Structure-activity relationships and human relevance for perfluoroalkyl acid-induced transcriptional activation of peroxisome proliferation in liver cell cultures.
Toxicol Sci
; 111(1): 89-99, 2009 Sep.
Article
em En
| MEDLINE
| ID: mdl-19407336
ABSTRACT
Perfluoroalkyl acids (PFAAs) are widely distributed and environmentally persistent agents whose potential toxicity is not yet fully characterized. Perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid elicit a number of potential toxicities in rodents, the most prevalent of which are governed by activation of the peroxisome proliferator-activated receptor alpha (PPARalpha). The purpose of this investigation was twofold (1) To conduct a structure-activity relationship study of the transcriptional activation of peroxisome proliferation in primary rat liver cell cultures for PFAA-related carboxylic and sulfonic acids of varying carbon chain length and (2) to explore whether this activity can be translated to human liver cells in culture. Exposure to PFOA caused a dose-dependent stimulation of the expression of acyl-CoA oxidase (Acox), Cte/Acot1, and Cyp4a1/11 transcripts that are indicative of peroxisome proliferation in primary rat hepatocytes. PFOA concentrations of 30 microM and above caused cell injury characterized by the expression of Ddit3. Perfluorobutanoic acid (PFBA), on the other hand, stimulated Acox, Cte/Acot1, and Cyp4a1/11 gene expression in primary rat hepatocytes only at concentrations of 100 microM and above. Neither PFOA nor PFBA at concentrations up to 200 microM stimulated PPARalpha-related gene expression in either primary or HepG2 human liver cells. These data demonstrate that (1) PFFAs cause a concentration- and chain length-dependent increase in expression of gene targets related to cell injury and PPARalpha activation in primary rat hepatocytes, (2) the sulfonates are less potent than the corresponding carboxylates in stimulating PPARalpha-related gene expression in rat hepatocytes, and (3) stimulation of PPARalpha-mediated gene transcription is a mechanism that is not shared by human liver cells, adding further substantiation that PPARalpha-dependent liver toxicity in rodents does not extrapolate to assessing human health concerns.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proliferadores de Peroxissomos
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Hepatócitos
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Fígado
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Toxicol Sci
Assunto da revista:
TOXICOLOGIA
Ano de publicação:
2009
Tipo de documento:
Article
País de afiliação:
Estados Unidos