Role of covalent modification by hepatic aldehydes in dictamnine-induced liver injury.

Dictamnine is a representative furan-containing hepatotoxic compound. Administration of dictamnine caused acute liver injury in mice and the metabolic activation of furan to reactive epoxy intermediate was responsible for the hepatotoxicity. This study aimed to characterize the protein adduction by endogenous hepatic aldehydes and investigate its role in dictamnine-induced hepatotoxicity. In the liver sample of dictamnine-treated mice, the protein adduction by five aldehydes was characterized as lysine residue-aldehyde adducts using high-resolution UPLC-Q/Orbitrap MS after exhaustive proteolytic digestion. The levels of protein adduct were increased at 2-3 h after the treatment with dictamnine. The formation of protein adduction increased with increasing doses of dictamnine. Inhibition of the bioactivation by CYP3A inhibitor ketoconazole prevented the protein adduction. Treatment with 2,3-dihydro-dictamnine, an analog of dictamnine that was unable to form the epoxy intermediate, did not lead to an increase in protein adduction. Application of aldehyde dehydrogenase-2 activator ALDA-1 or nucleophilic trapping reagent N-acetyl-L-lysine significantly reduced the protein adduction and attenuated dictamnine-induced liver injury without affecting the bioactivation. In conclusion, the metabolic activation of the furan ring of dictamnine resulted in the protein adduction by multiple hepatic aldehydes and the protein modification played a crucial role in dictamnine-induced liver injury.

K6-linked ubiquitylation marks formaldehyde-induced RNA-protein crosslinks for resolution.

Reactive aldehydes are produced by normal cellular metabolism or after alcohol consumption, and they accumulate in human tissues if aldehyde clearance mechanisms are impaired. Their toxicity has been attributed to the damage they cause to genomic DNA and the subsequent inhibition of transcription and replication. However, whether interference with other cellular processes contributes to aldehyde toxicity has not been investigated. We demonstrate that formaldehyde induces RNA-protein crosslinks (RPCs) that stall the ribosome and inhibit translation in human cells. RPCs in the messenger RNA (mRNA) are recognized by the translating ribosomes, marked by atypical K6-linked ubiquitylation catalyzed by the RING-in-between-RING (RBR) E3 ligase RNF14, and subsequently resolved by the ubiquitin- and ATP-dependent unfoldase VCP. Our findings uncover an evolutionary conserved formaldehyde-induced stress response pathway that protects cells against RPC accumulation in the cytoplasm, and they suggest that RPCs contribute to the cellular and tissue toxicity of reactive aldehydes.

Rapid identification and monitoring of cooking oil fume-based toxic volatile organic aldehydes in lung tissue for predicting exposure level and cancer risks.

Cooking oil fumes (COFs) comprised of a mixture of cancer-causing volatile organic aldehydes (VOAs), particularly trans, trans-2,4-decadienal (t,t-DDE), 4-hydroxy-hexenal (4-HHE), and 4-hydroxy-nonenal (4-HNE). Monitoring toxic VOAs levels in people exposed to different cooking conditions is vital to predicting the cancer risk. For this purpose, we developed a fast tissue extraction (FaTEx) technique combined with UHPLC-MS/MS to monitor three toxic VOAs in mice lung tissue samples. FaTEx pre-treatment protocol was developed by combining two syringes for extraction and clean-up process. The various procedural steps affecting the FaTEx sample pre-treatment process were optimized to enhance the target VOAs' extraction efficiency from the sample matrix. Under the optimal experimental conditions, results exhibit good correlation coefficient values > 0.99, detection limits were between 0.5-3 ng/g, quantification limits were between 1-10 ng/g, and the matrix effect was <18.1%. Furthermore, the extraction recovery values of the spiked tissue exhibited between 88.9-109.6% with <8.6% of RSD. Cooking oil fume (containing t,t-DDE) treated mice at various time durations were sacrificed to validate the developed technique, and it was found that t,t-DDE concentrations were from 14.8 to 33.8 µg/g. The obtained results were found to be a fast, reliable, and semi-automated sample pre-treatment technique with good extraction efficiency, trace level detection limit, and less matrix effect. Therefore, this method can be applied as a potential analytical method to determine the VOAs in humans exposed to long-term cooking oil fumes.

Liver enzymes mediate the association between aldehydes co-exposure and hypertriglyceridemia.

Aldehydes are recognized environmental toxicants that may affect lipid metabolism. For instance, acrolein has been found to increase serum triglyceride (TG) levels exclusively. However, it remains unclear whether other aldehydes are also associated with hypertriglyceridemia (HTG), and what mechanisms may be involved. This cross-sectional study analyzed data from the National Health and Nutrition Examination Survey (NHANES, 2013-2014) to identify associations between serum aldehydes, liver enzymes, and HTG. Serum aldehydes included crotonaldehyde (CRAL), propanaldehyde (3AL), butyraldehyde (4AL), pentanaldehyde (5AL), isopentanaldehyde (I5AL), and heptanaldehyde (7AL). Liver enzymes included alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and gamma-glutamyltransferase (GGT). HTG was defined as fasting TG levels ≥ 1.7 mmol/L. Aldehyde co-exposure was quantified using weighted quantile sum (WQS) regression and Bayesian kernel machine regression (BKMR), while mediation analysis was performed to investigate the role of liver enzymes. Among 1474 participants (mean age 38.6 years, male 50.0%), 426 were diagnosed with HTG. 4AL, 5AL, I5AL, and 7AL were shown to be positively associated with HTG (all P values <0.05). Aldehydes co-exposure was also positively associated with HTG (OR 1.706, 95%CI 1.299-2.240), with 5AL contributing the highest weight (35.3%). Furthermore, aldehydes co-exposure showed positive associations with ALT, AST, and GGT (all P values <0.05), and all four liver enzymes were positively associated with HTG (all P values <0.05). Mediation analysis revealed that liver enzymes (ALT, AST, and GGT) may mediate the associations of 5AL and 7AL with HTG (all P values <0.05). This study identified a positive association between aldehyde co-exposure and HTG, which may be partially mediated by liver enzymes.

Comparative evaluation of mutagenic, genotoxic, cytotoxic, and antimicrobial effects of flavour and fragrance aldehydes, ketones, oximes, and oxime ethers.

Despite the large number of odoriferous compounds available, new ones with interesting olfactory characteristics are desired due to their potentially high commercial value. Here, we report for the first time mutagenic, genotoxic, and cytotoxic effects, and antimicrobial properties of low-molecular fragrant oxime ethers, and we compare their properties with corresponding oximes and carbonyl compounds. 24 aldehydes, ketones, oximes, and oxime ethers were evaluated for mutagenic and cytotoxic effects in Ames (using Salmonella typhimurium strains TA 98 with genotype hisD3052, rfa, uvrB, pKM101, and TA100 with genotype hisG46, rfa, uvrB, pKM101, concentration range: 0.0781-40 mg/mL) and MTS (using HEK293T cell line concentration of tested substances: 0.025 mM) assays. Antimicrobial evaluation was carried out against Bacillus cereus (ATCC 10876), Staphylococcus aureus (ATCC 6538), Enterococcus hirae (ATCC 10541), Pseudomonas aeruginosa (ATCC 15442), Escherichia coli (ATCC 10536), Legionella pneumophila (ATCC 33152); Candida albicans (ATCC 10231) and Aspergillus brasiliensis (ATCC 16404) with concentration range of tested substances 9.375 - 2.400 mg/mL. Furthermore, 5 representatives of carbonyl compounds, oximes, and an oxime ether (stemone, buccoxime, citral, citral oxime, and propiophenone oxime O-ethyl ether) were evaluated for genotoxic properties in SOS-Chromotest (concentration range: 7.8·10-5 - 5·10-3 mg/mL). All of the tested compounds did not exhibit mutagenic, genotoxic, or cytotoxic effects. Oximes and oxime ethers showed relevant antimicrobial activity against pathogenic species (P. aeruginosa, S. aureus, E.coli, L. pneumophila, A. brasiliensis, C. albicans) in the MIC range 0.075 - 2.400 mg/mL compared to the common preservative methylparaben with the MIC range 0.400-3.600 mg/mL. Our study shows that oxime ethers have the potential to be used as fragrant agents in functional products.

Lipid peroxide-derived short-chain aldehydes promote programmed cell death in wheat roots under aluminum stress.

Lipid peroxidation is a primary event in plant roots exposed to aluminum (Al) toxicity, which leads to the formation of reactive aldehydes. Current evidence demonstrates that the resultant aldehydes are integrated components of cellular damage in plants. Here, we investigated the roles of aldehydes in mediating Al-induced damage, particularly cell death, using two wheat genotypes with different Al resistances. Aluminum treatment significantly induced cell death, which was accompanied by decreased root activity and cell length. Al-induced cell death displayed granular nuclei and internucleosomal fragmentation of nuclear DNA, suggesting these cells underwent programmed cell death (PCD). During this process, caspase-3-like protease activity was extensively enhanced and showed a significant difference between these two wheat genotypes. Further experiments showed that Al-induced cell death was positively correlated with aldehydes levels. Al-induced representative diagnostic markers for PCD, such as TUNEL-positive nuclei and DNA fragmentation, were further enhanced by the aldehyde donor (E)-2-hexenal, but significantly suppressed by the aldehyde scavenger carnosine. As the crucial executioner of Al-induced PCD, the activity of caspase-3-like protease was further enhanced by (E)-2-hexenal but inhibited by carnosine in wheat roots. These results suggest that reactive aldehydes sourced from lipid peroxidation mediate Al-initiated PCD probably through activating caspase-3-like protease in wheat roots.

Cytotoxicity of a Novel Compound Produced in Foods via the Reaction of Amino Acids with Acrolein along with Formaldehyde.

Acrolein (ACR) and formaldehyde (FA) are toxic aldehydes co-produced in foods. This work found that amino acids, the nucleophiles ubiquitously existing in foods, can react simultaneously with them. Six amino acids, including γ-aminobutyric acid (GABA), glycine, alanine, serine, threonine, and glutamine, can scavenge ACR and FA at 37, 85, and 160 °C. GABA had the highest scavenging capacity for ACR and FA, by 79 and 13% at 37 °C for 2 h, and 99 and 48% at 160 °C for 30 min, respectively. Moreover, a new type of compound with a basic structure of 5-formyl-3-methylene-3,6-dihydropyridin was identified in all reactions and formed by 1 molecule of FA and amino acid and 2 molecules of ACR. The content of this compound was higher than that of free ACR in typical thermally processed foods. Moreover, the compounds produced from different amino acids showed different cytotoxicity values. In gastric epithelial and human intestinal epithelial cell lines, the cytotoxicity values of serine-sourced and threonine-sourced products were lower than that of ACR but higher than that of FA, whereas others had less toxicity compared with the two aldehydes. Considering that the content of serine-sourced products was the highest in almost all tested foods, their safety needs to be evaluated.

Electronic cigarette vaping with aged coils causes acute lung injury in mice.

Electronic cigarettes (e-cigarettes) have been used widely as an alternative to conventional cigarettes and have become particularly popular among young adults. A growing body of evidence has shown that e-cigarettes are associated with acute lung injury and adverse effects in multiple other organs. Previous studies showed that high emissions of aldehydes (formaldehyde and acetaldehyde) in aerosols were associated with increased usage of the same e-cigarette coils. However, the impact on lung function of using aged coils has not been reported. We investigated the relationship between coil age and acute lung injury in mice exposed to experimental vaping for 1 h (2 puffs/min, 100 ml/puff). The e-liquid contains propylene glycol and vegetable glycerin (50:50, vol) only. The concentrations of formaldehyde and acetaldehyde in the vaping aerosols increased with age of the nichrome coils starting at 1200 puffs. Mice exposed to e-cigarette aerosols produced from 1800, but not 0 or 900, puff-aged coils caused acute lung injury, increased lung wet/dry weight ratio, and induced lung inflammation (IL-6, TNF-α, IL-1ß, MIP-2). Exposure to vaping aerosols from 1800 puff-aged coils decreased heart rate, respiratory rate, and oxygen saturation in mice compared to mice exposed to air or aerosols from new coils. In conclusion, we observed that the concentration of aldehydes (formaldehyde and acetaldehyde) increased with repeated and prolonged usage of e-cigarette coils. Exposure to high levels of aldehyde in vaping aerosol was associated with acute lung injury in mice. These findings show significant risk of lung injury associated with prolonged use of e-cigarette devices.

In vitro and in vivo low-dose exposure of simulated cooking oil fumes to assess adverse biological effects.

Cooking oil fumes (COFs) represent a major indoor environmental pollutant and exhibit potent mutagenic or carcinogenic health effects caused by containing various heterocyclic aromatic amines (HAAs) and long-chain aldehydes. Despite some evaluation of the cumulative exposure of COFs to cancer cells under high concentration were evaluated, their biological adverse effects with low-dose exposure to healthy cells had been inadequately investigated. Herein, we firstly scrutinized the three selected typically toxic compounds of heterocyclic amine 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), 3,8-dimethylammidazo[4,5-f]quinoxalin-2-amine (MeIQx) and trans, trans-2,4-decadienal (TDA)) emitted from COFs. In vitro studies revealed that the PhIP, MeIQx and TDA aerosol particles were negligible toxicity to cancer cells (A549 and HepG-2) but strong cytotoxicity to normal healthy cells (HelF and L02) under 0.5-4 µg/mL low dose exposure based on the reactive oxygen species (ROS) mechanism. In vivo studies demonstrated that PhIP caused significant lung and liver damage after exposure to PhIP for 30 days with mice. These results indicated the direct proof of healthy cell damage even at low-dose exposure to HAAs and aldehydes.

Chemicals in European residences - Part I: A review of emissions, concentrations and health effects of volatile organic compounds (VOCs).

One of the more important classes of potentially toxic indoor air chemicals are the Volatile Organic Compounds (VOCs). However, due to a limited understanding of the relationships between indoor concentrations of individual VOCs and health outcomes, there are currently no universal health-based guideline values for VOCs within Europe including the UK. In this study, a systematic search was conducted designed to capture evidence on concentrations, emissions from indoor sources, and health effects for VOCs measured in European residences. We identified 65 individual VOCs, and the most commonly measured were aromatic hydrocarbons (14 chemicals), alkane hydrocarbons (9), aldehydes (8), aliphatic hydrocarbons (5), terpenes (6), chlorinated hydrocarbons (4), glycol and glycol ethers (3) and esters (2). The pathway of interest was inhalation and 8 individual aromatic hydrocarbons, 7 alkanes and 6 aldehydes were associated with respiratory health effects. Members of the chlorinated hydrocarbon family were associated with cardiovascular neurological and carcinogenic health effects and some were irritants as were esters and terpenes. Eight individual aromatic hydrocarbons, 7 alkanes and 6 aldehydes identified in European residences were associated with respiratory health effects. Of the 65 individual VOCs, 52 were from sources associated with building and construction materials (e.g. brick, wood products, adhesives and materials for flooring installation etc.), 41 were linked with consumer products (passive, electric and combustible air fresheners, hair sprays, deodorants) and 9 VOCs were associated with space heating, which may reflect the relatively small number of studies discussing emissions from this category of sources. A clear decrease in concentrations of formaldehyde was observed over the last few years, whilst acetone was found to be one of the most abundant but underreported species. A new approach based on the operational indoor air quality surveillance will both reveal trends in known VOCs and identify new compounds.

Short-chain aldehydes increase aluminum retention and sensitivity by enhancing cell wall polysaccharide contents and pectin demethylation in wheat seedlings.

Upon environmental stimuli, aldehydes are generated downstream of reactive oxygen species and thereby contribute to severe cell damage. In this study, using two wheat genotypes differing in aluminum (Al) tolerance, we investigated the effects of lipid peroxidation-derived aldehydes on cell wall composition and subsequent Al-binding capacities. The spatial accumulation of Al along wheat roots was found to the generation of reactive aldehydes, which are highly localized to the apical regions of roots. Elimination of aldehydes by carnosine significantly reduced Al contents in root tips, with a concomitant alleviation of root growth inhibition. In contrast, root growth and Al accumulation were exacerbated by application of the short-chain aldehyde (E)-2-hexenal. We further confirmed that cell wall binding capacity, rather than malate efflux or pH alteration strategies, is associated with the aldehyde-induced accumulation of Al. Scavenging of lipid-derived aldehydes reduced Al accumulation in the pectin and hemicellulose 1 (HC1) fractions of root cell walls, whereas exposure to (E)-2-hexenal promoted a further accumulation of Al, particularly in the cell wall HC1 fraction of the Al-sensitive genotype. Different strategies were introduced by pectin and HC1 to accumulate Al in response to aldehydes in wheat roots. Accumulation in pectin is based on a reduction of methylation levels in response to elevated pectin methylesterase activity and gene expression, whereas that in HC1 is associated with an increase in polysaccharide contents. These findings indicate that aldehydes exacerbate Al phytotoxicity by enhancing Al retention in cell wall polysaccharides.