2,2′,3,5′,6-Pentachlorobiphenyl (PCB 95) and Its Hydroxylated Metabolites Are Enantiomerically Enriched in Female Mice

Kania-Korwel, Izabela; Barnhart, Christopher D.; Stamou, Marianna; Truong, Kim; Elkomy, Mohammed H.; Lein, Pamela J.; Veng‐Pedersen, Peter; Lehmler, Hans‐Joachim

doi:10.1021/es302810t

Cited by 62 publications

(159 citation statements)

References 56 publications

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“…Moreover, the extent, but not the direction of the atropisomeric enrichment of 4,5-HO-PCB 95 are different between 5-HO-PCB 95 and 4-HO-PCB 95, with a more pronounced enrichment of 4,5-HO-PCB 95 observed in incubations with 5-HO-PCB 95. In contrast, an in vivo disposition study in mice reports near racemic chiral signatures for 4,5-HO-PCB 95 (Kania-Korwel et al 2012). As shown in Fig.…”

Section: Metabolism Of C-pcbs To Ho-pcbsmentioning

confidence: 92%

“…The 4,5-epoxide intermediate of C-PCBs with a 2,3,6-trichloro substitution pattern can rearrange to form both 4- or 5-hydroxylated PCB metabolites. In addition, a 1,2-shift (or NIH-shift) (Guroff et al 1967, Jerina and Daly 1974) of the 3-chloro substituent can lead to the formation of HO-PCBs with a 2,4,6-trichloro-3-hydroxy substitution pattern as minor metabolites (Kania-Korwel et al 2012, Kania-Korwel et al 2011, Wu et al 2013a, Wu et al 2014). Studies with recombinant P450 enzymes demonstrate that CYP2B isoforms, such as rat CYP2B1 (Lu et al 2013, Waller et al 1999, Warner et al 2009), human CYP2B6 (Warner et al.…”

Section: Metabolism Of C-pcbs To Ho-pcbsmentioning

confidence: 99%

“…Moreover, the atropisomeric enrichment of E 2 -PCB 95 in the in vitro metabolism experiments is consistent with the atropisomeric enrichment of PCB 95 observed in rats treated with an Aroclor 1254 mixture (Kania-Korwel et al 2006). Similarly, in vitro metabolism studies (Wu et al 2013a) accurately predict the direction of the atropisomeric enrichment of PCB 136 (Kania-Korwel et al 2010, Kania-Korwel et al 2008a, Kania-Korwel et al 2007, Kania-Korwel et al 2008d, Milanowski et al 2010) and PCB 95 (Kania-Korwel et al 2012, Kania-Korwel et al 2010, Milanowski et al 2010) in mice in vivo . Incubations with human CYP2B6 result in biotransformation of PCBs 45, 91 and 132; however, only the biotransformation of PCBs 45 and 132 is enantioselective.…”

Section: Metabolism Of C-pcbs To Ho-pcbsmentioning

confidence: 99%

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Chiral polychlorinated biphenyls: absorption, metabolism and excretion—a review

Kania-Korwel

Lehmler

2015

Environ Sci Pollut Res

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103

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Seventy eight out of the 209 possible polychlorinated biphenyl (PCB) congeners are chiral, nineteen of which exist under ambient conditions as stable rotational isomers that are non-superimposable mirror images of each other. These congeners (C-PCBs) represent up to 6% by weight of technical PCB mixtures and undergo considerable atropisomeric enrichment in wildlife, laboratory animals and humans. The objective of this review is to summarize our current knowledge of the processes involved in the absorption, metabolism and excretion of C-PCBs and their metabolites in laboratory animals and humans. C-PCBs are absorbed and excreted by passive diffusion, a process that, like other physicochemical processes, is inherently not atropselective. In mammals, metabolism by cytochrome P450 (P450) enzymes represents a major route of elimination for many C-PCBs. In vitro studies demonstrate that C-PCBs with a 2,3,6-trichlorosubstituion pattern in one phenyl ring are readily oxidized to hydroxylated PCB metabolites (HO-PCBs) by P450 enzymes, such as rat CYP2B1, human CYP2B6 and dog CYP2B11. The oxidation of C-PCBs is atropselective, thus resulting in a species and congener-dependent atropisomeric enrichment of C-PCBs and their metabolites. This atropisomeric enrichment of C-PCBs and their metabolites likely plays a poorly understood role in the atropselective toxicity of C-PCBs and, therefore, warrants further investigation.

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Section: Metabolism Of C-pcbs To Ho-pcbsmentioning

confidence: 92%

Section: Metabolism Of C-pcbs To Ho-pcbsmentioning

confidence: 99%

Section: Metabolism Of C-pcbs To Ho-pcbsmentioning

confidence: 99%

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Chiral polychlorinated biphenyls: absorption, metabolism and excretion—a review

Kania-Korwel

Lehmler

2015

Environ Sci Pollut Res

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103

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“…Female C57Bl/6 mice (8 weeks old) were purchased from Charles Rivers Laboratories (Hollister, CA) and dosed daily for a total of 56 days with three different doses of PCB 95 (0.1, 1.0 or 6.0 mg/kg body weight/day [bw/d], which corresponds to 5.6, 56 or 336 mg/kg bw total dose) in peanut butter/peanut oil or vehicle alone according to previously described protocols. 32 After one week of acclimatization to the vehicle and two weeks of PCB 95 dosing, exposed and control dams were mated over a period of three days with congenic male mice. Dosing continued during mating and throughout gestation and lactation.…”

Section: Methodsmentioning

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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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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“…The formation rate of 5-OH-PCBs formation is congener-specific for these four PCBs. In vivo, tissue levels of OH-PCBs increased with increasing dose of racemic PCB 95 in adult female mice following subchronic exposure [36]. …”

Section: Enantioselectivity In Accumulationmentioning

confidence: 96%