The pesticide adjuvant, Toximul, alters hepatic metabolism through effects on downstream targets of PPARalpha.
Previous studies demonstrated that chronic dermal exposure to the pesticide adjuvant (surfactant), Toximul (Tox), has significant detrimental effects on hepatic lipid metabolism. This study demonstrated that young mice dermally exposed to Tox for 12 days have significant increases in expression of peroxisomal acyl-CoA oxidase (mRNA and protein), bifunctional enzyme (mRNA) and thiolase (mRNA), as well as the P450 oxidizing enzymes Cyp4A10 and Cyp4A14 (mRNA and protein). Tox produced a similar pattern of increases in wild type adult female mice but did not induce these responses in PPARalpha-null mice. These data support the hypothesis that Tox, a heterogeneous blend of nonionic and anionic surfactants, modulates hepatic metabolism at least in part through activation of PPARalpha. Notably, all three groups of Tox-treated mice had increased relative liver weights due to significant accumulation of lipid. This could be endogenous in nature and/or a component(s) of Tox or a metabolite thereof. The ability of Tox and other hydrocarbon pollutants to induce fatty liver despite being PPARalpha agonists indicates a novel consequence of exposure to this class of chemicals, and may provide a new understanding of fatty liver in populations with industrial exposure.
Upham
Jacqueline
J
Departments of Physiology and Biophysics, 5850 College Street, Sir Charles Tupper Medical Building, Dalhousie University, Halifax, Nova Scotia, Canada B3H 1X5.
Acott
Philip D
PD
O'regan
Patrick
P
Sinal
Christopher J
CJ
Crocker
John F S
JF
Geldenhuys
Laurette
L
Murphy
Mary G
MG
D015094:3-Hydroxyacyl CoA Dehydrogenases / Q000378:metabolism; D000102:Acetyl-CoA C-Acyltransferase / Q000378:metabolism; D042962:Acyl-CoA Oxidase; D000818:Animals; D042926:Cytochrome P-450 CYP4A / Q000235:genetics / Q000378:metabolism; D004746:Enoyl-CoA Hydratase / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism; D005234:Fatty Liver / Q000139:chemically induced / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D007535:Isomerases / Q000378:metabolism; D008099:Liver / Q000033:anatomy & histology / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D009097:Multienzyme Complexes / Q000378:metabolism; D009930:Organic Chemicals / Q000633:toxicity; D010088:Oxidoreductases / Q000378:metabolism; D047493:PPAR alpha / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D063994:Peroxisomal Bifunctional Enzyme; D010574:Pesticide Synergists / Q000633:toxicity; D013501:Surface-Active Agents / Q000633:toxicity
D005227:Fatty Acids; D009097:Multienzyme Complexes; D009930:Organic Chemicals; D047493:PPAR alpha; D010574:Pesticide Synergists; D013501:Surface-Active Agents; C019116:Toximul MP8; D010088:Oxidoreductases; D015094:3-Hydroxyacyl CoA Dehydrogenases; D042926:Cytochrome P-450 CYP4A; C107176:peroxisomal acyl-CoA oxidase; D042962:Acyl-CoA Oxidase; C486233:Acaa1a protein, mouse; C486234:Acaa1b protein, mouse; D000102:Acetyl-CoA C-Acyltransferase; C576254:Ehhadh protein, mouse; D004746:Enoyl-CoA Hydratase; D063994:Peroxisomal Bifunctional Enzyme; D007535:Isomerases