Hepatic Metabolism Affects the Atropselective Disposition of 2,2′,3,3′,6,6′-Hexachlorobiphenyl (PCB 136) in Mice

Wu, Xianai; Barnhart, Christopher D.; Lein, Pamela J.; Lehmler, Hans‐Joachim

doi:10.1021/es504766p

Cited by 41 publications

(126 citation statements)

References 76 publications

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“…12–15, 43 The OH-PCB metabolite profiles in tissues from pregnant mice were consistent with our earlier in vivo study in non-pregnant mice, 32 with 4-95 being the major metabolite detected in blood and liver. 4-95 was also a major metabolite in liver and blood from weaned pups on PND 30–33 at the higher doses.…”

Section: Discussionsupporting

confidence: 89%

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Effect of Pregnancy on the Disposition of 2,2′,3,5′,6-Pentachlorobiphenyl (PCB 95) Atropisomers and Their Hydroxylated Metabolites in Female Mice

Kania-Korwel

Barnhart

Lein

et al. 2015

Chem. Res. Toxicol.

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Chiral PCBs, such as PCB 95, are developmental neurotoxicants that undergo atropisomeric enrichment in non-pregnant, adult mice. Because pregnancy is associated with changes in hepatic cytochrome P450 enzyme activity as well as lipid disposition and metabolism, this study investigates the effect of pregnancy on the maternal disposition of chiral PCBs. Female C57Bl/6 mice (8 weeks old) were dosed daily beginning 2 weeks prior to conception and continuing throughout gestation and lactation (56 days total) with racemic PCB 95 (0, 0.1, 1.0 or 6.0 mg/kg body wt/day) in peanut butter. Levels and chiral signatures of PCB 95 and its hydroxylated metabolites (OH-PCBs) were determined in adipose, blood, brain and liver. Tissue levels of PCB 95 increased 4 to 12 fold with increasing dose, with considerable enrichment of the second eluting atropisomer in all tissues (EF range 0.11 to 0.26). OH-PCBs displayed atropisomeric enrichment in blood and liver, but were not detected in adipose and brain. Levels of PCB 95 and its metabolites were 2 to 11 fold lower in pregnant dams relative to those previously reported in non-pregnant age-matched female mice; however, PCB 95 and OH-PCB profiles and chiral signatures were similar between both studies. In contrast, human brain samples contained racemic PCB 95 residues (EF=0.50). These results demonstrate that changes in cytochrome P450 enzyme activity and lipid disposition during pregnancy reduce the PCB body burden in dams, but do not affect metabolite profiles or chiral signatures. The differences in chiral signatures between mice and humans suggest species-specific differences in atropisomeric disposition, the toxicological significance of which remain to be determined.

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Section: Discussionsupporting

confidence: 89%

“…Taken together, these observations are consistent with the rapid elimination of chiral PCBs, such as PCB 95, in rodents. 32, 42, 43 …”

Section: Discussionmentioning

confidence: 99%

Effect of Pregnancy on the Disposition of 2,2′,3,5′,6-Pentachlorobiphenyl (PCB 95) Atropisomers and Their Hydroxylated Metabolites in Female Mice

Kania-Korwel

Barnhart

Lein

et al. 2015

Chem. Res. Toxicol.

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“…A similar effect on 4,5-136 levels was observed in experiments using NAC. Several animal studies demonstrate that PCB catechol metabolites, such as 3′,4′-dihydroxy-4-chlorobiphenyl and 4,5-136, are efficiently eliminated, most likely as the corresponding sulfate or glucuronide conjugates (Birnbaum 1983, Dhakal et al 2014, Haraguchi et al 2004, Wu et al 2015). It is therefore possible that reduced hepatic glutathione stores are associated with a decreased formation and elimination of 4,5-136 conjugates, and additional studies are needed to investigate whether reduced glutathione levels, e.g.…”

Section: Discussionmentioning

confidence: 99%

Effects of thiol antioxidants on the atropselective oxidation of 2,2′,3,3′,6,6′-hexachlorobiphenyl (PCB 136) by rat liver microsomes

Lehmler

2015

Environ Sci Pollut Res

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Chiral polychlorinated biphenyl (PCB) congeners, such as PCB 136, are atropselectively metabolized to various hydroxylated PCB metabolites (HO-PCBs). The present study investigates the effect of two thiol antioxidants, glutathione and N-acetyl-cysteine (NAC), on profiles and chiral signatures of PCB 136 and its HO-PCB metabolites in rat liver microsomal incubations. Liver microsomes prepared from rats pretreated with phenobarbital were incubated with PCB 136 (5 μM) in the presence of the respective antioxidant (0–10 mM), and levels and chiral signatures of PCB 136 and its HO-PCB metabolites were determined. Three metabolites, 5-136 (2,2′,3,3′,6,6′-hexachlorobiphenyl-5-ol), 4-136 (2,2′,3,3′,6,6′-hexachlorobiphenyl-4-ol) and 4,5-136 (2,2′,3,3′,6,6′-hexachlorobiphenyl-4,5-diol), were detected in all incubations, with 5-136 being the major metabolite. Compared to microsomal incubations without antioxidant, levels of 4,5-136 increased with increasing antioxidant concentration, whereas levels of PCB 136 and both mono-HO-PCBs were not affected by the presence of either antioxidant. PCB 136, 4-136 and 5-136 displayed significant atropisomeric enrichment; however, the direction and extent of the atropisomeric enrichment was not altered in the presence of an antioxidant. Because 4,5-136 can either be conjugated to a sulfate or glucuronide metabolite that is readily excreted or further oxidized a potentially toxic PCB 136 quinone, the effect of both thiol antioxidants on 4,5-136 formation suggests that disruptions of glutathione homeostasis may alter the balance between both metabolic pathways and, thus, PCB 136 toxicity in vivo.

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“…Such interactions influence metabolism required for toxicant inactivation and excretion [37–41] and metabolism required for toxicant activation, thus altering toxicity [42–44]. For example, Cytochrome p450 (Cyp450) enzymes have been shown to play critical roles in metabolizing POPs [35, 45]. Cyp450 enzyme levels are altered by many nutrients including dietary protein [46, 47], fat [48], sugar [49], vitamin C [50, 51], vitamin E [39], folate[40], betaine [52], iodine and selenium [53].…”

Section: Introductionmentioning

confidence: 99%

An assessment of molecular pathways of obesity susceptible to nutrient, toxicant and genetically induced epigenetic perturbation

Xue

Ideraabdullah

2016

The Journal of Nutritional Biochemistry

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In recent years, the etiology of human disease has greatly improved with the inclusion of epigenetic mechanisms, in particular as a common link between environment and disease. However, for most diseases we lack a detailed interpretation of the epigenetic regulatory pathways perturbed by environment and causal mechanisms. Here, we focus on recent findings elucidating nutrient-related epigenetic changes linked to obesity. We highlight studies demonstrating that obesity is a complex disease linked to disruption of epigenetically regulated metabolic pathways in the brain, adipose tissue and liver. These pathways regulate (1) homeostatic and hedonic eating behaviors (2) adipocyte differentiation and fat accumulation, and (3) energy expenditure. By compiling these data we illustrate that obesity-related phenotypes are repeatedly linked to disruption of critical epigenetic mechanisms that regulate of key metabolic genes. These data are supported by genetic mutation of key epigenetic regulators and many of the diet induced epigenetic mechanisms of obesity are also perturbed by exposure to environmental toxicants. Identifying similarly perturbed epigenetic mechanisms in multiple experimental models of obesity strengthens the translational applications of these findings. We also discuss many of the ongoing challenges to understanding the role of environmentally-induced epigenetic pathways in obesity and suggest future studies to elucidate these roles. This assessment illustrates our current understanding of molecular pathways of obesity that are susceptible to environmental perturbation via epigenetic mechanisms. Thus, it lays the groundwork for dissecting the complex interactions between diet, genes, and toxicants that contribute to obesity and obesity-related phenotypes.

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Hepatic Metabolism Affects the Atropselective Disposition of 2,2′,3,3′,6,6′-Hexachlorobiphenyl (PCB 136) in Mice

Cited by 41 publications

References 76 publications

Effect of Pregnancy on the Disposition of 2,2′,3,5′,6-Pentachlorobiphenyl (PCB 95) Atropisomers and Their Hydroxylated Metabolites in Female Mice

Effect of Pregnancy on the Disposition of 2,2′,3,5′,6-Pentachlorobiphenyl (PCB 95) Atropisomers and Their Hydroxylated Metabolites in Female Mice

Effects of thiol antioxidants on the atropselective oxidation of 2,2′,3,3′,6,6′-hexachlorobiphenyl (PCB 136) by rat liver microsomes

An assessment of molecular pathways of obesity susceptible to nutrient, toxicant and genetically induced epigenetic perturbation

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