PMID- 19042947
OWN - NLM
STAT- MEDLINE
DCOM- 20090311
LR  - 20191210
IS  - 1096-0929 (Electronic)
IS  - 1096-0929 (Linking)
VI  - 107
IP  - 2
DP  - 2009 Feb
TI  - Evaluation of a toxicogenomic approach to the local lymph node assay (LLNA).
PG  - 427-39
LID - 10.1093/toxsci/kfn247 [doi]
AB  - Genomic technologies have the potential to enhance and complement existing 
      toxicology endpoints; however, assessment of these approaches requires a 
      systematic evaluation including a robust experimental design with genomic 
      endpoints anchored to traditional toxicology endpoints. The present study was 
      conducted to assess the sensitivity of genomic responses when compared with the 
      traditional local lymph node assay (LLNA) endpoint of lymph node cell 
      proliferation and to evaluate the responses for their ability to provide insights 
      into mode of action. Female BALB/c mice were treated with the sensitizer 
      trimellitic anhydride (TMA), following the standard LLNA dosing regimen, at doses 
      of 0.1, 1, or 10% and traditional tritiated thymidine ((3)HTdR) incorporation and 
      gene expression responses were monitored in the auricular lymph nodes. Additional 
      mice dosed with either vehicle or 10% TMA and sacrificed on day 4 or 10, were 
      also included to examine temporal effects on gene expression. Analysis of (3)HTdR 
      incorporation revealed TMA-induced stimulation indices of 2.8, 22.9, and 61.0 
      relative to vehicle with an EC(3) of 0.11%. Examination of the dose-response gene 
      expression responses identified 9, 833, and 2122 differentially expressed genes 
      relative to vehicle for the 0.1, 1, and 10% TMA dose groups, respectively. 
      Calculation of EC(3) values for differentially expressed genes did not identify a 
      response that was more sensitive than the (3)HTdR value, although a number of 
      genes displayed comparable sensitivity. Examination of temporal responses 
      revealed 1760, 1870, and 953 differentially expressed genes at the 4-, 6-, and 
      10-day time points respectively. Functional analysis revealed many responses 
      displayed dose- and time-specific induction patterns within the functional 
      categories of cellular proliferation and immune response, including numerous 
      immunoglobin genes which were highly induced at the day 10 time point. Overall, 
      these experiments have systematically illustrated the potential utility of 
      genomic endpoints to enhance the LLNA and support further exploration of this 
      approach through examination of a more diverse array of chemicals.
FAU - Boverhof, Darrell R
AU  - Boverhof DR
AD  - Toxicology & Environmental Research and Consulting, The Dow Chemical Company, 
      Midland, Michigan 48674, USA. RBoverhof@dow.com
FAU - Gollapudi, B Bhaskar
AU  - Gollapudi BB
FAU - Hotchkiss, Jon A
AU  - Hotchkiss JA
FAU - Osterloh-Quiroz, Mandy
AU  - Osterloh-Quiroz M
FAU - Woolhiser, Michael R
AU  - Woolhiser MR
LA  - eng
PT  - Evaluation Study
PT  - Journal Article
DEP - 20081128
PL  - United States
TA  - Toxicol Sci
JT  - Toxicological sciences : an official journal of the Society of Toxicology
JID - 9805461
RN  - 0 (Phthalic Anhydrides)
RN  - 63231-63-0 (RNA)
RN  - 80T61EUU7H (trimellitic anhydride)
RN  - VC2W18DGKR (Thymidine)
SB  - IM
MH  - Algorithms
MH  - Animals
MH  - Cell Proliferation/drug effects
MH  - Cluster Analysis
MH  - Data Interpretation, Statistical
MH  - Dose-Response Relationship, Drug
MH  - Endpoint Determination
MH  - Female
MH  - Gene Expression/drug effects
MH  - Immunity, Cellular/drug effects
MH  - *Local Lymph Node Assay
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Oligonucleotide Array Sequence Analysis
MH  - Phthalic Anhydrides/toxicity
MH  - RNA/biosynthesis/genetics
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Thymidine/metabolism
MH  - Toxicogenetics/*methods
EDAT- 2008/12/02 09:00
MHDA- 2009/03/12 09:00
CRDT- 2008/12/02 09:00
PHST- 2008/12/02 09:00 [pubmed]
PHST- 2009/03/12 09:00 [medline]
PHST- 2008/12/02 09:00 [entrez]
AID - kfn247 [pii]
AID - 10.1093/toxsci/kfn247 [doi]
PST - ppublish
SO  - Toxicol Sci. 2009 Feb;107(2):427-39. doi: 10.1093/toxsci/kfn247. Epub 2008 Nov 
      28.