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D-penicillamine (PA) is the primary chelator of choice to treat Wilson disease (WD). There are limitations in obtaining comprehensive data on PA metabolites in biological specimens by conventional approaches. Hence, the aim of the present was to identify the major hepatic PA metabolites and draw clear conclusions of the drug's xenobiotic in WD. Urine samples were collected from children with hepatic WD (n = 63, aged 14.8 ± 4 years) 5 h after PA administration (16.3 ± 3.8 mg/kg/day) and age-matched healthy volunteers comprised as controls (n = 30). High-resolution 800 MHz nuclear magnetic resonance spectroscopy (NMR) and mass spectrometry was applied to reveal unambiguous appraisals of different excretory by-products of PA metabolism. Four new products comprising penicillamine disulphide (PD), penicillamine cysteine disulphide (PCD), S -methyl penicillamine (SMP), and N -acetyl penicillamine (NAP) of PA xenobiotic metabolites were identified using high-resolution NMR spectroscopy. Quantitative levels of PCD and SMP were approximately three-fold higher than those of PD and NAP, respectively. High-resolution NMR identifies the major PA metabolites with certainty. Reduction, sulfation, and methylation are the predominant pathways of PA metabolism. There is a potential application for assessing therapeutic monitoring of chelation in hepatic WD. [Display omitted] • This study detected hepatic metabolites of D-penicillamine by proton NMR spectroscopy validated by LCMS. • Well-resolved resonances of D-penicillamine metabolites were unambiguously identified and quantified. • Sulfation and methylation are predominant metabolic pathways of D-pencillamine in hepatic Wilson disease. [ABSTRACT FROM AUTHOR]

Electronic cigarette and vaping-associated lung injury (EVALI) is a more recent type of lung injury. Initial complaints of presenting patients include respiratory, gastrointestinal, and constitutional symptoms. Chest x-ray imaging studies show bilateral opacities, and computed tomography scans show diffuse, ground-glass opacities often with subpleural spacing. Through rigorous public health surveillance, ultimately, it was determined to be highly associated with the vaping of black-market THC liquid containing vitamin E oil. This article will address the types of devices used, the chemistry involved in vaping, the possible adverse effects, and the circumstances that led to this phenomenon. • An e-cigarette is a type of a vaping device which allows a user to inhale the vapor of a liquid by pressing a button and generating an electrical current that heats a coil of wire in a reservoir of the liquid. • A xenobiotic is a substance that is foreign to the body and the first one used in a vaping device was nicotine. As vaping devices evolved more popular xenobiotics were used, with the most desirable being THC. • THC liquid sold in states where it is legal is quite expensive. Black market versions of THC were comparatively less expensive, and the thickening agent used to make the counterfeit seem genuine, vitamin E oil, appears to have caused EVALI. • Other possible causes of lung injury associated with vaping before EVALI have been investigated and include the vehicles, flavors, and even the bits of metal that are inhaled into the lungs. [ABSTRACT FROM AUTHOR]

The enzyme dehaloperoxidase (DHP) found in the marine worm Amphitrite ornata is capable of enzymatic peroxidation of 2,4-dichlorophenol (DCP) and 2,4-dibromophenol (DBP). There is also at least one parallel oxidative pathway and the major products 2-chloro-1,4-benzoquinone (2-ClQ) and 2-bromo-1,4-benzoquinone (2-BrQ) undergo aspontaneous secondary hydroxylation reaction. The oxidation and hydroxylation reactions have been monitored by UV–visible spectroscopy, High Performance Liquid Chromatography (HPLC), and mass spectrometry. Evidence from time-resolved UV–visible spectroscopy suggests that the hydroxylations of 2-ClQ and 2-BrQ in the presence of hydrogen peroxide (H 2 O 2) are non-enzymatic spontaneous processes approximately ∼10 and ∼ 5 times slower, respectively, than the enzymatic oxidation of DCP or DBP by DHP in identical solvent conditions. The products 2-ClQ and 2-BrQ have λ max at 255 nm and 260 nm, respectively. Both substrates, DCP and DBP, react to form a parallel product peaked at 240 nm on the same time scale as the formation of 2-ClQ and 2-BrQ. The 240 nm band is not associated with the hydroxylation process, nor is it attributable to the catechol 3,5-dihalobenzene-1,3-diol observed by mass spectrometry. One possible explanation is that muconic acid is formed as a decomposition product, which could follow decomposition either the catechol or hydroxyquinone. These reactions give a more complete understanding of the biodegradation of xenobiotics by the multi-functional hemoglobin, DHP, in Amphitrite ornata. The decomposition of 2,4-dihalophenols catalyzed by dehaloperoxidase was studied by UV–visible spectroscopy, High Performance Liquid Chromatography and Liquid Chromatography-Mass Spectrometry. Spectroscopic evidence suggests two major products, which we propose are 2-halo-1,4-benzoquinone and 2-halomuconic acid. These complementary techniques give a high-level view of the degradation of xenobiotics in marine ecosystems. The enzyme dehaloperoxidase dehalogenates chlorinated phenols to produce chlorinated-1,4-benzoquinones in the presence of H 2 O 2. A second step that involves hydroxylation of the 1,4-benzoquinone has also been observed. It apparently involves a spontaneous reaction of a second H 2 O 2 molecule with the quinone product. Time-resolved spectroscopic studies also show parallel reaction pathways. [Display omitted] • Peroxidase-catalyzed oxidation of phenol to quinone in the presence of H 2 O 2. • Spontaneous non-enzymatic hydroxylation of quinone also in the presence of H 2 O 2. • Hydroxylation of quinone is 10 times slower than the enzymatic oxidation of phenol. • Application of Singular Value Decomposition analysis to understand complex reactions. • Reactions monitored by UV–visible spectroscopy, HPLC, mass spectrometry [ABSTRACT FROM AUTHOR]

Le génome humain présente des variations de séquence pouvant modifier l'efficacité d'un traitement médicamenteux ou le risque d'effets indésirables associé à sa prise. Elles concernent en particulier les gènes codant les enzymes de métabolisme des médicaments. Deux approches sont utilisées pour évaluer la capacité métabolique d'un individu vis-à-vis d'une enzyme donnée, le phénotypage et le génotypage. La seconde nécessite le recueil préalable d'un échantillon biologique à partir duquel est extrait, purifié et analysé l'acide désoxyribonucléique génomique de la personne. The human genome presents sequence variations that can modify the efficacy of a drug treatment or the risk of adverse effects associated with its use. They concern in particular the genes coding for drug metabolism enzymes. Two approaches are used to evaluate the metabolic capacity of an individual with respect to a given enzyme: phenotyping and genotyping. The latter requires the prior collection of a biological sample from which the individual's genomic deoxyribonucleic acid is extracted, purified and analyzed. [ABSTRACT FROM AUTHOR]

Metabolic dysfunction-associated steatotic liver disease (MASLD) affects one-third of the global population. Understanding the metabolic pathways involved can provide insights into disease progression and treatment. Untargeted metabolomics of livers from mice with early-stage steatosis uncovered decreased methylated metabolites, suggesting altered one-carbon metabolism. The levels of glycine, a central component of one-carbon metabolism, were lower in mice with hepatic steatosis, consistent with clinical evidence. Stable-isotope tracing demonstrated that increased serine synthesis from glycine via reverse serine hydroxymethyltransferase (SHMT) is the underlying cause for decreased glycine in steatotic livers. Consequently, limited glycine availability in steatotic livers impaired glutathione synthesis under acetaminophen-induced oxidative stress, enhancing acute hepatotoxicity. Glycine supplementation or hepatocyte-specific ablation of the mitochondrial SHMT2 isoform in mice with hepatic steatosis mitigated acetaminophen-induced hepatotoxicity by supporting de novo glutathione synthesis. Thus, early metabolic changes in MASLD that limit glycine availability sensitize mice to xenobiotics even at the reversible stage of this disease. [Display omitted] • Altered one-carbon metabolism occurs in the early reversible stage of MASLD • Limited glycine in hepatic steatosis drives redox stress and acetaminophen toxicity • Serine synthesis via hepatocyte SHMT2 causes glycine depletion in hepatic steatosis • Elevating glycine levels by diet or genetic means alleviates acetaminophen toxicity Ghrayeb et al. reveal enhanced serine synthesis via reversed serine hydroxymethyltransferase 2 (SHMT2) activity in hepatic steatosis, uncovering a mechanism for the commonly observed glycine decrease in metabolic dysfunction-associated steatotic liver disease (MASLD). This restricts glutathione synthesis and causes acetaminophen hypersensitivity, which is alleviated by dietary or genetic glycine elevation. [ABSTRACT FROM AUTHOR]

Along with the typical biochemical alterations that occur during pregnancy, certain metabolic changes might be associated with the development of several psychiatric disorders, including postpartum depression (PPD), which is the most common type of psychiatric disorder during pregnancy or first postpartum year, and it develops in about 15% of women. Metabolomics is a rapidly developing discipline that deals with the metabolites as the final products of all genetically controlled biochemical pathways, highly influenced by external and internal changes. The aim of this paper was to review the published studies whose results suggest or deny a possible association between the fine regulation of the metabolome and PPD, enabling conclusions about whether metabolomics could be a useful tool in defining the biochemical pathways directly involved in the etiology, diagnosis and course of PPD. Beside numerous hormonal changes, a lot of different metabolic pathways have been discovered to be affected in women with PPD or associated with its development, including alterations in the energy metabolism, tryptophan and amino acid metabolism, steroid metabolism, purine cycle, as well as neurotransmitter metabolism. Additionally, metabolomics helped in defining the association between PPD and the exposure to various endocrine disrupting metabolites during pregnancy. Finally, metabolome reflects different PPD therapies and exposure of fetus or breastfed infants to pharmacotherapy prescribed to a mother suffering from PPD. This review can help in creating the picture about metabolomics' broad application in PPD studies, but it also implies that its potential is still not completely used. [Display omitted] • Pregnancy associated hormonal changes lead to postpartum depression. • Altered energy and amino acid metabolisms are associated with postpartum depression. • Purine cycle and neurotransmitter metabolism are disrupted in postpartum depression. • Exposure to xenobiotics during pregnancy might contribute to postpartum depression. • Metabolomes of mother and child can reflect mother's antidepressant therapy. [ABSTRACT FROM AUTHOR]

Abstract The variations of haematological parameters hematocrit, hemoglobin concentration, leukocyte and erythrocyte count have been used as pollution and physiological indicators of organic dysfunction in both environmental and aquaculture studies. These parameters are commonly applied as prognostic and diagnostic tools in fish health status. However, there are both extrinsic and intrinsic factors to consider when performing a blood test, because a major limitation for field researchers is that the "rules" for animal or human haematology do not always apply to wildlife. The main objective of this review is to show how some environmental and xenobiotic factors are capable to modulating the haematic cells. Visualizing the strengths and limitations of a haematological analysis in the health assessment of wild and culture fish. Finally, we point out the importance of the use of mitochondrial activities as part of haematological evaluations associated to environment or aquaculture stress. Graphical abstract Unlabelled Image Highlights • Haematology can evaluate normal blood cells variation by intrinsic or extrinsic factors. • Fish blood cells alteration can be observed through eritrogram and leukogram. • Haematological parameters can be indicator of environmental quality. • Haematologic evaluation may assist the veterinary staff with detecting disease in fish. • Mitochondrial activity can be a good indicator of fish health state. • Mitochondria dysfunction may be associated with anemia development. [ABSTRACT FROM AUTHOR]

Two volatile alkaloids, methyl (MMA) and isopropyl N -methylanthranilates (IMA), identified in the essential oil of Choisya ternata Kunth (Rutaceae), have been proven to possess polypharmacological properties (antinociceptive, anti-inflammatory, gastro-, hepato-, nephroprotective activities, anxiolytic and antidepressant properties, and likewise an effect on diazepam-induced sleep). In the continuation of our investigation of their urinary-metabolite profiles, we performed GC-MS analyses of the diethyl-ether extracts of selected tissues (liver, kidneys, heart, brain, lungs, quadriceps femoris muscle, and spleen) of rats intraperitoneally treated with MMA or IMA (2 g kg−1). Organ-metabolite profiles of MMA and IMA were qualitatively mutually analogous (varying only in the alcohol moiety of the metabolites), and generally analogous to their urinary-metabolite profiles. The greatest diversity and the highest overall amount of anthranilate metabolites was found in the hepatic tissue. The principal anthranilate-related compounds in the organs of rats treated with MMA, among 12 detected, were the products of ester hydrolysis, N -methylanthranilic and anthranilic acids. In the tissues of IMA-treated rats, among 16 compounds, the most abundant ones were the unmetabolized IMA and N -methylanthranilic acid. A collection of the compositional data regarding the anthranilate-related metabolites was statistically treated by multivariate statistical analysis that provided a better insight into the possible biotransformation pathways. Image 1 • Metabolism of methyl (MMA) and isopropyl N -methylanthranilates (IMA) was investigated. • GC-MS analyses of the Et 2 O extracts of the homogenates of the chosen tissues of MMA/IMA-treated rats were performed. • Organ-metabolite profiles of MMA and IMA were qualitatively analogous and analogous to their urinary-metabolite profiles. • Products of ester group hydrolysis and the unmetabolized compounds were the major anthranilates detected in the organs. • Multivariate statistical analysis pinpointed to specific connections between the analyzed xenobiotic metabolites. [ABSTRACT FROM AUTHOR]

Highlights • Metalloproteomic study in muscle samples of fish. • P. squamosissimus (carnivorous species) demonstrate highest mercury concentration. • Nineteen mercury-associated proteins were identified by ESI-MS/MS. • Three protein identified in the protein spots presented mercury biomarkers properties. Abstract Mercury has the ability to bind to a variety of biomolecules, which can compromise its structure and functionality and thus promote its toxic effects. The aim of this study is to identify possible mercury biomarkers in muscle samples of Plagioscion squamosissimus (carnivorous fish) and Colossoma macropomum (omnivorous fish), from the Amazon region. The muscle proteome of fish species was separated by two-dimensional polyacrylamide gel electrophoresis (2D-PAGE), and the total mercury concentrations in protein spots were determined by graphite furnace atomic absorption spectrometry (GFAAS). The protein spots containing mercury were characterized by electrospray ionization tandem mass spectrometry (ESI-MS/MS). The mercury concentrations in the protein spots were in the range of 1.10 ± 0.02–23.90 ± 0.33 μg g−1. The proteins phosphoglycerate mutase 2 (P. squamosissimus), hemoglobin β and cytochrome P450scc (C. macropomum), identified by ESI-MS/MS and showing the highest values of mercury concentration, may be considered possible mercury biomarkers. [ABSTRACT FROM AUTHOR]

Abstract Birds are exposed to many xenobiotics during their lifetime. For accurate prediction of xenobiotic-induced toxic effects on avian species, it is necessary to understand metabolic capacities in a comprehensive range of bird species. However, there is a lack of information about avian xenobiotic metabolizing enzymes (XMEs), particularly in wild birds. Uridine diphosphate glucuronosyltransferase (UGT) is an XME that plays an important role in phase II metabolism in the livers of mammals and birds. This study was performed to determine the characteristics of UGT1E isoform in avian species, those are related to mammals UGT 1A. To understand the characteristics of avian UGT1E isoforms, in vitro metabolic activity and genetic characteristics were investigated. Furthermore, mRNA expression levels of all chicken UGT1E isoforms were measured. On in vitro enzymatic analysis, the white-tailed eagle, great horned owl, and Humboldt penguin showed lower UGT-dependent activity than domestic birds. In synteny analysis, carnivorous birds were shown to have fewer UGT1E isoforms than herbivorous and omnivorous birds, which may explain why they have lower in vitro UGT activity. These observations suggested that raptors and seabirds, in which UGT activity is low, may be at high risk if exposed to elevated levels of xenobiotics in the environment. Phylogenetic analysis suggested that avian UGT1Es have evolved independently from mammalian UGT1As. We identified the important UGT isoforms, such as UGT1E13, and suspected their substrate specificities in avian xenobiotic metabolism by phylogenetic and quantitative real-time PCR analysis. This is the first report regarding the genetic characteristics and interspecies differences of UGT1Es in avian species. Graphical abstract Unlabelled Image Highlights • There is a lack of information about avian xenobiotic metabolizing enzymes (XMEs). • Uridine diphosphate glucuronosyltransferase 1E family (UGT1E) is an XME that plays an important role in phase II metabolism in birds. • Based on in vitro enzymatic analysis, carnivorous birds showed lower UGT1E activity than domestic birds. • Those observations suggested that carnivorous species may be at high risk if exposed to xenobiotics in the environment. [ABSTRACT FROM AUTHOR]

• 2,4-D concentrations used provoked oxidative stress in shoots but not in roots. • Tomato plants were able to tolerate and conjugate 2,4-D at the shoot level. • It differentially activated protective mechanisms on an organ-dependent manner. • Reduced glutathione was the most important metabolite in response to 2,4-D exposure. In the last 60 years, auxinic herbicides like 2,4-dichlorophenoxyacetic acid (2,4-D) have been among the widest and successful herbicides used in agriculture because it is a selective herbicide that kills dicots and mimics the natural plant phytohormone indol-3-acetic acid (IAA) at the molecular level. In spite of industry attempts to reformulate 2,4-D-based herbicides and reduce their off-target movement, damage has been reported on sensitive plants, like tomato, at low ratesdi. Therefore, it is important to study the responses of such species to such conditions so that yield losses can be avoided or, at least, reduced. It is known that ethylene, abscisic acid (ABA) and reactive oxygen species (ROS) play a central role in 2,4-D toxicity, leading to numerous unbeneficial changes in plant tissues. Yet, how glutathione-related defense- and/or stress-related genes' expressions are affected needs to be more studied. In this study, tomato plants (Solanum lycopersicum L.) were used to determine the expression and participation of the different GST phi class gene family members, plus the plans' antioxidant system, in response to 2,4-D. When tomato plants were root-treated with 2.26 mM 2,4-D for 48 h, H 2 O 2 and O 2 •− levels increased in shoots. Contrarily, in roots, 2,4-D did not provoke clear symptoms of oxidative stress, as lipid peroxidation, H 2 O 2 and O 2 •− levels decreased. Despite the difference in ROS levels observed in both organs, the exposure of tomato plants to 2,4-D lead to the activation of key antioxidant enzymes in both organs, apart from superoxide dismutase (SOD), whose activity increased only in roots, while ascorbate peroxidase (APX) and catalase (CAT) activities increased in both. Also, tomato plants responded to 2.26 mM 2,4-D by increasing Ascorbate (AsA) levels in both organs while an increase in Glutathione (GSH) was only observed in shoots. The herbicide increased both the synthesis and the regeneration of GSH, as well as its usage to conjugate 2,4-D, as shoot γ-glutamyl-cysteinyl synthetase (γ-ECS), glutathione reductase (GR) and glutathione S-transferase (GST) activities increased. Shoot GST increased activity was due to an increased expression of SlGSTF4 and SlGSTF5 , while no SlGSTF s increased their expression in roots. Shoots and roots of tomato plants were differentially affected by 2.26 mM 2,4-D, with 2,4-D detoxification occurring predominantly in leaves, with the specific participation of the GST phi class members SlGSTF4 and SlGSTF5. Also, this study reinforces the notion that the cultivation of tomato in 2,4-D-contaminated soils may result in yield reduction. [ABSTRACT FROM AUTHOR]

The calanoid copepod Acartia tonsa is a reference species in standardized ecotoxicology bioassay. Despite this interest, there is a lack of knowledge on molecular responses of A. tonsa to contaminants. We generated a de novo assembled transcriptome of A. tonsa exposed 4 days to 8.5 and 17 mg/L nickel nanoparticles (NiNPs), which have been shown to reduce egg hatching success and larval survival but had no effects on the adults. Aims of our study were to 1) improve the knowledge on the molecular responses of A. tonsa copepod and 2) increase the genomic resources of this copepod for further identification of potential biomarkers of NP exposure. The de novo assembled transcriptome of A. tonsa consisted of 53,619 unigenes, which were further annotated to nr, GO, KOG and KEGG databases. In particular, most unigenes were assigned to Metabolic and Cellular processes (34–45%) GO terms, and to Human disease (28%) and Organismal systems (23%) KEGG categories. Comparison among treatments showed that 373 unigenes were differentially expressed in A. tonsa exposed to NiNPs at 8.5 and 17 mg/L, with respect to control. Most of these genes were downregulated and took part in ribosome biogenesis, translation and protein turnover, thus suggesting that NiNPs could affect the copepod ribosome synthesis machinery and functioning. Overall, our study highlights the potential of toxicogenomic approach in gaining more mechanistic and functional information about the mode of action of emerging compounds on marine organisms, for biomarker discovering in crustaceans. [ABSTRACT FROM AUTHOR]

Abstract Mitochondrial DNA mutations in genes encoding respiratory complex I polypeptides can cause Leber hereditary optic neuropathy. Toxics affecting oxidative phosphorylation system can also cause mitochondrial optic neuropathy. Some complex I inhibitors found in edible plants might differentially interact with these pathologic mutations and modify their penetrance. To analyze this interaction, we have compared the effect of rotenone, capsaicin and rolliniastatin-1 on cybrids harboring the most frequent Leber hereditary optic neuropathy mutations and found that m.3460G > A mutation increases rotenone resistance but capsaicin and rolliniastatin-1 susceptibility. Thus, to explain the pathogenicity of mitochondrial diseases due to mitochondrial DNA mutations, their potential interactions with environment factors will have to be considered. Highlights • Some mitochondrial DNA (mtDNA) mutations cause Leber hereditary optic neuropathy (LHON). • Some oxidative phosphorylation system inhibitors cause mitochondrial optic neuropathies. • Food derived xenobiotics modify the penetrance of LHON mtDNA mutations. • The m.3460G > A mutation increases rotenone resistance but capsaicin and rolliniastatin-1 susceptibility. • Gene-environment interactions must be considered to explain mitochondrial disease pathogenicity. [ABSTRACT FROM AUTHOR]

The wide ranges of uses for acetophenone make it more available and expected to accumulate in the biosphere, where consequently it can threat ecosystems. To remediate this problem, the use of Solanum nigrum L. plants for the clean-up of acetophenone-contaminated sites was explored. Also, plant root and shoot biometry and metabolism where assayed to better understand the effects of this organic compound and to pinpoint possible metabolic pathways to be targeted for future manipulations for increasing this plant species' remediation efficiency. Although undergoing through some stress, detected by increases in ROS and lipid peroxidation in both organs, plants were able to rapidly eliminate all acetophenone from the nutrient solution after 7 days of exposure, being this compound mainly detoxified at the root level. Additionally, acetophenone lead to a differential metabolic response in roots and shoots, where antioxidant mechanisms where differentially activated, while nitrogen assimilation was repressed in shoots and activated in roots. These results confirm that S. nigrum is a good phytoremediation tool for acetophenone and suggest that enhancing shoot GS activity may provide more nitrogen precursors for the synthesis of thiolated proteins and glutathione to increase tolerance to acetophenone in roots and shoots, respectively. [ABSTRACT FROM AUTHOR]

Hairy roots induced by Agrobacterium rhizogenes are well established models to study the metabolism of xenobiotics in plants for phytoremediation purposes. However, the model requires special skills and resources for growing and is a time-consuming process. The roots induction process alters the genetic construct of a plant and is known to express genes that are normally absent from the non-transgenic plants. In this study, we propose and establish a non-transgenic maize root model to study xenobiotic metabolism in plants for phytoremediation purpose using azoxystrobin as a xenobiotic compound. Maize roots were grown aseptically in Murashige and Skoog medium for two weeks and were incubated in 100 μM azoxystrobin solution. Azoxystrobin was taken up by the roots to the highest concentration within 15 min of treatment and its phase I metabolites were also detected at the same time. Conjugated metabolites of azoxystrobin were detected and their identities were confirmed by enzymatic and mass spectrometric methods. Further, azoxystrobin metabolites identified in maize root culture were compared against azoxystrobin metabolites in azoxystrobin sprayed lettuce grown in green house. A very close similarity between metabolites identified in maize root culture and lettuce plant was obtained. The results from this study establish that non-transgenic maize roots can be used for xenobiotic metabolism studies instead of genetically transformed hairy roots due to the ease of growing and handling. [ABSTRACT FROM AUTHOR]

Erythrocytes are the main cells in circulation. They are devoid of internal membrane structures and easy to be isolated and handled providing a good model for different assays. Red blood cells (RBCs) plasma membrane is a multi-component structure that keeps the cell morphology, elasticity, flexibility and deformability. Alteration of membrane structure upon exposure to xenobiotics could induce various cellular abnormalities and releasing of intracellular components. Therefore the morphological changes and extracellular release of haemoglobin [hemolysis] and increased content of extracellular adenosine triphosphate (ATP) [as signs of membrane stability] could be used to evaluate the cytotoxic effects of various molecules. The nucleated RBCs from birds, fish and amphibians can be used to evaluate genotoxicity of different xenobiotics using comet, DNA fragmentation and micronucleus assays. The RBCs could undergo programmed cell death (eryptosis) in response to injury providing a useful model to analyze some mechanisms of toxicity that could be implicated in apoptosis of nucleated cells. Erythrocytes are vulnerable to peroxidation making it a good biological membrane model for analyzing the oxidative stress and lipid peroxidation of various xenobiotics. The RBCs contain a large number of enzymatic and non-enzymatic antioxidants. The changes of the RBCs antioxidant capacity could reflect the capability of xenobiotics to generate reactive oxygen species (ROS) resulting in oxidative damage of tissue. These criteria make RBCs a valuable in vitro model to evaluate the cytotoxicity of different natural or synthetic and organic or inorganic molecules by cellular damage measures. [ABSTRACT FROM AUTHOR]

Efficient biodegradation of 5-tolyltriazole (5-TTri) in wastewater treatment would minimize its potential detrimental effects on aquatic systems. Therefore, in order to profile 5-TTri biodegrading activated sludge communities (ASC) by DGGE and NGS, acclimation experiments with (i) easily degradable substrates, and (ii) various complex substrates mimicking wastewater conditions were performed. DGGE revealed four genera: Aminobacter (family Phyllobacteriaceae ), Flavobacterium (family Flavobacteriaceae ), Pseudomonas (family Pseudomonaceae ), and Hydrogenophaga (family Comamonadaceae ). Metagenomics (DNA) revealed the dominant families Alcaligenaceae , Pseudomonadaceae and Comamonadaceae that also represented the most active families at the RNA level (metatranscriptomics), which might indicate their importance for 5-TTri biodegradation. ASC acclimation and the composition of the substrate significantly affected 5-TTri biodegradation and the development of biodegrading communities. Using acetate only, a moderate 5-TTri degrading community was detected with a very low biodiversity and Pseudomonas spp. as dominant organisms. In contrast, setups fed ‘sludge supernatant’ (a complex substrate) efficiently biodegraded 5-TTri and formed a more diverse microbial community but with Hydrogenophaga spp. as the dominant group. Finally, a hypothetical 5-TTri biodegradation pathway was constructed based exclusively on the detected, biodegradation-related, Hydrogenophaga spp. genes. [ABSTRACT FROM AUTHOR]

Alphamethrin is one of the extensively used pyrethroids. Its non-specific mode-of-action might affect the non-target-organisms. Its toxicity data on aquatic organisms are lacking. We determined the toxicity (35 days) of alphamethrin (0.6 µg/L and 1.2 µg/L) on non-target-organisms by evaluating the efficiency of hematological, enzymological and antioxidants biomarkers of Cyprinus carpio. Compared with the control group, the efficiency of the biomarkers studied was significantly (p < 0.05) impaired in the alphamethrin treated groups. Alphamethrin-toxicity altered hematology, transaminases and the potency of LDH of fish. ACP and ALP activity and biomarkers of oxidative stress in the gills, liver and muscle tissues were affected. IBRv2 index reveals that the biomarkers were inhibited. The observed impairments were the toxicity effects of alphamethrin with respect to concentration and time. The effectiveness of biomarkers for alphamethrin toxicity was like the toxicity data available on other banned insecticides. Alphamethrin could cause multiorgan toxicity on aquatic organisms at µg/L level. [Display omitted] • Toxicity of alphamethrin on freshwater fish was investigated (35 days). • Alphamethrin affected the effectiveness of the biomarkers investigated. • Alphamethrin is a multiorgan toxin. • Blood and tissue biomarkers were comprehensively evaluated by IBRv2 index. [ABSTRACT FROM AUTHOR]

The biodegradation of microcystins (MCs) by bacteria constitutes an important process in freshwater ecosystems to prevent the accumulation of toxins. However, little is known about the diversity and the seasonal dynamics of the bacterial community composition (BCC) involved in the degradation of MCs in nature. To explore these BCC shifts, high-throughput sequencing was used to analyse the 16S rRNA, mcy E and mlr A genes during a year in a freshwater reservoir with a toxic cyanobacterial bloom episode. The analysis of the mcy E and mlr A genes from water samples revealed the coexistence of different MC-producing and MC-degrading genotypes, respectively. The patchy temporal distribution of the mlr A genotypes (from the families Sphingomonadaceae and Xanthomonadaceae ) suggests their dissimilar response to environmental conditions and the influence of other factors besides the MCs that may control their presence and relative abundance. During the maximum toxic cyanobacterial biomass and cell lysis, other bacterial taxa that lack mlr genes increased their relative abundance. Among these bacteria, those with a recognized role in the degradation of xenobiotic and other complex organic compounds (e.g., orders Myxococcales , Ellin6067 , Spirobacillales and Cytophagales ) were the most representative and suggest their possible involvement in the removal of MCs in the environment. [ABSTRACT FROM AUTHOR]

Two volatile alkaloids, isopropyl N -methylanthranilate (IMA) and methyl N -methylanthranilate (MMA), present in the human diet and cosmetic products, were recently demonstrated to possess important pharmacological activities. While MMA is considered to be phototoxic, there is scarce data on the toxicity of IMA. Herein, we analyzed urinary metabolites of IMA and MMA in rats (200 mg kg −1 , i.p. , 7 days) by combining three different approaches: 1) preparative chromatography, 2) synthesis, and 3) SPR. The preparative approach, Sephadex LH-20 chromatography of the extract of urine samples of IMA treated animals, in conjunction with NMR, enabled the identification of 16 different anthranilate derivatives, among which products of aromatic core hydroxylation (isopropyl 5-hydroxy- N -methylanthranilate, isopropyl 5-hydroxyantranilate, isopropyl 3-hydroxyantranilate) were the major ones. The first application of the synthetic/combinatorial approach led to a successful identification of MMA metabolites, where 2-(methylamino)benzamide and N -methylanthranilic acid were the principal ones, among 14 others. Generally, MMA and IMA undergo analogous biotransformation pathways; however, MMA predominantly underwent chemical conversions of the ester group, i.e. transformation into derivatives of anthranilamide and anthranilic acid, while the major metabolic pathway of IMA was hydroxylation of the aromatic core. Additionally, pathohistological examinations revealed no signs of liver toxicity, or other signs of toxicity. [ABSTRACT FROM AUTHOR]

Two stages of selection from a pool of 56 fatty acids analyzed in Helix pomatia yielded a set of 12 biomarker acids undergoing significant changes in contact with three microdoses of toxic substances, i.e. three molluscicides containing metaldehyde, methiocarb, and potassium chloride (PC). The proposed palette of acids, including saturated fatty acids (SFA), monounsaturated fatty acids (MUFA), and polyunsaturated fatty acids (PUFA), determined separately in the foot tissues and hepatopancreas of Gastropoda , can be used in ecotoxicological research as a reliable test of the effect of trace doses of stressors. The final set of the biomarker FA comprised C16:0; C18:0; C23:0; C18:1 n-9; C20:1 n-9; C18:2 n-6; C18:3 n-3; C20:2; C20:4 n-6; C20:5 n-3; C22:4 n-6; and C22:5 n-3. A clear physiological response manifested as changes in the content of fatty acids (FA) was observed in the snails even in the case of the lowest doses of the pollutants. All experimental factors analyzed, i.e., the dose (5, 10, or 15 μl 0.01% w/v concentration) and the type of preparation (metaldehyde, methiocarb or PC), had a significant (p ≤ 0.01) impact on the FA composition of the foot and hepatopancreas. Limitation of the analysis to a narrow pool of reactive FA meets the requirements of parameters of biomarkers of exposure and facilitates and accelerates visualization of the bioindicator organism's response to the presence of the stressor in the environment. [ABSTRACT FROM AUTHOR]

This study explores the effect of tributyltin (TBT) treatment on lipid homeostasis of D. magna using chemometric methods. The experimental design included two factors ‘time’ and ‘dose’ of TBT, and lipids were measured in replicate samples for each combination of factors. This study represents a case of multivariate multi-set data, obtained using a two factorial balanced design and explored using different multivariate chemometric techniques, to have an insight into data patterns, to separate main sources of variance and to identify lipid profiles associated with TBT dose. ANOVA- Simultaneous Component Analysis (ASCA) allowed the separation of the two sources of variation, suggesting thatthe TBT dose affected the evolution of the concentrations of lipids over time, although when the whole development process was considered, the interaction between time and dose factors was rather low. Multivariate Curve Resolution Alternating Least Squares (MCR-ALS) helped to resolve four distinct profiles associated with the different phases of D. magna development, showing changes in their lipids composition, and in their relation with TBT dose. A discussion of the meaning of these changes on lipid profiles and of their time evolution is performed. [ABSTRACT FROM AUTHOR]

Background: Enzyme-treated wheat bran (ETWB) contains a fermentable dietary fiber previously shown to decrease liver triglycerides (TGs) and modify the gut microbiome in mice. It is not clear which mechanisms explain how ETWB feeding affects hepatic metabolism, but factors (i.e., xenometabolites) associated with specific microbes may be involved.Objective: The objective of this study was to characterize ETWB-driven shifts in the cecal microbiome and to identify correlates between microbial changes and diet-related differences in liver metabolism in diet-induced obese mice that typically display steatosis.Methods: Five-week-old male C57BL/6J mice fed a 45%-lard-based fat diet supplemented with ETWB (20% wt:wt) or rapidly digestible starch (control) (n = 15/group) for 10 wk were characterized by using a multi-omics approach. Multivariate statistical analysis was used to identify variables that were strong discriminators between the ETWB and control groups.Results: Body weight and liver TGs were decreased by ETWB feeding (by 10% and 25%, respectively; P < 0.001), and an index of liver reactive oxygen species was increased (by 29%; P < 0.01). The cecal microbiome showed an increase in Bacteroidetes (by 42%; P < 0.05) and a decrease in Firmicutes (by 16%; P < 0.05). Metabolites that were strong discriminators between the ETWB and control groups included decreased liver antioxidants (glutathione and α-tocopherol); decreased liver carbohydrate metabolites, including glucose; lower hepatic arachidonic acid; and increased liver and plasma β-hydroxybutyrate. Liver transcriptomics revealed key metabolic pathways affected by ETWB, especially those related to lipid metabolism and some fed- or fasting-regulated genes.Conclusions: Together, these changes indicate that dietary fibers such as ETWB regulate hepatic metabolism concurrently with specific gut bacteria community shifts in C57BL/6J mice. It is proposed that these changes may elicit gut-derived signals that reach the liver via enterohepatic circulation, ultimately affecting host liver metabolism in a manner that mimics, in part, the fasting state. [ABSTRACT FROM AUTHOR]

Background Oxidant stress is arguably a universal feature in toxicology. Research studies on the role of oxidant stress induced by xenobiotic exposures have typically relied on the identification of damaged biomolecules using a variety of conventional biochemical and molecular techniques. However, there is increasing evidence that low-level exposure to a variety of toxicants dysregulates cellular physiology by interfering with redox-dependent processes. Scope of review The study of events involved in redox toxicology requires methodology capable of detecting transient modifications at relatively low signal strength. This article reviews the advantages of live-cell imaging for redox toxicology studies. Major conclusions Toxicological studies with xenobiotics of supra-physiological reactivity require careful consideration when using fluorogenic sensors in order to avoid potential artifacts and false negatives. Fortunately, experiments conducted for the purpose of validating the use of these sensors in toxicological applications often yield unexpected insights into the mechanisms through which xenobiotic exposure induces oxidant stress. General significance Live-cell imaging using a new generation of small molecule and genetically encoded fluorophores with excellent sensitivity and specificity affords unprecedented spatiotemporal resolution that is optimal for redox toxicology studies. This article is part of a Special Issue entitled Air Pollution, edited by Wenjun Ding, Andrew J. Ghio and Weidong Wu. [ABSTRACT FROM AUTHOR]

Tannery effluents constitute highly polluting residues, which can cause negative impacts to people’s health and the environment. However, studies that have investigated the effects of the exposure to these xenobiotics on the central nervous system of mammal experimental models are rare, the few that have been published focusing on the exposure via oral intake (ingestion of water containing tannery effluent concentrations). In this sense, and with the objective of expanding the knowledge beyond the neurotoxic effects observed when water contaminated by these xenobiotics is ingested, the neurobehavioral effects of dermal exposure of male C57Bl/6J and Swiss mice were analyzed. The animals were exposed to raw (wet blue-type) tannery effluent for two hours during five days, totalizing 15 days of exposure. Afterwards, the animals underwent the elevated plus-maze (predictive of anxiety) and the object recognition tests (identification of memory deficit). Our data show that the dermal exposure to the tannery effluent caused an anxiogenic behavior in these animals, when compared those that did not have direct contact with these xenobiotics. It was also observed that the animals exposed to the tannery effluent obtained lower novel object recognition indices, thus evidencing memory deficit and indicating a possible influence of the tannery effluent constituents in animal cognition. The present study attests the hypothesis that dermal exposure to tannery effluents containing neurotoxic substances causes behavioral disorders in C57Bl/6J and Swiss mice. [ABSTRACT FROM AUTHOR]

Human Cytochrome P450s (CYP450) are a group of heme-containing metalloenzymes responsible for recognition and metabolism of numerous xenobiotics, including drugs and environmental contaminants. CYP2B6, a member of CYP450, is well known for being a highly inducible and polymorphic enzyme and for its important role in the oxidative metabolism of environmental pollutants, such as the Polybrominated Diphenyl Ethers (PBDEs) and Polychlorinated Biphenyls (PCBs). However the mechanisms of interaction of PBDEs and PCBs with CYP2B6 is not entirely known. In this work, a computational approach was carried out to study the interactions of 41 POPs (17 PBDEs, 17 PCBs, and 7 Dioxins) with four CYP2B6 protein structures downloaded from PDB data base (PDB: 3UA5 , 3QOA , 3QU8 and 4I91 ) using molecular docking protocols with AutoDock Vina. The best binding affinity values (kcal/mol) were obtained for PBDE-99 (−8.5), PCB-187 (−9.6), and octachloro-dibenzo-dioxin (−9.8) that can be attributed to the hydrophobic interactions with important residues, such as Phe-363, in the catalytic site of CYP2B6. Molecular docking validation revealed the best values for PDB: 3UA5 (R = 0.622, p = 0.001) demonstrating the reliability of molecular docking predictions. The information obtained in this work can be useful in evaluating the modes of interaction of xenobiotic compounds with the catalytic site of CYP2B6 and provide insights on the important role of these enzymes in the metabolism of potentially toxic compounds in humans. [ABSTRACT FROM AUTHOR]

Two nuclear receptors, the pregnane X receptor (PXR) and the constitutive androstane receptor (CAR), participate in the xenobiotic detoxification system by regulating the expression of drug-metabolizing enzymes and transporters in order to degrade and excrete foreign chemicals or endogenous metabolites. This review aims to expand the perceived relevance of PXR and CAR beyond their established role as master xenosensors to disease-oriented areas, emphasizing their modulation by small molecules. Structural studies of these receptors have provided much-needed insight into the nature of their binding promiscuity and the important elements that lead to ligand binding. Reports of species- and isoform-selective activation highlight the need for further scrutiny when extrapolating from animal data to humans, as animal models are at the forefront of early drug discovery. This article is part of a Special Issue entitled: Xenobiotic nuclear receptors: New Tricks for An Old Dog, edited by Dr. Wen Xie. [ABSTRACT FROM AUTHOR]

The zebrafish embryo (ZFE) is increasingly used in ecotoxicology research but detailed knowledge of its metabolic potential is still limited. This study focuses on the xenobiotic metabolism of ZFE at different life-stages using the pharmaceutical compound clofibric acid as study compound. Liquid chromatography with quadrupole-time-of-flight mass spectrometry (LC-QToF-MS) is used to detect and to identify the transformation products (TPs). In screening experiments, a total of 18 TPs was detected and structure proposals were elaborated for 17 TPs, formed by phase I and phase II metabolism. Biotransformation of clofibric acid by the ZFE involves conjugation with sulfate or glucuronic acid, and, reported here for the first time, with carnitine, taurine, and aminomethanesulfonic acid. Further yet unknown cyclization products were identified using non-target screening that may represent a new detoxification pathway. Sulfate containing TPs occurred already after 3 h of exposure (7 hpf), and from 48 h of exposure (52 hpf) onwards, all TPs were detected. The detection of these TPs indicates the activity of phase I and phase II enzymes already at early life-stages. Additionally, the excretion of one TP into the exposure medium was observed. The results of this study outline the high metabolic potential of the ZFE with respect to the transformation of xenobiotics. Similarities but also differences to other test systems were observed. Biotransformation of test chemicals in toxicity testing with ZFE may therefore need further consideration. [ABSTRACT FROM AUTHOR]

Although it is known that tannery effluents constitute highly toxic pollutants whose effects in humans represent public health problems in several countries, studies involving experimental mammalian models are rare. In this context, the objective of the present study was to assess the effect of the exposure to tannery effluent on the memory of male and female Swiss mice. Animals of each sex were distributed into two experimental groups: the control group, in which the animals received only drinking water and the effluent group, in which the mice received 1% of gross tannery effluent diluted in water. The animals were exposed to the effluent by gavage, oral dosing, for 15 days, ensuring the administration of 0.1 mL of liquid (water or effluent)/10 g of body weight/day. On the 14th and 15th experimental days the animals were submitted to the object recognition test. It was observed that the new object recognition indices calculated for the animals exposed to the effluent (males and females) were significantly lower than those obtained with the control group. The exposure to tannery effluent caused memory deficit in Swiss mice in a similar way for both sexes, reinforcing previous findings that these pollutants affect the central nervous system. It contributes to the knowledge in the area by attesting harmful effects to the cognition of such animals. [ABSTRACT FROM AUTHOR]

While the biodegradation of 2,4,6-trinitrotoluene (TNT) via the release of nitrite is well established, mechanistic details of the reaction in mammals are unknown. To address this issue, we attempted to identify the enzyme from rat liver responsible for the production of nitrite from TNT. A NADPH-cytochrome P450 reductase (P450R) was isolated and identified from rat liver microsomes as the enzyme responsible for not only the release of nitrite from TNT but also formation of superoxide and 4-hydroxyamino-2,6-dinitrotoluene (4-HADNT) under aerobic conditions. In this context, reactive oxygen species generated during P450R-catalyzed TNT reduction were found to be, at least in part, a mediator for the production of 4-HADNT from TNT via formation of 4-nitroso-2,6-dinitrotoluene. P450R did not catalyze the formation of the hydride-Meisenheimer complex (H - -TNT) that is thought to be an intermediate for nitrite release from TNT. Furthermore, in a time-course experiment, 4-HADNT formation reached a plateau level and then declined during the reaction between TNT and P450R with NADPH, while the release of nitrite was subjected to a lag period. Notably, the produced 4-HADNT can react with the parent compound TNT to produce nitrite and dimerized products via formation of a Janovsky complex. Our results demonstrate for the first time that P450R-mediated release of nitrite from TNT results from the process of chemical interaction of TNT and its 4-electron reduction metabolite 4-HADNT. [ABSTRACT FROM AUTHOR]

This study aimed to investigate whether combined supplementation with vitamin C and vitamin E was able to modify the superoxide dismutase (SOD) and malondialdehyde (MDA) levels in the ovarium of rats exposed to rhodamine B. Twenty-five female Wistar albino rats were divided into five groups ( n = 5 each), including control (untreated group); rhodamine B group; rhodamine B group which received vitamin C (0.2 mg) + vitamin E (0.04 IU/g body weight); rhodamine B group which received vitamin C (0.4 mg) + vitamin E (0.04 IU/g body weight); and the rhodamine B group which received vitamin C (0.8 mg) + vitamin E (0.04 IU/g body weight). Analysis of MDA levels as a marker of lipid peroxidation was done spectrophotometrically. Analysis of SOD levels was done by enzyme-linked immunosorbent assay technically. Endometrial histology was analyzed in hematoxylin eosin staining. This increase in ovarian MDA was significantly ( p < 0.05) attenuated by the two highest dose treatments of combined vitamin C and vitamin E. Rhodamine B significantly decreased SOD levels compared to the untreated group. This decrease in ovarian SOD level was significantly attenuated by the second and third doses of the combined vitamin C and vitamin E. The vascular number and gland density were significantly lower in the rhodamine B group compared to the untreated control group ( p > 0.05). All doses also significantly prevented rhodamine B-induced decrease in the vascular number and gland density. In conclusion, the protective effect of combined vitamin C and vitamin E against ovarian and endometrial toxicity in rats receiving oral rhodamine B is due to inhibition of the lipid peroxidation, modulation of SOD levels, and the endometrium repairing effect. [ABSTRACT FROM AUTHOR]

Abstract The effect of age on larkspur poisoning of cattle is unknown. An experiment consisting of oral dosing of dried, ground, Delphinium barbeyi to ten Angus steers as yearlings, and again at two years was performed. There was a significant difference between the responses of yearling and two year old steers (P = 0.0015), with yearling steers being more susceptible. These results suggest that the adverse response of Angus cattle to larkspur is age-dependent. Highlights • Larkspurs ( Delphinium spp. ) are a significant problem for cattle grazing on rangelands of the western North America. • Oral dosing of dried, ground, Delphinium barbeyi to ten Angus steers as yearlings, and again at two years was performed. • There was a significant difference between the responses of yearling and two year old steers (P = 0.0015). [ABSTRACT FROM AUTHOR]

Occurrence of human carcinogen aflatoxin B1 (AFB1) in feed and foodstuffs is expected to increase in the next years due to climate change. This work aimed to assess the possible recovery of energy and nutrients from AFB1 contaminated corn through the integration of anaerobic digestion and composting. Pilot scale anaerobic digestion and composting of the digestate were carried out using AFB1 contaminated corn (100 µg g-1) and pig slurry. Biomethane yields, compost quality and AFB1 degradation were evaluated during the trials. Results of this research showed that anaerobic digestion and composting integration can represent a suitable solution for the safe valorisation of a hazardous waste like AFB1 contaminated corn. Neither biomethane yields (214 NL kg-1 VS) nor compost quality were affected from AFB1 contamination (i.e., C/N ratio and germination index of the compost were 10.8% and 100.9%, respectively). In addition, the mycotoxin was completely removed at the end of the process (the concentration was under the detection limit already after the active phase of composting). This confirms that AFB1 contaminated feed and foodstuffs might be safely treated in conventional anaerobic and composting facilities, without negative effects on process stability and products quality. [Display omitted] • AFB1 contaminated corn was treated by integrated anaerobic digestion and composting. • Biomethane yield (214 NL kg-1 VS) was not affected by AFB1 contamination. • Digestate composting completely removed AFB1 already after the active phase. • Compost was highly stabilized and mature (i.e., C/N ratio was 11 and GI was 101%). • Energy and nutrients can be effectively recovered from AFB1 contaminated corn. [ABSTRACT FROM AUTHOR]

The human pregnane X receptor (hPXR), a member of the nuclear receptor superfamily, senses xenobiotics and controls the transcription of genes encoding drug-metabolizing enzymes and transporters. The regulation of hPXR's transcriptional activation of its target genes is important for xenobiotic detoxification and endobiotic metabolism, and hPXR dysregulation can cause various adverse drug effects. Studies have implicated the putative phosphorylation site serine 350 (Ser 350 ) in regulating hPXR transcriptional activity, but the mechanism of regulation remains elusive. Here we investigated the transactivation of hPXR target genes in vitro and in vivo by hPXR with a phosphomimetic mutation at Ser 350 (hPXR S350D ). The S350D phosphomimetic mutation reduced the endogenous expression of cytochrome P450 3A4 (an hPXR target gene) in HepG2 and LS180 cells. Biochemical assays and structural modeling revealed that Ser 350 of hPXR is crucial for formation of the hPXR–retinoid X receptor alpha (RXRα) heterodimer. The S350D mutation abrogated heterodimerization in a ligand-independent manner, impairing hPXR-mediated transactivation. Further, in a novel humanized transgenic mouse model expressing the hPXR S350D transgene, we demonstrated that the S350D mutation alone is sufficient to impair hPXR transcriptional activity in mouse liver. This transgenic mouse model provides a unique tool to investigate the regulation and function of hPXR, including its non-genomic function, in vivo . Our finding that phosphorylation regulates hPXR activity has implications for development of novel hPXR antagonists and for safety evaluation during drug development. [ABSTRACT FROM AUTHOR]

11β-Hydroxysteroid dehydrogenase 1 (11β-HSD1) is an endoplasmic reticulum membrane enzyme with its catalytic site facing the luminal space. It functions primarily as a reductase, driven by the supply of its cosubstrate NADPH by hexose-6-phosphate dehydrogenase (H6PDH). Extensive research has been performed on the role of 11β-HSD1 in the regeneration of active glucocorticoids and its role in inflammation and metabolic disease. Besides its important role in the fine-tuning of glucocorticoid action, 11β-HSD1 is a multi-functional carbonyl reductase converting several 11- and 7-oxosterols into the respective 7-hydroxylated forms. Moreover, 11β-HSD1 has a role in phase I biotransformation reactions and catalyzes the carbonyl reduction of several non-steroidal xenobiotics. Recent observations from experiments using selective inhibitors and studies with transgenic mice indicated a role for 11β-HSD1 in oxysterol metabolism and in bile acid homeostasis, with evidence for glucocorticoid-independent effects on gene expression. This review focuses on the promiscuity of 11β-HSD1 to accept structurally distinct substrates and discusses recent progress mainly on non-glucocorticoid substrates. This article is part of a Special Issue entitled ‘Enzyme Promiscuity and Diversity’. [ABSTRACT FROM AUTHOR]

Red gourami ( Colisa labiosa ) have previously been shown to have low levels of pyrene-metabolizing activity. In this study, other pharmacokinetic factors of pyrene in C. labiosa were compared to those in Japanese medaka ( Oryzias latipes ). Results indicated that the two species labiosa absorbed pyrene in similar amounts. However, excretion of pyrene metabolites from C. labiosa over an 8-day period was lower than those from O. latipes . These findings show that C. labiosa has low ability to metabolize pyrene and to excrete pyrene and its metabolites from the body, and is therefore considered an accumulator of these chemicals. C. labiosa has unique characteristics with regard to pyrene pharmacokinetics. Knowledge about interspecies differences in pharmacokinetics is crucial in determining the endangered species to xenobiotic exposure. [ABSTRACT FROM AUTHOR]

Evaluating immunomodulatory effects of xenobiotics is an important component of the toxicity studies. Herein we report on the establishment of a novel in vitro test system for the immunotoxicity screening of xenobiotics based on human lymphoblastoid cell lines (LCLs). Four immunotoxic compounds; tributyltin chloride, cyclosporine A, benzo(a)pyrene and verapamil hydrochloride, as well as three immune-inert compounds; urethane, furosemide and mannitol were selected for characterization. The treatment of LCLs with immunosuppressive compounds resulted in reduced viability. The IC 50 values determined in human LCLs were in agreement with the data obtained for human peripheral mononuclear cells. Since cytokine production reflects lymphocytes responses to external stimuli, we evaluated the functional responses of LCLs by monitoring their pro-inflammatory and immunoregulatory cytokine production. Our findings prove that LCLs allowed for reliable differentiation between immunomodulatory and immune-inert compounds. Hence, pre-treatment with immunomodulatory compounds led to a decrease in the production of pro-inflammatory TNFα, IL-6 and immunoregulatory IL-2, IL-4, IL-10 and IFNγ cytokines, when compared to untreated ionomycin/PMA stimulated cells. Moreover, testing a panel of ten LCLs derived from unrelated healthy individuals reflects inter-individual variability in response to immunomodulatory xenobiotics. In conclusion, LCLs provide a novel alternative method for the testing of the immunotoxic effects of xenobiotics. [ABSTRACT FROM AUTHOR]

Endocrine disrupting chemicals (EDCs) are a group of compounds that affect the endocrine system, frequently found in everyday products and epidemiologically associated with several diseases. The purpose of this work was to develop EDCs DataBank, the only database of EDCs with three-dimensional structures. This database was built on MySQL using the EU list of potential endocrine disruptors and TEDX list. It contains the three-dimensional structures available on PubChem, as well as a wide variety of information from different databases and text mining tools, useful for almost any kind of research regarding EDCs. The web platform was developed employing HTML, CSS and PHP languages, with dynamic contents in a graphic environment, facilitating information analysis. Currently EDCs DataBank has 615 molecules, including pesticides, natural and industrial products, cosmetics, drugs and food additives, among other low molecular weight xenobiotics. Therefore, this database can be used to study the toxicological effects of these molecules, or to develop pharmaceuticals targeting hormone receptors, through docking studies, high-throughput virtual screening and ligand-protein interaction analysis. EDCs DataBank is totally user-friendly and the 3D-structures of the molecules can be downloaded in several formats. This database is freely available at http://edcs.unicartagena.edu.co . [ABSTRACT FROM AUTHOR]

The microbial communities from two upflow anaerobic sludge blanket (UASB) reactors treating synthetic wastewater supplemented with linear alkylbenzene sulfonate (LAS) (RS) and laundry wastewater (RL) were analyzed by pyrosequencing of 16S rRNA genes. A higher LAS degradation rate was observed in RL (82 ± 9%) than RS (45 ± 16%). A high proportion of the LAS removal rate (55–90%) was observed in the PS region for both reactors, most likely due to the low concentration of co–substrates and oxygen diffusion in this region. A microbiological analysis of samples taken at 112 days of operation from the sludge blanket (SB) and the phase–separator (PS) region of both reactors confirmed these findings. The distinct microbial communities found in each reactor resulting from the different wastewaters used were related to the LAS degradation rates obtained. The microbial community from reactor RL was more capable of degrading LAS, most likely because of the presence of xenobiotics. [ABSTRACT FROM AUTHOR]

Every day we are exposed to a cocktail of anthropogenic compounds many of which are biologically active and capable of inducing negative effects. The simplest way to monitor contaminants in a population is via human biomonitoring (HBM), however conventional targeted approaches require foreknowledge of chemicals of concern, often have compound specific extractions and provide information only for those compounds. This study developed an extraction process for human biomarkers of interest (BoE) in urine that is less compound specific. Combining this with an ultra-high resolution mass spectrometer capable of operating in full scan, and a suspect and non-targeted analysis (SS/NTA) approach, this method provides a more holistic characterization of human exposure. Sample preparation development was based on enzymatically hydrolysed urine spiked with 34 native standards and extracted by solid-phase extraction (SPE). HRMS data was processed by MzMine2 and 80% of standards were identified in the final data matrix using typical NTA data processing procedures. [Display omitted] • Enzymatic hydrolysis of phase II metabolites is the vital sample preparation step. • The method supports high-throughput HBM analysis of urine samples. • The method demonstrates low retention time drifts and high mass accuracies. • Limits of detection are relevant for HBM exposure studies. • 80% of the spiked standards were identified following the non-targeted workflow. [ABSTRACT FROM AUTHOR]

Nonylphenols (NPs) are toxic organic pollutants that cause deleterious effects in various ecosystems. It was formerly documented by us that the cosmopolitan non-ligninolytic fungus Metarhizium robertsii is capable of degrading 4- n -nonylphenol (4- n -NP) with significant efficiency (initial xenobiotic content 50 mg l −1 ). The present study revealed that M. robertsii is able to survive in the presence of high NPs amounts (up to 100 mg l −1 ), and the observed phenomenon is combined with intensive xenobiotic utilization. Additionally, the formation of small densely packed pellets that predominated during the efficient NP utilization process was observed. Larger pellets emerged in the cultures with “hairy” morphology, which indicated the removal process was complete. The observed changes in pellet morphology resulted from the detrimental influence of NPs on M. robertsii as evidenced by viability and cell ultrastructure. For the first time, this study documented the presence of this toxic substrate in the fungal cell wall. It is suggested that the M. robertsii morphological changes may serve as a biomarker for the progress of the intense NP utilization process. [ABSTRACT FROM AUTHOR]

Most members of the large ATP-binding cassette (ABC) gene family are transporters involved in substrate translocation across biological membranes. In eukaryotes, ABC proteins functioning as drug transporters are located in the plasma membrane and mediate the cellular efflux of a wide range of organic chemicals, with some transporters also transporting certain metals. As the enhanced expression of ABC drug transporters can confer multidrug resistance (MDR) to cancers and multixenobiotic resistance (MXR) to organisms from polluted habitats, these ABC family members are also referred to as MDR or MXR proteins. In mammals, ABC drug transporters show predominant expression in tissues involved in excretion or constituting internal or external body boundaries, where they facilitate the excretion of chemicals and their metabolites, and limit chemical uptake and penetration into "sanctuary" sites of the body. Available knowledge about ABC proteins is still limited in teleost fish, a large vertebrate group of high ecological and economic importance. Using transport activity measurements and immunochemical approaches, early studies demonstrated similarities in the tissue distribution of ABC drug transporters between teleosts and mammals, suggesting conserved roles of the transporters in the biochemical defence against toxicants. Recently, the availability of teleost genome assemblies has stimulated studies of the ABC family in this taxon. This review summarises the current knowledge regarding the genetics, functional properties, physiological function, and ecotoxicological relevance of teleostean ABC transporters. The available literature is reviewed with emphasis on recent studies addressing the tissue distribution, substrate spectrum, regulation, physiological function and phylogenetic origin of teleostean ABC transporters. [ABSTRACT FROM AUTHOR]

Pharmaceutical and personal care products (PPCPs) discharged with wastewater treatment effluents are a surface water quality concern. PPCPs are partially removed during wastewater treatment and biological transformation is an important removal mechanism. To investigate the potential for enhanced PPCP removal using bioaugmentation, bacteria were previously isolated from activated sludge capable of degrading PPCPs to ng/L concentrations. This study examined the degradation kinetics of triclosan and bisphenol A by five of these bacteria, both in pure culture and when augmented to activated sludge. Sorption coefficients were determined to account for the influence of partitioning during bioremoval. When the bacteria were added to activated sludge, degradation increased. Experimentally determined kinetic parameters were used to model a full-scale continuous treatment process, showing that low biomass could achieve reduced effluent PPCP concentrations. These results demonstrated that bioaugmentation may improve PPCP removal using established wastewater infrastructure under conditions of high solids partitioning. [ABSTRACT FROM AUTHOR]

Résumé: Un nombre croissant d’investigations cliniques et expérimentales indique que certains xénobiotiques peuvent aggraver les hépatopathies associées à l’obésité. En effet, différents médicaments, certains toxiques industriels et l’intoxication alcoolique peuvent majorer la stéatose dysmétabolique, ou accélérer la progression de cette stéatose en stéatohépatite non alcoolique. De plus, du fait de l’augmentation de l’activité de différents cytochromes P450 au cours des hépatopathies dysmétaboliques, certains xénobiotiques peuvent être biotransformés plus facilement en métabolites réactifs cytotoxiques et entraîner une cytolyse hépatique aiguë plus sévère. Des études cliniques et des recherches expérimentales sont maintenant nécessaires afin d’identifier tous les xénobiotiques qui sont particulièrement hépatotoxiques dans un contexte d’obésité et de déterminer les mécanismes mis en jeu. Cette problématique est d’autant plus importante si l’on considère la prévalence alarmante du surpoids et de l’obésité dans de nombreux pays, ainsi que le nombre important de médicaments administrés aux patients obèses pour le traitement de leurs pathologies dysmétaboliques. [Copyright &y& Elsevier]

Abstract: In a previous study we had shown that treatment of male Fischer rats with exogenous chemicals for three months resulted in prominent, mode-of-action dependent effects on liver microRNA (miRNA) (Koufaris et al., 2012). Here we investigated how the effects of chemicals on liver miRNA in male Fischer rats relate to the length and dose of exposure to phenobarbital (PB), a drug with multiple established hepatic effects. Importantly, although acute PB treatment (1–7 days) had significant effects on liver mRNA and the expected effects on the liver phenotype (transient hyperplasia, hepatomegaly, cytochrome P450 induction), limited effects on liver miRNA were observed. However, at 14 days of PB treatment clear dose-dependent effects on miRNA were observed. The main effect of PB treatment from days 1 to 90 on liver miRNA was found to be the persistent, progressive, and highly correlated induction of the miR-200a/200b/429 and miR-96/182 clusters, occurring after the termination of the xenobiotic-induced transient hyperplasia. Moreover, in agreement with their reported functions in the literature we found associations between perturbations of miR-29b and miR-200a/200b by PB with global DNA methylation and zeb1/zeb2 proteins respectively. Our data suggest that miRNA are unlikely to play an important role in the acute responses of the adult rodent liver to PB treatment. However, the miRNA responses to longer PB exposures suggest a potential role for maintaining liver homeostasis in response to sub-chronic and chronic xenobiotic-induced perturbations. Similar studies for more chemicals are needed to clarify whether the temporal and dose pattern of miRNA–toxicant interaction identified here for PB are widely applicable to other xenobiotics. [Copyright &y& Elsevier]