PMID- 24046277
OWN - NLM
STAT- MEDLINE
DCOM- 20140804
LR  - 20131211
IS  - 1096-0929 (Electronic)
IS  - 1096-0929 (Linking)
VI  - 136
IP  - 2
DP  - 2013 Dec
TI  - A genomics-based analysis of relative potencies of dioxin-like compounds in 
      primary rat hepatocytes.
PG  - 595-604
LID - 10.1093/toxsci/kft203 [doi]
AB  - Toxic equivalency factors (TEFs) for dioxin-like compounds are largely based on 
      relative potency (REP) values derived from biochemical endpoints such as enzyme 
      activity. As of yet, REPs based on gene expression changes have not been 
      accounted for in the TEF values. In this study, primary rat hepatocytes were 
      treated for 24h with 11 concentrations of 2,3,7,8-tetrachlorodibenzo-p-dioxin, 
      2,3,4,7,8-pentachlorodibenzofuran (4-PeCDF), or 2,3,7,8-tetrachlorodibenzofuran 
      (TCDF) ranging from 0.00001 to 100 nM. Differential changes in gene expression 
      were analyzed using analysis of variance to assess the relative contributions of 
      concentration, congener, and the interaction between concentration and congener 
      for each gene. A total of 3283 genes showed significant changes with 
      concentration (false discovery rate < .05 and fold-change +/- 1.5 in at least 1 
      concentration for 1 congener). Among these genes, 399 were significant for both 
      concentration and congener effects indicating parallel concentration-response 
      curves with significant differences in potency. Only 8 genes showed a significant 
      concentration and congener interaction term indicating a minority of genes show 
      nonparallel dose-response curves among the 3 congeners. Benchmark dose (BMD) 
      modeling was used to derive BMD values for induced individual genes and signaling 
      pathways. The REP values for 4-PeCDF and TCDF were generally 3- to 5-fold lower 
      than the World Health Organization (WHO) TEF values on both a gene and pathway 
      basis. These findings suggest that the WHO TEF values may possibly overpredict 
      the potency of these polychlorinated dibenzofuran congeners and demonstrate the 
      importance of identifying functional pathways relevant to the toxicological modes 
      of action for establishing pertinent REPs.
FAU - Rowlands, J Craig
AU  - Rowlands JC
AD  - * Toxicology and Environmental Research and Consulting, The Dow Chemical Company, 
      Midland, Michigan 48674;
FAU - Budinsky, Robert
AU  - Budinsky R
FAU - Gollapudi, Bhaskar
AU  - Gollapudi B
FAU - Black, Michael B
AU  - Black MB
FAU - Wolfinger, Russell D
AU  - Wolfinger RD
FAU - Cukovic, Daniela
AU  - Cukovic D
FAU - Dombkowski, Alan
AU  - Dombkowski A
FAU - Thompson, Chad M
AU  - Thompson CM
FAU - Urban, Jonathan D
AU  - Urban JD
FAU - Thomas, Russell S
AU  - Thomas RS
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20130917
PL  - United States
TA  - Toxicol Sci
JT  - Toxicological sciences : an official journal of the Society of Toxicology
JID - 9805461
RN  - 0 (Dioxins)
SB  - IM
MH  - Animals
MH  - Cells, Cultured
MH  - Dioxins/*toxicity
MH  - Female
MH  - Gene Expression Regulation/drug effects
MH  - *Genomics
MH  - Hepatocytes/*drug effects/metabolism
MH  - Oligonucleotide Array Sequence Analysis
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Signal Transduction
OTO - NOTNLM
OT  - aryl hydrocarbon receptor
OT  - dioxin
OT  - dose response
OT  - risk assessment.
OT  - toxicogenomics
EDAT- 2013/09/21 06:00
MHDA- 2014/08/05 06:00
CRDT- 2013/09/19 06:00
PHST- 2013/09/19 06:00 [entrez]
PHST- 2013/09/21 06:00 [pubmed]
PHST- 2014/08/05 06:00 [medline]
AID - kft203 [pii]
AID - 10.1093/toxsci/kft203 [doi]
PST - ppublish
SO  - Toxicol Sci. 2013 Dec;136(2):595-604. doi: 10.1093/toxsci/kft203. Epub 2013 Sep 
      17.