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Using nuclear receptor activity to stratify hepatocarcinogens.

Shah I, Houck K, Judson RS, Kavlock RJ, Martin MT, Reif DM, Wambaugh J, Dix DJ - PLoS ONE (2011)

Bottom Line: The effects of 309 environmental chemicals on human constitutive androstane receptors (CAR/NR1I3), pregnane X receptor (PXR/NR1I2), aryl hydrocarbon receptor (AhR), peroxisome proliferator-activated receptors (PPAR/NR1C), liver X receptors (LXR/NR1H), retinoic X receptors (RXR/NR2B) and steroid receptors (SR/NR3) were determined using in vitro data.The rodent carcinogens had higher in vitro potency for human NR relative to non-carcinogens.More importantly, these findings suggest the utility of in vitro assays for stratifying environmental contaminants based on a combination of human bioactivity and rodent toxicity.

View Article: PubMed Central - PubMed

Affiliation: National Center for Computational Toxicology, Office of Research and Development, United States Environmental Protection Agency, Research Triangle Park, North Carolina, United States of America. shah.imran@epa.gov

ABSTRACT

Background: Nuclear receptors (NR) are a superfamily of ligand-activated transcription factors that control a range of cellular processes. Persistent stimulation of some NR is a non-genotoxic mechanism of rodent liver cancer with unclear relevance to humans. Here we report on a systematic analysis of new in vitro human NR activity data on 309 environmental chemicals in relationship to their liver cancer-related chronic outcomes in rodents.

Results: The effects of 309 environmental chemicals on human constitutive androstane receptors (CAR/NR1I3), pregnane X receptor (PXR/NR1I2), aryl hydrocarbon receptor (AhR), peroxisome proliferator-activated receptors (PPAR/NR1C), liver X receptors (LXR/NR1H), retinoic X receptors (RXR/NR2B) and steroid receptors (SR/NR3) were determined using in vitro data. Hepatic histopathology, observed in rodents after two years of chronic treatment for 171 of the 309 chemicals, was summarized by a cancer lesion progression grade. Chemicals that caused proliferative liver lesions in both rat and mouse were generally more active for the human receptors, relative to the compounds that only affected one rodent species, and these changes were significant for PPAR (p0.001), PXR (p0.01) and CAR (p0.05). Though most chemicals exhibited receptor promiscuity, multivariate analysis clustered them into relatively few NR activity combinations. The human NR activity pattern of chemicals weakly associated with the severity of rodent liver cancer lesion progression (p0.05).

Conclusions: The rodent carcinogens had higher in vitro potency for human NR relative to non-carcinogens. Structurally diverse chemicals with similar NR promiscuity patterns weakly associated with the severity of rodent liver cancer progression. While these results do not prove the role of NR activation in human liver cancer, they do have implications for nuclear receptor chemical biology and provide insights into putative toxicity pathways. More importantly, these findings suggest the utility of in vitro assays for stratifying environmental contaminants based on a combination of human bioactivity and rodent toxicity.

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Nuclear receptor activity and cancer lesion progression.Visualizing the relationship between the aggregate nuclear receptor activities across the lesion progression group as a heatmap. The rows of the heatmap signify the lesion progression groups I-VIII and the columns show the aggregate nuclear receptor activities. The colors represent the ratio of the aggregate nuclear receptor activity between chemicals in a lesion progression group compared to others: decreased activities are shown in blue, no changes are shown in white and increased activity is shown in red. Statistically significant changes are shown with a yellow asterisk in the cell.
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pone-0014584-g003: Nuclear receptor activity and cancer lesion progression.Visualizing the relationship between the aggregate nuclear receptor activities across the lesion progression group as a heatmap. The rows of the heatmap signify the lesion progression groups I-VIII and the columns show the aggregate nuclear receptor activities. The colors represent the ratio of the aggregate nuclear receptor activity between chemicals in a lesion progression group compared to others: decreased activities are shown in blue, no changes are shown in white and increased activity is shown in red. Statistically significant changes are shown with a yellow asterisk in the cell.

Mentions: We assumed that dose selection was not an issue for the 171 chemicals that produced at least some liver toxicity in chronic rodent testing. Out of these 171 chemicals, 66 were mild hepatotoxicants, 43 produced different grades of proliferative lesions in rat and mouse, and 13 chemicals caused neoplastic lesions in both species. The severity and concordance of hepatic lesions across these 171 chemicals were clustered by similarity into eight lesion progression groups shown in Figure 2(c) (see Methods). The aggregate NR activities were systematically compared across all lesion progression groups (LPG) and visualized in Figure 3. The rows in Figure 3 correspond to the eight lesion progression groups (LPG I, II, III, IV, V, VI, VII, VIII) shown in Figure 2(c), and the columns are the NR: AhR, CAR, PXR, PPAR, LXR, SR, RXR. Each cell in the heatmap shows the ratio of the mean NR activities of chemicals in a LPG compared to all other LPG. The statistical significance of differences in mean NR activity was evaluated by permutation and corrected for multiple testing (see Methods). AhR, PPAR, SR and RXR showed 9% to 250% higher average activity for chemicals in LPG I as compared to the other chemicals but only PPAR showed a statistically significant (p0.001) increase of 150%. For LPG II chemicals, all NR showed some increased activity except LXR, but only PPAR and PXR had statistically significant (p0.05) increases in activity of 80% and 50%, respectively. There were no statistically significant differences in NR activities for chemicals that produced only mouse proliferative lesions, however, the subset of mouse carcinogens showed a 30% increase in AhR activity but a 30% decrease in PPAR activity. Chemicals that produced only rat hepatic neoplasms had a 75% increase in PPAR activity, 23% increase in CAR activity and 30% increase LXR activity but none were statistically significant.


Using nuclear receptor activity to stratify hepatocarcinogens.

Shah I, Houck K, Judson RS, Kavlock RJ, Martin MT, Reif DM, Wambaugh J, Dix DJ - PLoS ONE (2011)

Nuclear receptor activity and cancer lesion progression.Visualizing the relationship between the aggregate nuclear receptor activities across the lesion progression group as a heatmap. The rows of the heatmap signify the lesion progression groups I-VIII and the columns show the aggregate nuclear receptor activities. The colors represent the ratio of the aggregate nuclear receptor activity between chemicals in a lesion progression group compared to others: decreased activities are shown in blue, no changes are shown in white and increased activity is shown in red. Statistically significant changes are shown with a yellow asterisk in the cell.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3038857&req=5

pone-0014584-g003: Nuclear receptor activity and cancer lesion progression.Visualizing the relationship between the aggregate nuclear receptor activities across the lesion progression group as a heatmap. The rows of the heatmap signify the lesion progression groups I-VIII and the columns show the aggregate nuclear receptor activities. The colors represent the ratio of the aggregate nuclear receptor activity between chemicals in a lesion progression group compared to others: decreased activities are shown in blue, no changes are shown in white and increased activity is shown in red. Statistically significant changes are shown with a yellow asterisk in the cell.
Mentions: We assumed that dose selection was not an issue for the 171 chemicals that produced at least some liver toxicity in chronic rodent testing. Out of these 171 chemicals, 66 were mild hepatotoxicants, 43 produced different grades of proliferative lesions in rat and mouse, and 13 chemicals caused neoplastic lesions in both species. The severity and concordance of hepatic lesions across these 171 chemicals were clustered by similarity into eight lesion progression groups shown in Figure 2(c) (see Methods). The aggregate NR activities were systematically compared across all lesion progression groups (LPG) and visualized in Figure 3. The rows in Figure 3 correspond to the eight lesion progression groups (LPG I, II, III, IV, V, VI, VII, VIII) shown in Figure 2(c), and the columns are the NR: AhR, CAR, PXR, PPAR, LXR, SR, RXR. Each cell in the heatmap shows the ratio of the mean NR activities of chemicals in a LPG compared to all other LPG. The statistical significance of differences in mean NR activity was evaluated by permutation and corrected for multiple testing (see Methods). AhR, PPAR, SR and RXR showed 9% to 250% higher average activity for chemicals in LPG I as compared to the other chemicals but only PPAR showed a statistically significant (p0.001) increase of 150%. For LPG II chemicals, all NR showed some increased activity except LXR, but only PPAR and PXR had statistically significant (p0.05) increases in activity of 80% and 50%, respectively. There were no statistically significant differences in NR activities for chemicals that produced only mouse proliferative lesions, however, the subset of mouse carcinogens showed a 30% increase in AhR activity but a 30% decrease in PPAR activity. Chemicals that produced only rat hepatic neoplasms had a 75% increase in PPAR activity, 23% increase in CAR activity and 30% increase LXR activity but none were statistically significant.

Bottom Line: The effects of 309 environmental chemicals on human constitutive androstane receptors (CAR/NR1I3), pregnane X receptor (PXR/NR1I2), aryl hydrocarbon receptor (AhR), peroxisome proliferator-activated receptors (PPAR/NR1C), liver X receptors (LXR/NR1H), retinoic X receptors (RXR/NR2B) and steroid receptors (SR/NR3) were determined using in vitro data.The rodent carcinogens had higher in vitro potency for human NR relative to non-carcinogens.More importantly, these findings suggest the utility of in vitro assays for stratifying environmental contaminants based on a combination of human bioactivity and rodent toxicity.

View Article: PubMed Central - PubMed

Affiliation: National Center for Computational Toxicology, Office of Research and Development, United States Environmental Protection Agency, Research Triangle Park, North Carolina, United States of America. shah.imran@epa.gov

ABSTRACT

Background: Nuclear receptors (NR) are a superfamily of ligand-activated transcription factors that control a range of cellular processes. Persistent stimulation of some NR is a non-genotoxic mechanism of rodent liver cancer with unclear relevance to humans. Here we report on a systematic analysis of new in vitro human NR activity data on 309 environmental chemicals in relationship to their liver cancer-related chronic outcomes in rodents.

Results: The effects of 309 environmental chemicals on human constitutive androstane receptors (CAR/NR1I3), pregnane X receptor (PXR/NR1I2), aryl hydrocarbon receptor (AhR), peroxisome proliferator-activated receptors (PPAR/NR1C), liver X receptors (LXR/NR1H), retinoic X receptors (RXR/NR2B) and steroid receptors (SR/NR3) were determined using in vitro data. Hepatic histopathology, observed in rodents after two years of chronic treatment for 171 of the 309 chemicals, was summarized by a cancer lesion progression grade. Chemicals that caused proliferative liver lesions in both rat and mouse were generally more active for the human receptors, relative to the compounds that only affected one rodent species, and these changes were significant for PPAR (p0.001), PXR (p0.01) and CAR (p0.05). Though most chemicals exhibited receptor promiscuity, multivariate analysis clustered them into relatively few NR activity combinations. The human NR activity pattern of chemicals weakly associated with the severity of rodent liver cancer lesion progression (p0.05).

Conclusions: The rodent carcinogens had higher in vitro potency for human NR relative to non-carcinogens. Structurally diverse chemicals with similar NR promiscuity patterns weakly associated with the severity of rodent liver cancer progression. While these results do not prove the role of NR activation in human liver cancer, they do have implications for nuclear receptor chemical biology and provide insights into putative toxicity pathways. More importantly, these findings suggest the utility of in vitro assays for stratifying environmental contaminants based on a combination of human bioactivity and rodent toxicity.

Show MeSH
Related in: MedlinePlus