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Butylated hydroxytoluene (BHT) and its analogs, butylated hydroxyanisole (BHA) and tert-butyl-hydroquinone (TBHQ), are widely used synthetic preservatives to inhibit lipid oxidation in the food, cosmetic and pharmaceutical industries. Despite their widespread use, little is known about their human exposure and related biotransformation products. The metabolism of these compounds was investigated using in vitro incubations with human and rat liver fractions. Liquid chromatography coupled to high-resolution tandem mass spectrometry was employed to detect and characterize stable and reactive species formed via oxidative metabolism, as well as phase II conjugates. Several oxidative metabolites have been detected, as well as glutathione, glucuronide, and sulfate conjugates, many of which were not previously reported. A combination of accurate mass measurements, MS/MS fragmentation behavior, and isotope-labeling studies were used to elucidate metabolite structures.

Butylated hydroxytoluene (BHT) is among the most widely used synthetic phenolic antioxidants. However, BHT and its metabolites have been detected in aquatic ecosystems, posing potential risks to aquatic organisms. The present study aimed to investigate the effects of BHT metabolites on embryonic development in zebrafish. To this end, embryos were exposed to BHT metabolites, including 3,5-di-tert-butyl-4 hydroxybenzaldehyde (BHT-CHO), 2,6-di-tert-butyl-4-(hydroxymethyl) phenol (BHT-OH), 3,5-di-tert-butyl-4 hydroxybenzoic acid (BHT-COOH), 2,6-di-tert-butyl-P-benzoquinone (BHT-Q), and 2,6-di-tert-butyl-4-hydroxy-4-methylcyclohexa-2,5-dien-1-one (BHT-quinol), from 1–120 h post-fertilization (hpf). BHT-CHO, -OH, -COOH, -Q, and -quinol were toxic to zebrafish larvae with 96 h LC 50 values of > 0.10, 15.85, 4.51, > 1.30, and 3.46 mg/L, respectively. Moreover, the acute toxicity of BHT metabolites to zebrafish larvae was indicated by morphological abnormalities, changes in heart rate, and alterations in locomotory behavior. The results indicated that exposure to BHT-COOH and BHT-OH caused intestinal developmental abnormalities, blood coagulation, tail deformities, and pericardial edema. Exposure to BHT-Q and BHT-quinol resulted in abnormal swim bladder development. Moreover, alterations in heart rate and locomotory behavior were observed in zebrafish larvae exposed to BHT-COOH, BHT-OH, and BHT-quinol. These findings demonstrate that exposure to BHT metabolites significantly affects the early growth and developmental stages of zebrafish larvae.

Butylated hydroxytoluene (BHT) is widely employed as an antioxidant in various industries. However, concerns persist regarding its safety and environmental impact, as its toxicological mechanisms remain poorly understood. Zebrafish embryos were exposed to BHT at 3, 5, and 7 mg/L to assess developmental toxicity. BHT exposure dose-dependently induced spinal cord malformations concomitant with reduced larval motility. Mechanistically, BHT suppressed Hedgehog signaling, evidenced by dysregulation of Shha, Gli1, and Smo. Notably, pharmacological activation of the Hh pathway by SAG rescued both structural defects and gene expression anomalies, confirming Hh inhibition as the primary toxicity mechanism. These results indicate that BHT inhibits Hh signaling, disrupting floor plate function and leading to spinal curvature.

Butylated hydroxytoluene (BHT) is one of the most commonly used synthetic antioxidants in food, cosmetic, pharmaceutical and petrochemical products. BHT is considered safe for human health; however, its widespread use together with the potential toxicological effects have increased consumers concern about the use of this synthetic food additive. In addition, the estimated daily intake of BHT has been demonstrated to exceed the recommended acceptable threshold. In the present work, using BHT as a case study, the usefulness of computational techniques, such as reverse screening and molecular docking, in identifying protein–ligand interactions of food additives at the bases of their toxicological effects has been probed. The computational methods here employed have been useful for the identification of several potential unknown targets of BHT, suggesting a possible explanation for its toxic effects. In silico analyses can be employed to identify new macromolecular targets of synthetic food additives and to explore their functional mechanisms or side effects. Noteworthy, this could be important for the cases in which there is an evident lack of experimental studies, as is the case for BHT.

This study evaluated the oxidative stability and physicochemical attributes of fish balls made from Pangasius pangasius (Pangus) by the addition of natural antioxidant Ficus carica (Fig fruit) and other synthetic antioxidants, Butylated hydroxytoluene (BHT) and Ascorbic Acid (AA), and the fish balls were stored under freezing conditions for two months. Four different types of fish balls were made with or without antioxidants: 1) T0 (without antioxidants); 2) T1 (0.02% BHT); 3) T2 (0.05% AA); 4) T3 (1% fig powder). Incorporating antioxidants significantly retained (p < 0.05) lower TBARS, pH, and yellowness while holding higher DPPH and redness values throughout storage. The addition of fig powder (FP) significantly (p < 0.05) reduced oxidation, free radical scavenging activity, and pH values. The fig's antioxidant potential was non-significantly (p > 0.05) different from BHT and AA. Moreover, the fig retained a significantly higher moisture content (p < 0.05), essential for maintaining fish ball quality. Furthermore, the cooking loss increased non-significantly (p > 0.05) among treated samples due to lower moisture and fat loss. Sensory assessment regarding color values of all treated and non-treated samples, FP showed a significantly (p < 0.05) higher redness value and a significantly (p < 0.05) lower yellowness when compared to control samples throughout the storage period. Therefore, adding FP as a natural antioxidant could reduce oxidation and maintain the others physicochemical characteristics of fish balls under freezing conditions.

A computer-aided predictions of antioxidant activities were performed with the Prediction Activity Spectra of Substances (PASS) program. Antioxidant activity of compounds 1, 3, 4 and 5 were studied using 1,1-diphenyl-2-picrylhydrazyl (DPPH) and lipid peroxidation assays to verify the predictions obtained by the PASS program. Compounds 3 and 5 showed more inhibition of DPPH stable free radical at 10−4 M than the well-known standard antioxidant, butylated hydroxytoluene (BHT). Compound 5 exhibited promising in vitro inhibition of Fe2+-induced lipid peroxidation of the essential egg yolk as a lipid-rich medium (83.99%, IC50 16.07 ± 3.51 µM/mL) compared to a-tocopherol (a-TOH, 84.6%, IC50 5.6 ± 1.09 µM/mL). The parameters for drug-likeness of these BHT analogues were also evaluated according to the Lipinski’s “rule-of-five” (RO5). All the BHT analogues were found to violate one of the Lipinski’s parameters (LogP > 5), even though they have been found to be soluble in protic solvents. The predictive polar surface area (PSA) and absorption percent (% ABS) data allow us to conclude that they could have a good capacity for penetrating cell membranes. Therefore, one can propose these new multipotent antioxidants (MPAOs) as potential antioxidants for tackling oxidative stress and lipid peroxidation processes.

Butylated Hydroxytoluene (BHT) is found to exert cellular toxicity through induction of oxidative stress although being used as antioxidant in many food products. This study investigates the protective effects of two herbal compounds Boeravinone B (BB) and Chebulinic acid (CA) in combination (B4C3 i.e. BB 4 µg/mL and CA 3 µg/mL). Key findings revealed that BHT exerted toxicity through induction of ROS (234.47 a.u.) and RNS (0.042 µM/mL), but B4C3 has significantly reduced it (115.46 a.u. and 0.018 µM/mL respecctively). BHT exposure raised the activities of antioxidant enzymes such as SOD (70.9%), CAT (7.08 units/mL), GPX (1.21 units/mL), levels of protein carbonyls (3.52 units/mg) and lipid peroxides (418.34%). Whereas treatment with B4C3 decreased the levels of SOD (29.92%), CAT (3.12 units/mL), GPX (0.36 units/mL), protein carbonyls (0.91 units/mg of protein) and lipid peroxides (106.67%) during BHT exposure. It was found that 20.56% cells were apoptotic while 73.83% were autophagic during BHT treatment. However, proposed phytotherapy rescued the cells from apoptotic and autophagic death and supported cell growth which was confirmed by RT-PCR and growth analysis. Collectively, B4C3 offered a significant protection against BHT-induced cellular damage, suggesting its potential as therapeutic agents for oxidative stress-related hepatotoxicity.

Background Alzheimer’s disease (AD) is the most common human neurodegenerative disorder worldwide. Owing to its chronic nature, our limited understanding of its pathophysiological mechanisms, and because of the lack of effective anti-AD drugs, AD represents a significant socio-economic challenge for all industrialized countries. Neuronal cell death is a key factor in AD pathogenesis and recent studies have suggested that neuronal ferroptosis may play a major patho-physiological role. Since ferroptosis involves free radical-mediated lipid peroxidation, we hypothesized that enteral administration of the radical scavenger butylated hydroxytoluene (BHT) might slow down or even prevent the development of AD-related symptoms in an in vivo animal AD model. Material and methods To test this hypothesis, we employed the rat model of streptozotocin-induced AD and administered butylated hydroxytoluene orally at a dose of 120 mg/kg body weight. Following BHT treatment, neuronal cell death was induced by bilateral stereotactic intraventricular injection of streptozotocin at a dose of 3.0 mg/kg body weight. Three weeks after surgery, we assessed the learning capabilities and the short-term memory of three experimental groups using the conventional y-maze test: (i) streptozotocin-treated rats (BHT pre-treatment), (ii) streptozotocin-treated rats (no BHT pre-treatment), (iii) sham-operated rats (BHT pre-treatment but no streptozotocin administration). After the y-maze test, the animals were sacrificed, hippocampal tissue was prepared and several biochemical (malonyl dialdehyde formation, glutathione homeostasis, gene expression patterns) and histochemical (Congo-red staining, Nissl staining, Perls staining) readout parameters were quantified. Results Intraventricular streptozotocin injection induced the development of AD-related symptoms, elevated the degree of lipid peroxidation and upregulated the expression of ferroptosis-related genes. Histochemical analysis indicated neuronal cell death and neuroinflammation, which were paralleled by aberrant intraneuronal iron deposition. The streptozotocin-induced alterations were significantly reduced and sometimes even abolished by oral BHT treatment. Conclusion Our data indicate that oral BHT treatment attenuated the development of AD-related symptoms in an in vivo rat model, most probably via inhibiting neuronal ferroptosis. These findings suggest that BHT might constitute a promising candidate as anti-AD drug. However, more work is needed to explore the potential applicability of BHT in other models of neurodegeneration and in additional ferroptosis-related disorders.

Cells produce free radicals and antioxidants when exposed to toxic compounds during cellular metabolism. However, free radicals are deleterious to lipids, proteins, and nucleic acids. Antioxidants neutralize and eliminate free radicals from cells, preventing cell damage. Therefore, the study aims to determine whether the antioxidants butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) will ameliorate the maximum dose of acrylamide and alpha (α)-solanine synergistic toxic effects in exposed BEAS-2B cells. These toxic compounds are consumed worldwide by eating potato products. BEAS-2B cells were simultaneously treated with BHA 10 μM and BHT 20 μM and incubated in a 5% CO2 humidified incubator for 24 h, followed by individual or combined treatment with acrylamide (3.5 mM) and α-solanine (44 mM) for 48 h, including the controls. Cell morphology, DNA, RNA, and protein were analyzed. The antioxidants did not prevent acrylamide and α-solanine synergistic effects in exposed BEAS-2B cells. However, cell morphology was altered; polymerase chain reaction (PCR) showed reduced RNA constituents but not DNA. In addition, the toxic compounds synergistically inhibited AKT/PKB expression and its downstream genes. The study showed BHA and BHT are not protective against the synergetic toxic effects of acrylamide and α-solanine in exposed BEAS-2B cells.

At present, there are few reports about the proteomics changes provoked by butylated hydroxytoluene (BHT) supplementation on cryopreserved semen in mammals. Thus, we aimed to evaluate the effects of different concentrations of BHT on goat sperm and to investigate the proteomics changes of adding BHT to cryopreserved goat ( Capra hircus ) sperm. Firstly, semen samples were collected from four goats, and frozen in the basic extenders containing different concentrations of BHT (0.5 mM, 1.0 mM, 2.0 mM) and a control without BHT, respectively. After thawing, the protective effects of dose-dependent replenished BHT to the freezing medium on post-thaw sperm motility, integrities of plasma membrane and acrosome, reactive oxygen species levels were confirmed, with 0.5 mM BHT being the best (B group) as compared to the control (without BHT, C group). Afterwards, TMT-based quantitative proteomic technique was performed to profile proteome of the goat sperm between C group and B group. Parallel reaction monitoring was used to confirm reliability of the data. Overall, 2,476 proteins were identified and quantified via this approach. Comparing the C and B groups directly (C vs . B), there were 17 differentially abundant proteins (DAPs) po-tentially associated with sperm characteristics and functions were identified, wherein three were upregulated and 14 were downregulated, respectively. GO annotation analysis demonstrated the potential involvement of the identified DAPs in metabolic process, multi-organism process, reproduction, reproductive process, and cellular process. KEGG enrichment analysis further indicated their potential roles in renin-angiotensin system and glutathione metabolism pathways. Together, this novel study clearly shows that BHT can effectively improve quality parameters and fertility potential of post-thawed goat sperm at the optimal concentration, and its cryoprotection may be realized through regulation of sperm metabolism and antioxidative capability from the perspective of sperm proteomic modification.