Polyploidy-induction by dihydroxylated monochlorobiphenyls: structure-activity-relationships.
Recently semivolatile lower chlorinated biphenyls have been identified in inner city air, in public buildings like schools, and at many other sites. Inhalation exposure to these compounds, which are readily metabolized to mono- and dihydroxy-biphenyls and further to quinones, is of great concern in light of new studies revealing that at least one such compound, 4-monochlorobiphenyl (PCB3), has tumor initiating and mutagenic activity in rats. In vitro the quinone metabolites of PCB3 induced gene mutations, whereas its mono- and dihydroxylated metabolites increased micronuclei frequency. To gain further insight into the genotoxicity and possible structure-activity-relationships of the dihydroxy-metabolites, we measured the effects of the 2-chloro-, 3-chloro-, and 4-chloro-2',5'-dihydroxybiphenyl (PCB1-HQ, PCB2-HQ, and PCB3-HQ, respectively), and of 4-chloro-3',4'-dihydroxybiphenyl (PCB3-Cat) on cytotoxicity, sister chromatid exchange (SCE), cellular proliferation and chromosome number. Notably only PCB3-Cat caused a significant increase in SCE levels. Cell cycle progression during exposure, which is indicated indirectly in this assay by the occurrence of metaphases with Harlequin-stained chromosomes (cell underwent two S-phases) or uniformly dark-stained chromosomes (underwent less than two S-phases) was inhibited by PCB2-HQ and PCB3-HQ. Most surprising was the finding that up to 96% of metaphases from cells treated with PCB2- or PCB3-HQ were tetraploid, some of which had dark and some Harlequin-stained chromosomes. Neither PCB1-HQ nor PCB3-Cat or the negative (solvent) or positive control (ethylmethane sulfonate, EMS) induced this effect. The mechanism of this polyploidization is unknown. Nearly all cancer cells are hyperdiploid and polyploidization, followed by uneven chromosome loss, is hypothesized as one possible underlying mechanism of carcinogenesis. Thus different PCB metabolites may induce carcinogenesis by different mechanisms, including SCE induction or polyploidization. Understanding the mechanism(s) and structure-activity-relationships of these unexpected effects is needed before we can perform fully data-driven risk assessment of these compounds.
Flor
Susanne
S
Dept of Occupational and Environmental Health, The University of Iowa, College of Public Health, 100 Oakdale Campus IREH, Iowa City, IA 52242-5000, United States.
Ludewig
Gabriele
G
D000818:Animals; D001713:Biphenyl Compounds / Q000737:chemistry* / Q000633:toxicity*; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D005347:Fibroblasts / Q000187:drug effects; D007621:Karyotyping; D015394:Molecular Structure; D009153:Mutagens / Q000737:chemistry* / Q000633:toxicity*; D011123:Polyploidy; D013329:Structure-Activity Relationship
D001713:Biphenyl Compounds; D009153:Mutagens
Exp Cell Res. 1984 Nov;155(1):315-9
6489464
Arh Hig Rada Toksikol. 2001 Jun;52(2):239-51
11370309
Environ Res. 2005 Jul;98(3):284-302
15910784
Environ Pollut. 2005 Nov;138(1):18-27
15899540
Mutat Res. 1983 May;120(2-3):193-9
6843582
Proc Natl Acad Sci U S A. 2000 Mar 28;97(7):3236-41
10725343
Mutat Res. 1993 Sep;297(2):101-80
7687323
Nat Rev Cancer. 2005 Oct;5(10):773-85
16195750
Environ Int. 2010 Nov;36(8):819-27
19375801
Proc Natl Acad Sci U S A. 1974 Aug;71(8):3162-6
4137928
Chem Res Toxicol. 2008 May;21(5):1017-27
18402468
Proc Natl Acad Sci U S A. 1993 Oct 15;90(20):9552-6
8105478
Chem Res Toxicol. 1996 Jan-Feb;9(1):158-64
8924585
Exp Cell Res. 1973 Oct;81(2):401-6
4128136
Environ Sci Technol. 2002 Nov 15;36(22):4735-40
12487293
Annu Rev Genet. 1977;11:183-201
74232
Arch Biochem Biophys. 2000 Apr 15;376(2):449-55
10775433
Arch Environ Contam Toxicol. 1996 Aug;31(2):271-6
8785012
Mutagenesis. 1997 Sep;12(5):365-72
9379916
Cell Motil Cytoskeleton. 2000 Oct;47(2):81-107
11013390
Toxicol Sci. 2007 Nov;100(1):88-98
17686921
J Biomed Mater Res A. 2005 Nov 1;75(2):439-44
16088893
Mutat Res. 1998 Nov 9;419(1-3):1-12
9804867
IUBMB Life. 2004 Feb;56(2):65-81
15085930
Cell Struct Funct. 2000 Feb;25(1):41-6
10791893
Biochem Pharmacol. 2008 Aug 1;76(3):312-21
18571148
J Environ Sci Health A Tox Hazard Subst Environ Eng. 2004;39(11-12):2755-72
15533002
Chemosphere. 2007 Apr;67(9):1838-51
17267022
Curr Opin Genet Dev. 2007 Apr;17(2):157-62
17324569
Methods Mol Biol. 1990;5:65-74
21374116
Mutagenesis. 1991 Jul;6(4):279-83
1943718
Nature. 1974 Sep 13;251(5471):156-8
4138930
Carcinogenesis. 2007 Feb;28(2):471-8
16950798
Chromosoma. 1998 Dec;107(6-7):486-90
9914381
Environ Health Perspect. 1989 Jul;82:81-9
2676505
J Natl Cancer Inst. 1990 Jul 4;82(13):1107-12
2359136
Toxicol Sci. 2004 May;79(1):41-6
14976334
Toxicol Appl Pharmacol. 2003 Jan 1;186(1):55-62
12583993
Chem Biol Interact. 2001 Sep 28;137(3):243-58
11566292
Proc Natl Acad Sci U S A. 1997 Dec 23;94(26):14506-11
9405643
Mutat Res. 1991 Sep;261(1):29-39
1715512
Cancer Res. 2001 Feb 1;61(3):818-22
11221861
Environ Sci Technol. 2008 Nov 1;42(21):7873-7
19031874
Chem Res Toxicol. 2002 Oct;15(10):1259-66
12387623