the role of the metabolite methoxyacetic acid in their toxicity.

Ethylene glycol ethers are a well-known series of solvents and hydraulic fluids derived from the reaction of ethylene oxide and monoalcohols. Use of methanol as the alcohol results in a series of mono, di and triethylene glycol methyl ethers. The first in the series, monoethylene glycol methyl ether (EGME or 2-methoxyethanol) is well characterised and metabolises in vivo to methoxyacetic acid (MAA), a known reproductive toxicant. Metabolism data is not available for the di and triethylene glycol ethers (DEGME and TEGME respectively). This study evaluated the metabolism of these two substances in male rats following single oral gavage doses of 500, 1000 and 2000 mg/kg for DEGME and 1000 mg/kg for TEGME. As for EGME, the dominant metabolite of each was the acid metabolite derived by oxidation of the terminal hydroxyl group. Elimination of these metabolites was rapid, with half-lives <4 h for each one. Both substances were also found to produce small amounts of MAA (~0.5% for TEGME and ~1.1% for DEGME at doses of 1000 mg/kg) through cleavage of the ether groups in the molecules. These small amounts of MAA produced can explain the effects seen at high doses in reproductive studies using DEGME and TEGME.

Effect of methyl tert-butyl ether on adipogenesis and glucose metabolism in vitro and in vivo.

Methyl tert-butyl ether (MTBE), as a widely used gasoline additive, is suspected of being environmentally toxic. MTBE accumulates mainly in adipose tissue, but its effect on obesity or obesity-related metabolic disorders has not been well understood yet. Therefore, we examined the effect of MTBE on the adipose function and the related metabolic processes with both 3T3-L1 cell line and C57BL/6J mice model. We found that exposure to MTBE at the environmental relevant concentration (100 µmol/L) could significantly induce differentiation of preadipocyte and disturb insulin-stimulated glucose uptake of mature adipocyte. The in vivo observation in male mice showed a positive correlation of visceral white adipose tissue (vWAT) expansion and cell size increase with MTBE treatment in 14 weeks. Glucose tolerance and insulin sensitivity tests demonstrated that MTBE at 1000 µg/(kg·day) disturbed the systemic glucose metabolism in a gender-specific manner, which might be partly attributed to the alterations of gut microbiota community at genus level with respect to Akkermansia, Clostridium XlVb, and Megamonas. In summary, our study characterized the effect of MTBE on adipose tissue function and glucose homeostasis in vitro and in vivo, and revealed that systemic disorders of the glucose metabolism might be modulated by the related gut microbiota.