Analysis of the CYP1A1 mRNA dose-response in human keratinocytes indicates that relative potencies of dioxins, furans, and PCBs are species and congener specific.
Reports indicate that toxic equivalency factors (TEFs) based primarily on rodent data do not accurately predict in vitro human responsiveness to certain dioxin-like chemicals (DLCs). To investigate this in cells responsive to dioxins and relevant to chloracne, normal human epidermal keratinocytes were treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and several DLCs, each with a TEF value of 0.1, representing three classes of congeners. We estimated half maximal effective concentration (EC50)-based donor-specific relative potency (REP) values for cytochrome P450 1A1 (CYP1A1) messenger RNA (mRNA) induction for TCDD, 1,2,3,6,7,8-hexachlorodibenzo-p-dioxin (HxCDD), 2,3,7,8-tetrachlorodibenzofuran (TCDF), 1,2,3,6,7,8-hexachlorodibenzofuran (HxCDF), and 3,3',4,4',5-pentachlorobiphenyl (PCB 126). We also determined EC50-based population-level REP values (n = 4) for CYP1A1 mRNA induction for TCDD, HxCDF, and PCB 126. Furthermore, an alternative factor, the relative threshold factor (RTF) based on the low end (threshold) of the dose-response curve, was calculated. Our results demonstrated that HxCDF had a population-based REP value of 0.98, 9.8-fold higher than its assigned TEF value of 0.1. Conversely, PCB 126 had an REP value of 0.0027 and an RTF of 0.0022, 37-fold and 45-fold less than its assigned TEF of 0.1, respectively. The REP values for HxCDD and TCDF were 0.24 and 0.10, respectively, similar to their assigned value of 0.1. Therefore, although the DLCs tested in the current study all possessed the same assigned TEF value of 0.1, congener-specific differences in REPs and RTFs were observed for human keratinocytes. These congener-specific discrepancies are likely because of differences in interspecies factors that have yet to be defined.
Sutter
Carrie H
CH
Department of Biological Sciences and W. Harry Feinstone Center for Genomic Research, University of Memphis, Memphis, Tennessee 38152-3560, USA. csutter@memphis.edu
Bodreddigari
Sridevi
S
Sutter
Thomas R
TR
Carlson
Erik A
EA
Silkworth
Jay B
JB
D000818:Animals; D001572:Benzofurans / Q000633:toxicity*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics* / Q000378:metabolism; D004147:Dioxins / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004785:Environmental Pollutants / Q000633:toxicity*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects* / Q000378:metabolism; D011078:Polychlorinated Biphenyls / Q000633:toxicity*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D018570:Risk Assessment; D013045:Species Specificity
D001572:Benzofurans; D004147:Dioxins; D004785:Environmental Pollutants; D012333:RNA, Messenger; D011078:Polychlorinated Biphenyls; D019363:Cytochrome P-450 CYP1A1; C023035:3,4,5,3',4'-pentachlorobiphenyl
Toxicol Sci. 2004 Dec;82(2):488-96
15456928
Toxicol Sci. 2004 Apr;78(2):178-80
14976344
Biometrics. 1990 Sep;46(3):673-87
2242409
Mol Pharmacol. 2007 Dec;72(6):1393-401
17901198
J Biol Chem. 1994 Nov 4;269(44):27337-43
7961644
Environ Health Perspect. 2010 May;118(5):666-72
20435555
Toxicol Appl Pharmacol. 1980 Jul;54(3):377-83
7394793
Toxicol Appl Pharmacol. 1996 Sep;140(1):173-9
8806883
Comp Biochem Physiol C Toxicol Pharmacol. 2009 Mar;149(2):175-81
19135172
Anal Biochem. 2009 Jan 15;384(2):279-87
18938125
Arch Toxicol. 2008 Dec;82(12):909-21
18493746
Chem Res Toxicol. 2009 Jul;22(7):1264-76
19449824
Annu Rev Pharmacol Toxicol. 1982;22:517-54
6282188
Biochem J. 1913 Oct;7(5):471-80
16742267
BMC Genomics. 2008 Dec 23;9:628
19105848
Toxicol Sci. 2000 Feb;53(2):316-25
10696780
Toxicol Sci. 2001 Sep;63(1):65-73
11509745
Toxicol Appl Pharmacol. 2008 Mar 1;227(2):196-206
18048071
Arch Biochem Biophys. 2008 Mar 15;471(2):215-23
18242161
Environ Health Perspect. 2009 May;117(5):811-7
19479026
Regul Toxicol Pharmacol. 2006 Apr;44(3):219-25
16460856
Toxicol Sci. 2004 Apr;78(2):276-86
15014209
Toxicol Sci. 2006 May;91(1):275-85
16455694
Toxicol Sci. 2009 Nov;112(1):257-72
19692669
Proc Natl Acad Sci U S A. 2009 Mar 17;106(11):4266-71
19255421
Toxicol Sci. 2006 Oct;93(2):223-41
16829543
Toxicol Appl Pharmacol. 2004 May 1;196(3):410-21
15094312
Cancer Res. 1988 May 1;48(9):2388-95
2833345
Cancer Res. 1992 Jun 15;52(12):3436-42
1596902
J Pharmacol Exp Ther. 2007 Jan;320(1):1-13
16803859
Nucleic Acids Res. 2001 May 1;29(9):e45
11328886
Toxicol Pathol. 2007 Oct;35(6):848-9
17987516
Proc Natl Acad Sci U S A. 2010 Jan 19;107(3):1247-52
20080566
Toxicol Sci. 2006 Jan;89(1):4-30
16120753
Arch Toxicol. 1980 Nov;46(1-2):21-30
7235996
Toxicol Appl Pharmacol. 2004 Jan 15;194(2):156-68
14736496
Mol Pharmacol. 2007 Nov;72(5):1097-9
17717108
Toxicol Sci. 2005 Oct;87(2):508-19
16049271
Environ Health Perspect. 1985 Feb;59:107-12
2985377
Biochem J. 1991 Jul 15;277 ( Pt 2):577-80
1859384
Mol Pharmacol. 2004 Jul;66(1):129-36
15213304
Environ Health Perspect. 1979 Oct;32:193-9
540593
Toxicol Sci. 2004 Apr;78(2):287-94
14976353
Mutat Res. 2009 Aug;678(2):118-22
19477296
Toxicol Sci. 2005 Nov;88(1):82-94
16081525
Arch Toxicol. 1992;66(3):220-3
1497488