RESUMEN
Inhalation of PCB-contaminated air is increasingly recognized as a route for PCB exposure. Because limited information about the disposition of PCBs following inhalation exposure is available, this study investigated the disposition of 2,2',5,5'-tetrachlorobiphenyl (PCB52) and its metabolites in rats following acute, nose-only inhalation of PCB52. Male and female Sprague-Dawley rats (50-58 days of age, 210 ± 27 g; n = 6) were exposed for 4 h by inhalation to approximately 14 or 23 µg/kg body weight of PCB52 using a nose-only exposure system. Sham animals (n = 6) were exposed to filtered lab air. Based on gas chromatography-tandem mass spectrometry (GC-MS/MS), PCB52 was present in adipose, brain, intestinal content, lung, liver, and serum. 2,2',5,5'-Tetrachlorobiphenyl-4-ol (4-OH-PCB52) and one unknown monohydroxylated metabolite were detected in these compartments except for the brain. Liquid chromatography-high resolution mass spectrometry (LC-HRMS) analysis identified several metabolites, including sulfated, methoxylated, and dechlorinated PCB52 metabolites. These metabolites were primarily found in the liver (7 metabolites), lung (9 metabolites), and serum (9 metabolites) due to the short exposure time. These results demonstrate for the first time that complex mixtures of sulfated, methoxylated, and dechlorinated PCB52 metabolites are formed in adolescent rats following PCB52 inhalation, laying the groundwork for future animal studies of the adverse effects of inhaled PCB52.
Asunto(s)
Exposición por Inhalación , Bifenilos Policlorados , Ratas , Masculino , Femenino , Animales , Exposición por Inhalación/análisis , Ratas Sprague-Dawley , Espectrometría de Masas en Tándem , Bifenilos Policlorados/análisis , Bifenilos Policlorados/metabolismoRESUMEN
Polychlorinated biphenyls (PCBs) are environmental contaminants that can cause neurotoxicity. PCBs, such as PCB 95 (2,2',3,5',6-pentachlorobiphenyl), can be metabolized by cytochrome P450 enzymes into neurotoxic metabolites. To better understand how the metabolism of PCB 95 affects neurotoxic outcomes, we conducted a study on the disposition of PCB 95 in transgenic mouse models. The mice were given a single oral dose of PCB 95 (1.0 mg/kg) and were euthanized 24 h later for analysis. PCB 95 levels were highest in adipose tissue, followed by the liver, brain, and blood. Adipose tissue levels were significantly higher in wild-type (WT) mice than in Cyp2abfgs-null (KO) or CYP2A6-transgenic (KI) mice. We also observed genotype-dependent differences in the enrichment of aS-PCB 95 in female mice, with a less pronounced enrichment in KO than WT and KI mice. Ten hydroxylated PCB 95 metabolites were detected in blood and tissue across all exposure groups. The metabolite profiles differed across tissues, while sex and genotype-dependent differences were less pronounced. Total OH-PCB levels were highest in the blood, followed by the liver, adipose tissue, and brain. Total OH-PCB blood levels were lower in KO than in WT mice, while the opposite trend was observed in the liver. In male mice, total OH-PCB metabolite levels were significantly lower in KI than in WT mice in blood and the liver, while the opposite trend was observed in female mice. In conclusion, the study highlights the differences in the atropselective disposition of PCB 95 and its metabolites in different types of mice, demonstrating the usefulness of these transgenic mouse models for characterizing the role of PCB metabolism in PCB neurotoxicity.
Asunto(s)
Bifenilos Policlorados , Ratones , Masculino , Femenino , Animales , Bifenilos Policlorados/toxicidad , Sistema Enzimático del Citocromo P-450/genética , Sistema Enzimático del Citocromo P-450/metabolismo , Hígado/metabolismo , Hidroxilación , Ratones TransgénicosRESUMEN
Polychlorinated biphenyl (PCB) accumulates in adipose where it may impact the growth and function of cells within the tissue. This is particularly concerning during adolescence when adipocytes expand rapidly. Herein, we sought to understand how exposure to PCB mixtures found in U.S. schools affects human adipose mesenchymal stem/stromal cell (MSC) health and function. We investigated how exposure to Aroclor 1016 and Aroclor 1254, as well as a newly characterized non-Aroclor mixture that resembles the PCB profile found in cabinets, Cabinet Mixture, affects adipose MSC growth, viability, and function in vitro. We found that exposure to all three mixtures resulted in two distinct types of toxicity. At PCB concentrations >20 µM, the majority of MSCs die, while at 1-10 µM, MSCs remained viable but display numerous alterations to their phenotype. At these sublethal concentrations, the MSC rate of expansion slowed and morphology changed. Further assessment revealed that PCB-exposed MSCs had impaired adipogenesis and a modest decrease in immunosuppressive capabilities. Thus, exposure to PCB mixtures found in schools negatively impacts the health and function of adipose MSCs. This work has implications for human health due to MSCs' role in supporting the growth and maintenance of adipose tissue.
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Bifenilos Policlorados , Humanos , Bifenilos Policlorados/toxicidad , Bifenilos Policlorados/metabolismo , Arocloros/metabolismo , Arocloros/toxicidad , Tejido Adiposo , Células del Estroma/metabolismoRESUMEN
BACKGROUND: Gestational exposure to polychlorinated biphenyls (PCBs) has been associated with elevated risk for neurodevelopmental disorders. Placental epigenetics may serve as a potential mechanism of risk or marker of altered placental function. Prior studies have associated differential placental DNA methylation with maternal PCB exposure or with increased risk of autism spectrum disorder (ASD). However, sequencing-based placental methylomes have not previously been tested for simultaneous associations with maternal PCB levels and child neurodevelopmental outcomes. OBJECTIVES: We aimed to identify placental DNA methylation patterns associated with maternal PCB levels and child neurodevelopmental outcomes in the high-risk ASD MARBLES cohort. METHODS: We measured 209 PCB congeners in 104 maternal serum samples collected at delivery. We identified networks of DNA methylation from 147 placenta samples using the Comethyl R package, which performs weighted gene correlation network analysis for whole genome bisulfite sequencing data. We tested placental DNA methylation modules for association with maternal serum PCB levels, child neurodevelopment, and other participant traits. RESULTS: PCBs 153 + 168, 170, 180 + 193, and 187 were detected in over 50% of maternal serum samples and were highly correlated with one another. Consistent with previous findings, maternal age was the strongest predictor of serum PCB levels, alongside year of sample collection, pre-pregnancy BMI, and polyunsaturated fatty acid levels. Twenty seven modules of placental DNA methylation were identified, including five which significantly correlated with one or more PCBs, and four which correlated with child neurodevelopment. Two modules associated with maternal PCB levels as well as child neurodevelopment, and mapped to CSMD1 and AUTS2, genes previously implicated in ASD and identified as differentially methylated regions in mouse brain and placenta following gestational PCB exposure. CONCLUSIONS: Placental DNA co-methylation modules were associated with maternal PCBs and child neurodevelopment. Methylation of CSMD1 and AUTS2 could be markers of altered placental function and/or ASD risk following maternal PCB exposure.
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Trastorno del Espectro Autista , Bifenilos Policlorados , Animales , Ratones , Humanos , Niño , Femenino , Embarazo , Bifenilos Policlorados/análisis , Placenta/química , Metilación de ADN , Exposición Materna/efectos adversosRESUMEN
We measured the concentrations of 837 hydroxylated polychlorinated biphenyls (OH-PCBs, in 275 chromatographic peaks) and 209 polychlorinated biphenyls (PCBs, in 174 chromatographic peaks) in sediments from New Bedford Harbor in Massachusetts, Altavista wastewater lagoon in Virginia, and the Indiana Harbor and Ship Canal in Indiana, USA and in the original commercial PCB mixtures Aroclors 1016, 1242, 1248, and 1254. We used the correlation between homologues and the peak responses to quantify the full suite of OH-PCBs including those without authentic standards available. We found that OH-PCB levels are approximately 0.4% of the PCB levels in sediments and less than 0.0025% in Aroclors. The OH-PCB congener distributions of sediments are different from those of Aroclors and are different according to sites. We also identified a previously unknown compound, 4-OH-PCB52, which together with 4'-OH-PCB18 made up almost 30% of the OH-PCBs in New Bedford Harbor sediments but less than 1.2% in the Aroclors and 3.3% in any other sediments. This indicates site-specific environmental transformations of PCBs to OH-PCBs. We conclude that the majority of OH-PCBs in these sediments are generated in the environment. Our findings suggest that these toxic breakdown products of PCBs are prevalent in PCB-contaminated sediments and present an emerging concern for humans and ecosystems.
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Contaminantes Ambientales , Bifenilos Policlorados , Arocloros/análisis , Ecosistema , Contaminantes Ambientales/análisis , Humanos , Bifenilos Policlorados/análisis , Aguas ResidualesRESUMEN
Lower chlorinated polychlorinated biphenyls (LC-PCBs) and their metabolites make up a class of environmental pollutants implicated in a range of adverse outcomes in humans; however, the metabolism of LC-PCBs in human models has received little attention. Here we characterize the metabolism of PCB 2 (3-chlorobiphenyl), an environmentally relevant LC-PCB congener, in HepG2 cells with in silico prediction and nontarget high-resolution mass spectrometry. Twenty PCB 2 metabolites belonging to 13 metabolite classes, including five dechlorinated metabolite classes, were identified in the cell culture media from HepG2 cells exposed for 24 h to 10 µM or 3.6 nM PCB 2. The PCB 2 metabolite profiles differed from the monochlorinated metabolite profiles identified in samples from an earlier study with PCB 11 (3,3'-dichlorobiphenyl) under identical experimental conditions. A dechlorinated dihydroxylated metabolite was also detected in human liver microsomal incubations with monohydroxylated PCB 2 metabolites but not PCB 2. These findings demonstrate that the metabolism of LC-PCBs in human-relevant models involves the formation of dechlorination products. In addition, untargeted metabolomic analyses revealed an altered bile acid biosynthesis in HepG2 cells. Our results indicate the need to study the disposition and toxicity of complex PCB 2 metabolites, including novel dechlorinated metabolites, in human-relevant models.
Asunto(s)
Contaminantes Ambientales , Bifenilos Policlorados , Compuestos de Bifenilo , Línea Celular , Contaminantes Ambientales/metabolismo , Humanos , Hidroxilación , Bifenilos Policlorados/metabolismoRESUMEN
Exposure to polychlorinated biphenyls (PCBs) and their hydroxylated metabolites (OH-PCBs) has been implicated in neurodevelopmental disorders. However, the distribution of PCBs and OH-PCBs in the human brain has not been characterized. This study investigated the age-, sex-, and brain region-specific distribution of all 209 PCBs using gaschromatography-tandem mass spectrometry (GC-MS/MS) in neonatal (N = 7) and adult (N = 7) postmortem brain samples. OH-PCB analyses were performed by GC-MS/MS (as methylated derivatives) and, in a subset of samples, by nontarget liquid chromatography high-resolution mass spectrometry (Nt-LCMS). Fourteen higher chlorinated PCB congeners were observed with a detection frequency >50%. Six lower chlorinated PCBs were detected with a detection frequency >10%. Higher chlorinated PCBs were observed with higher levels in samples from adult versus younger donors. PCB congener profiles from adult donors showed more similarities across brain regions and donors than younger donors. We also assess the potential neurotoxicity of the PCB residues in the human brain with neurotoxic equivalency (NEQ) approaches. The median ΣNEQs, calculated for the PCB homologues, were 40-fold higher in older versus younger donors. Importantly, lower chlorinated PCBs made considerable contributions to the neurotoxic potential of PCB residues in some donors. OH-PCBs were identified for the first time in a small number of human brain samples by GC-MS/MS and Nt-LCMS analyses, and all contained four or fewer chlorine.
Asunto(s)
Bifenilos Policlorados , Adulto , Anciano , Encéfalo , Cromatografía de Gases y Espectrometría de Masas/métodos , Humanos , Hidroxilación , Recién Nacido , Bifenilos Policlorados/análisis , Espectrometría de Masas en TándemRESUMEN
Laboratory studies of the disposition and toxicity of hydroxylated polychlorinated biphenyl (OH-PCB) metabolites are challenging because authentic analytical standards for most unknown OH-PCBs are not available. To assist with the characterization of these OH-PCBs (as methylated derivatives), we developed machine learning-based models with multiple linear regression (MLR) or random forest regression (RFR) to predict the relative retention times (RRT) and MS/MS responses of methoxylated (MeO-)PCBs on a gas chromatograph-tandem mass spectrometry system. The final MLR model estimated the retention times of MeO-PCBs with a mean absolute error of 0.55 min (n = 121). The similarity coefficients cos θ between the predicted (by RFR model) and experimental MS/MS data of MeO-PCBs were >0.95 for 92% of observations (n = 96). The levels of MeO-PCBs quantified with the predicted MS/MS response factors approximated the experimental values within a 2-fold difference for 85% of observations and 3-fold differences for all observations (n = 89). Subsequently, these model predictions were used to assist with the identification of OH-PCB 95 or OH-PCB 28 metabolites in mouse feces or liver by suggesting candidate ranking information for identifying the metabolite isomers. Thus, predicted retention and MS/MS response data can assist in identifying unknown OH-PCBs.
Asunto(s)
Bifenilos Policlorados , Animales , Cromatografía de Gases y Espectrometría de Masas , Hidroxilación , Aprendizaje Automático , Ratones , Bifenilos Policlorados/metabolismo , Espectrometría de Masas en TándemRESUMEN
Exposure to polychlorinated biphenyls (PCBs) has been implicated in adverse human health effects, including developmental neurotoxicity. Several neurotoxic PCBs are chiral and undergo atropisomeric enrichment in vivo due to atropselective metabolism by cytochrome P450 enzymes. Here we study how the liver-specific deletion of the cytochrome P450 reductase ( cpr) gene alters the toxicokinetics of 2,2',3,3',6,6'-hexachlorobiphenyl (PCB 136) in mice. Male and female mice with a liver-specific deletion of cpr (KO) and congenic wild-type (WT) mice were exposed to a single oral dose of racemic PCB 136 (6.63 mg/kg). Levels and chiral signatures of PCB 136 and its hydroxylated metabolites were determined 1-48 h after PCB exposure in whole blood. Blood levels of PCB 136 were typically higher in M-WT compared to F-WT mice. At the later time points, F-KO mice had significantly higher PCB 136 levels than F-WT mice. 2,2',3',4,6,6'-Hexachlorobiphenyl-3-ol (3-150), 2,2',3,3',6,6'-hexachlorobiphenyl-4-ol (4-136), 2,2',3,3',6,6'-hexachlorobiphenyl-5-ol (5-136), and 4,5-dihydroxy-2,2',3,3',6,6'-hexachlorobiphenyl (4,5-136) were detected in blood, with 5-136 and 4-136 being major metabolites. At later time points, the sum of HO-PCB (∑HO-PCB) levels exceeded PCB 136 levels in the blood; however, higher ∑HO-PCB than PCB 136 levels were observed later in KO than WT mice. PCB 136 and its major metabolites displayed atropisomeric enrichment in a manner that depended on the time point, sex, and genotype. Toxicokinetic analysis revealed sex and genotype-dependent differences in toxicokinetic parameters for PCB 136 atropisomers and its metabolites. The results suggest that mice with a liver-specific deletion of the cpr gene can potentially be used to assess how an altered metabolism of neurotoxic PCB congeners affects neurotoxic outcomes following exposure of the offspring to PCBs via the maternal diet.
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Hígado/efectos de los fármacos , NADPH-Ferrihemoproteína Reductasa/antagonistas & inhibidores , Bifenilos Policlorados/toxicidad , Animales , Cinética , Hígado/metabolismo , Ratones , Ratones Noqueados , Estructura Molecular , NADPH-Ferrihemoproteína Reductasa/deficiencia , NADPH-Ferrihemoproteína Reductasa/metabolismo , Bifenilos Policlorados/química , Bifenilos Policlorados/metabolismoRESUMEN
Exposure to chiral polychlorinated biphenyls (PCBs) has been associated with neurodevelopmental disorders. Their hydroxylated metabolites (OH-PCBs) are also potentially toxic to the developing human brain; however, the formation of OH-PCBs by human cytochrome P450 (P450) isoforms is poorly investigated. To address this knowledge gap, we investigated the atropselective biotransformation of 2,2',3,4',6-pentachlorobiphenyl (PCB 91), 2,2',3,5',6-pentachlorobiphenyl (PCB 95), 2,2',3,3',4,6'-hexachlorobiphenyl (PCB 132), and 2,2',3,3',6,6'-hexachlorobiphenyl (PCB 136) by different human P450 isoforms. In silico predictions with ADMET Predictor and MetaDrug software suggested a role of CYP1A2, CYP2A6, CYP2B6, CYP2E1, and CYP3A4 in the metabolism of chiral PCBs. Metabolism studies with recombinant human enzymes demonstrated that CYP2A6 and CYP2B6 oxidized PCB 91 and PCB 132 in the meta position and that CYP2A6 oxidized PCB 95 and PCB 136 in the para position. CYP2B6 played only a minor role in the metabolism of PCB 95 and PCB 136 and formed meta-hydroxylated metabolites. Traces of para-hydroxylated PCB metabolites were detected in incubations with CYP2E1. No hydroxylated metabolites were present in incubations with CYP1A2 or CYP3A4. Atropselective analysis revealed P450 isoform-dependent and congener-specific atropselective enrichment of OH-PCB metabolites. These findings suggest that CYP2A6 and CYP2B6 play an important role in the oxidation of neurotoxic PCBs to chiral OH-PCBs in humans.
Asunto(s)
Bifenilos Policlorados , Citocromo P-450 CYP2A6 , Citocromo P-450 CYP2B6 , Citocromo P-450 CYP2E1 , Humanos , Hidroxilación , EstereoisomerismoRESUMEN
Polychlorinated biphenyls (PCBs) pose significant risk to the developing human brain; however, mechanisms of PCB developmental neurotoxicity (DNT) remain controversial. Two widely posited mechanisms are tested here using PCBs identified in pregnant women in the MARBLES cohort who are at increased risk for having a child with a neurodevelopmental disorder (NDD). As determined by gas chromatography-triple quadruple mass spectrometry, the mean PCB level in maternal serum was 2.22 ng/mL. The 12 most abundant PCBs were tested singly and as a mixture mimicking the congener profile in maternal serum for activity at the thyroid hormone receptor (THR) and ryanodine receptor (RyR). Neither the mixture nor the individual congeners (2 fM to 2 µM) exhibited agonistic or antagonistic activity in a THR reporter cell line. However, as determined by equilibrium binding of [3H]ryanodine to RyR1-enriched microsomes, the mixture and the individual congeners (50 nM to 50 µM) increased RyR activity by 2.4-19.2-fold. 4-Hydroxy (OH) and 4-sulfate metabolites of PCBs 11 and 52 had no TH activity; but 4-OH PCB 52 had higher potency than the parent congener toward RyR. These data support evidence implicating RyRs as targets in environmentally triggered NDDs and suggest that PCB effects on the THR are not a predominant mechanism driving PCB DNT. These findings provide scientific rationale regarding a point of departure for quantitative risk assessment of PCB DNT, and identify in vitro assays for screening other environmental pollutants for DNT potential.
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Contaminantes Ambientales , Bifenilos Policlorados , Niño , Femenino , Humanos , Embarazo , Receptores de Hormona Tiroidea , Canal Liberador de Calcio Receptor de Rianodina , SueroRESUMEN
Polychlorinated biphenlys (PCBs) and their hydroxylated metabolites (OH-PCBs) have been implicated in neurodevelopmental disorders. Several neurotoxic PCBs, such as PCB 91, are chiral because they form stable rotational isomers, or atropisomers, that are nonsuperimposable mirror images of each other. Because only limited information about the metabolism of these PCBs by human cytochrome P450 (P450) enzymes is available, we investigated the biotransformation of PCB 91 to OH-PCBs by human liver microsomes (HLMs). Racemic PCB 91 was incubated with pooled or individual donor HLMs at 37 °C, and levels and chiral signatures of PCB 91 and its metabolites were determined. Several OH-PCBs were formed in the order 2,2',4,4',6-pentachlorobiphenyl-3-ol (3-100; 1,2 shift product) > 2,2',3,4',6-pentachlorobiphenyl-5-ol (5-91) â« 2,2',3,4',6-pentachlorobiphenyl-4-ol (4-91) â« 4,5-dihydroxy-2,2',3,4',6-pentachlorobiphenyl (4,5-91). Metabolite formation rates displayed interindividual variability. The first eluting atropisomers of PCB 91, 3-100 and 4-91, and the second eluting atropisomer of 5-91 were enriched in most metabolism studies. The unexpected, preferential formation of a 1,2-shift product and the variability of the OH-PCBs profiles in experiments with individual donor HLMs underline the need for further systematic studies of the atropselective metabolism of PCBs in humans.
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Microsomas Hepáticos , Bifenilos Policlorados , Sistema Enzimático del Citocromo P-450 , Humanos , Hidroxilación , EstereoisomerismoRESUMEN
Exposure of polar bears (Ursus maritimus) to persistent organic pollutants was discovered in the 1970s, but recent evidence suggests the presence of unknown toxic chemicals in their blood. Protein and phospholipid depleted serum was stirred with polyethersulfone capillaries to extract a broad range of analytes, and nontarget mass spectrometry with "fragmentation flagging" was used for detection. Hundreds of analytes were discovered belonging to 13 classes, including novel polychlorinated biphenyl (PCB) metabolites and many fluorinated or chlorinated substances not previously detected. All analytes were detected in the oldest (mid-1980s) archived polar bear serum from Hudson Bay and Beaufort Sea, and all fluorinated classes showed increasing trends. A mouse experiment confirmed the novel PCB metabolites, suggesting that these could be widespread in mammals. Historical exposure and toxic risk has been underestimated, and these halogenated contaminants pose uncertain risks to this threatened species.
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Contaminantes Ambientales/sangre , Hidrocarburos Halogenados/sangre , Ursidae/sangre , Animales , Monitoreo del Ambiente , Contaminantes Ambientales/análisis , Halogenación , Hidrocarburos Halogenados/análisis , Masculino , Espectrometría de Masas , Bifenilos Policlorados/análisis , Bifenilos Policlorados/sangreRESUMEN
New insensitive munitions explosives, including 2,4-dinitroanisole (DNAN), are replacing traditional explosive compounds to protect soldiers and simplify transport logistics. Despite the occupational safety benefits of these new explosives, feasible strategies for cleaning up DNAN from soil and water have not been developed. Here, we evaluate the metabolism of DNAN by the model plant Arabidopsis to determine whether phytoremediation can be used to clean up contaminated sites. Furthermore, we evaluate the role of photodegradation of DNAN and its plant metabolites within Arabidopsis leaves to determine the potential impact of photolysis on the phytoremediation of contaminants. When exposed to DNAN for three days, Arabidopsis took up and metabolized 67% of the DNAN in hydroponic solution. We used high resolution and tandem mass spectrometry in combination with stable-isotope labeled DNAN to confirm ten phase II DNAN metabolites in Arabidopsis. The plants separately reduced both the para- and ortho-nitro groups and produced glycosylated products that accumulated within plant tissues. Both DNAN and a glycosylated metabolite were subsequently photolyzed within leaf tissue under simulated sunlight, and [15N2]DNAN yielded 15NO2- in leaves. Therefore, photolysis inside leaves may be an important, yet under-explored, phytoremediation mechanism.
Asunto(s)
Anisoles , Arabidopsis , Fotólisis , Sustancias ExplosivasRESUMEN
Polychlorinated biphenyl (PCB) congeners with multiple ortho chlorine substituents and their metabolites exist as stable rotational isomers, or atropisomers, that are nonsuperimposable mirror images of each other. Additionally, the oxidation of certain axially prochiral PCBs, such as 2,2',4,6'-tetrachlorobiphenyl (PCB 51) and 2,2',4,5,6'-pentachlorobiphenyl (PCB 102), in the meta position of the symmetrically substituted phenyl ring is expected to form axially chiral hydroxylated metabolites (OH-PCBs); however, the formation of chiral OH-PCBs from prochiral PCBs has not been demonstrated experimentally. Here, we investigate if the oxidation of PCB 51 and PCB 102 by different microsomal preparations results in the formation of chiral OH-PCBs. Gas chromatographic analysis revealed that PCB 51 and PCB 102 were metabolized to 2,2',4,6'-tetrachlorobiphenyl-3'-ol (OH-PCB 51) and 2,2',4,5,6'-pentachlorobiphenyl-3'-ol (OH-PCB 102), respectively, by liver microsomes from male rats pretreated with different inducers; untreated male monkeys, guinea pigs, rabbits, and hamsters; and female dogs. The formation of both metabolites was inducer- and species-dependent. Both OH-PCB 51 and OH-PCB 102 were chiral and formed enantioselectively by all microsomal preparations investigated. These findings demonstrate that axially chiral PCB metabolites are formed from axially prochiral PCB congeners, a fact that should be considered when studying the environmental fate, transport, and toxicity of OH-PCBs.
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Microsomas Hepáticos/metabolismo , Bifenilos Policlorados/metabolismo , Animales , Cobayas , Hidroxilación , Masculino , Oxidación-Reducción , Bifenilos Policlorados/química , Ratas , EstereoisomerismoRESUMEN
Insensitive munitions explosives are new formulations that are less prone to unintended detonation compared to traditional explosives. While these formulations have safety benefits, the individual constituents, such as 2,4-dinitroanisole (DNAN), have an unknown ecosystem fate with potentially toxic impacts to flora and fauna exposed to DNAN and/or its metabolites. Fungi may be useful in remediation and have been shown to degrade traditional nitroaromatic explosives, such as 2,4,6-trinitrotoluene and 2,4-dinitrotoluene, that are structurally similar to DNAN. In this study, a fungal Penicillium sp., isolated from willow trees and designated strain KH1, was shown to degrade DNAN in solution within 14 days. Stable-isotope labeled DNAN and an untargeted metabolomics approach were used to discover 13 novel transformation products. Penicillium sp. KH1 produced DNAN metabolites resulting from ortho- and para-nitroreduction, demethylation, acetylation, hydroxylation, malonylation, and sulfation. Incubations with intermediate metabolites such as 2-amino-4-nitroanisole and 4-amino-2-nitroanisole as the primary substrates confirmed putative metabolite isomerism and pathways. No ring-cleavage products were observed, consistent with other reports that mineralization of DNAN is an uncommon metabolic outcome. The production of metabolites with unknown persistence and toxicity suggests further study will be needed to implement remediation with Penicillium sp. KH1. To our knowledge, this is the first report on the biotransformation of DNAN by a fungus.
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Anisoles/metabolismo , Penicillium/metabolismo , Acetilación , Biodegradación Ambiental , Biotransformación , Remoción de Radical Alquila , Sustancias Explosivas/metabolismoRESUMEN
Exposure to neurotoxic, chiral PCBs has been associated with neurodevelopmental disorders, but their metabolism in humans remains unexplored. We investigated the enantioselective metabolism of PCB 95 by human liver microsomes (HLMs) to potentially neurotoxic, hydroxylated metabolites (OH-PCBs). OH-PCB profiles formed in experiments with HLMs differed from metabolite profiles reported for rodent species. The second eluting atropisomer of 2,2',3,5',6-pentachlorobiphenyl-4'-ol, the major metabolite, was preferentially formed by all HLM preparations investigated. Differences in metabolite formation rates were observed with single donor HLMs. The metabolism of PCBs and its role in PCB-mediated neurodevelopmental disorders need to be further characterized.
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Microsomas Hepáticos/metabolismo , Humanos , Hidroxilación , Bifenilos Policlorados/metabolismoRESUMEN
The disposition of toxicants is often affected by their binding to serum proteins, of which the most abundant in humans is serum albumin (HSA). There is increasing interest in the toxicities of environmentally persistent polychlorinated biphenyls (PCBs) with lower numbers of chlorine atoms (LC-PCBs) due to their presence in both indoor and outdoor air. PCB sulfates derived from metabolic hydroxylation and sulfation of LC-PCBs have been implicated in endocrine disruption due to high affinity-binding to the thyroxine-carrying protein, transthyretin. Interactions of these sulfated metabolites of LC-PCBs with HSA, however, have not been previously explored. We have now determined the relative HSA-binding affinities for a group of LC-PCBs and their hydroxylated and sulfated derivatives by selective displacement of the fluorescent probes 5-dimethylamino-1-naphthalenesulfonamide and dansyl-l-proline from the two major drug-binding sites on HSA (previously designated as Site I and Site II). Values for half-maximal displacement of the probes indicated that the relative binding affinities were generally PCB sulfate ≥ OH-PCB > PCB, although this affinity was site- and congener-selective. Moreover, specificity for Site II increased as the numbers of chlorine atoms increased. Thus, hydroxylation and sulfation of LC-PCBs result in selective interactions with HSA which may affect their overall retention and toxicity.