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Assessment of the disposition of chiral polychlorinated biphenyls in female mdr 1a/b knockout versus wild-type mice using multivariate analyses.

ABSTRACT: Polychlorinated biphenyls (PCBs) are present in the environment as complex mixtures, which make it challenging to identify PCB congeners that may be subject to active transport processes. Here we employ a transgenic mouse model in combination with multivariate analyses to investigate if chiral PCBs 91, 95, 132, 136, 149, 174, 176 and 183 are subject to active (enantioselective) transport by multidrug resistance (MDR) transporters. A synthetic PCB mixture containing these congeners was administered orally to female FVB or mdr1a/1b knockout mice. Due to the short half-life of chiral PCB congeners, mice were euthanized after 24h and PCB concentrations and enantiomeric fractions were determined in selected tissues and excreta. Principal component analysis did not reveal differences between wild-type and mdr1a/1b knockout mice. However, Hotelling T(2)-test revealed significantly lower PCB concentrations and a more pronounced enantiomeric enrichment in the adipose tissue of mdr1a/1b knockout mice. These differences are due to higher body weights and higher fecal fat contents of mdr1a/1b knockout mice. Analysis of the enantiomeric fractions of PCBs 91, 95, 136, 149 and 174 showed a significant enantiomeric enrichment for all five congeners in wild-type and mdr1a/1b knockout mice. Overall, by studying a PCB mixture in a transgenic mouse model in combination with a multivariate data reduction approach, PCBs 91, 95, 136, 149 and 174 could be excluded as substrates of multidrug resistance transporters 1a/b.

SUBMITTER: Milanowski B

PROVIDER: S-EPMC2891895 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature

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Assessment of the disposition of chiral polychlorinated biphenyls in female mdr 1a/b knockout versus wild-type mice using multivariate analyses.

Milanowski Bartłomiej B Lulek Janina J Lehmler Hans-Joachim HJ Kania-Korwel Izabela I

Environment international 20091117 8

Polychlorinated biphenyls (PCBs) are present in the environment as complex mixtures, which make it challenging to identify PCB congeners that may be subject to active transport processes. Here we employ a transgenic mouse model in combination with multivariate analyses to investigate if chiral PCBs 91, 95, 132, 136, 149, 174, 176 and 183 are subject to active (enantioselective) transport by multidrug resistance (MDR) transporters. A synthetic PCB mixture containing these congeners was administer ...[more]

PMID: 19923000

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Project description:Polychlorinated biphenyls (PCBs) are organic chemicals that were traditionally produced and widely used in industry as mixtures and are presently formed as byproducts of pigment and dye manufacturing. They are known to persist and bioaccumulate in the environment. Some have been shown to induce liver cancer in rodents. Although the mechanism of the toxicity of PCBs is unknown, it has been shown that they increase oxidative stress, including lipid peroxidation. We hypothesized that oxidative stress-induced DNA damage could be a contributor for PCB carcinogenesis and analyzed several DNA adducts in female Sprague-Dawley rats exposed to 3,3',4,4',5-pentachlorobiphenyl (PCB 126), 2,2',4,4',5,5'-hexachlorobiphenyl (PCB 153), and a binary mixture (PCB 126 + 153) for 14, 31, and 53 wks. Eight adducts were measured to profile oxidative DNA lesions, including 8-oxo-deoxyguanosine (8-oxo-dG), 1,N(6)-ethenodeoxyadenosine (1,N(6)-εdA), N(2),3-ethenoguanine (N(2),3-εG), 1,N(2)-ethenodeoxyguanosine (1,N(2)-εdG), as well as malondialdehyde (M1dG), acrolein (AcrdG), crotonaldehyde (CrdG), and 4-hydroxynonenal-derived dG adducts (HNEdG) by LC-MS/MS analysis. Statistically significant increases were observed for 8-oxo-dG and 1,N(6)-εdA concentrations in hepatic DNA of female rats exposed to the binary mixture (1000 ng/kg/day + 1000 μg/kg/day) but not in rats exposed to PCB 126 (1000 ng/kg/day) or PCB 153 (1000 μg/kg/day) for 14 and 31 wks. However, exposure to PCB 126 (1000 ng/kg/day) for 53 wks significantly increased 8-oxo-dG, 1,N(6)-εdA, AcrdG, and M1dG. Exposure to PCB 153 (1000 μg/kg/day) for 53 wks increased 8-oxo-dG, and 1,N(6)-εdA. Exposure to the binary mixture for 53 wks increased 8-oxo-dG, 1,N(6)-εdA, AcrdG, 1,N(2)-εdG, and N(2),3-εG significantly above control groups. Increased hepatic oxidative DNA adducts following exposure to PCB 126, PCB 153, or the binary mixture shows that an increase in DNA damage may play an important role in hepatic toxicity and carcinogenesis in female Sprague-Dawley rats.

Project description:Hydroxylated metabolites of polychlorinated biphenyls (OH-PCBs) have been found to be ubiquitous in the environment due to the oxidative metabolism of their parent PCBs. With more polarity, OH-PCBs may be more toxic and mobile than their parent compounds. However, the behavior and fate of OH-PCBs have been neglected in the environment because they are not the original contaminants. Some of these hydroxylated metabolites are chiral, and chiral compounds can be used to probe biological metabolic processes. Therefore, chiral OH-PCBs were selected to study their uptake, translocation, transformation, and enantioselectivity in plants in this work. Poplars (Populus deltoides × nigra, DN34), a model plant with complete genomic sequence, were hydroponically exposed to 5-hydroxy-2,2',3,4',6-pentachlorobiphenyl (5-OH-PCB91) and 5-hydroxy-2,2',3,5',6-pentachlorobiphenyl (5-OH-PCB95) for 10 days. Chiral 5-OH-PCB91 and 5-OH-PCB95 were clearly shown to be sorbed, taken up, and translocated in whole poplars, and they were detected in various tissues of whole poplars. However, the enantioselectivity of poplar for 5-OH-PCB91 and 5-OH-PCB95 proved to be quite different. The second-eluting enantiomer of OH-PCB95, separated on a chiral column (Phenomenex Lux Cellulose-1), was enantioselectively removed in whole poplar. Enantiomeric fractions in the middle xylem, top bark, top xylem, and stem, reached 0.803 ± 0.022, 0.643 ± 0.110, 0.835 ± 0.087, and 0.830 ± 0.029, respectively. Therefore, 5-OH-PCB95 was significantly enantioselectively biotransformed inside poplar tissues, in contrast to nearly racemic mixtures of 5-OH-PCB95 remaining in hydroponic solutions. Unlike 5-OH-PCB95, 5-OH-PCB91 remained nearly racemic in most tissues of whole poplars during 10 day exposure, suggesting the enantiomers of 5-OH-PCB91 were equally transported and metabolized in whole poplars. This is the first evidence of enantioselectivity of chiral OH-PCBs and suggests that poplars can enantioselectively biotransform at least one chiral OH-PCB: namely, 5-OH-PCB95.

Dataset Information

Assessment of the disposition of chiral polychlorinated biphenyls in female mdr 1a/b knockout versus wild-type mice using multivariate analyses.

Publications

Assessment of the disposition of chiral polychlorinated biphenyls in female mdr 1a/b knockout versus wild-type mice using multivariate analyses.

Similar Datasets

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