Administration of high doses of copper to capuchin monkeys does not cause liver damage but induces transcriptional activation of hepatic proliferative responses.
Liver cells respond to copper loading upregulating protective mechanisms. However, to date, except for liver content, there are no good indicators that identify individuals with excess liver copper. We hypothesized that administering high doses of copper to young (5.5 mg Cu · kg⁻¹ . d⁻¹) and adult (7.5 mg Cu · kg⁻¹ . d⁻¹) capuchin monkeys would induce detectable liver damage. Study groups included adult monkeys (2 females, 2 males) 3-3.5 y old at enrollment treated with copper for 36 mo (ACu); age-matched controls (1 female, 3 males) that did not receive additional copper (AC); young monkeys (2 female, 2 males) treated from birth with copper for 36 mo (YCu); and young age-matched controls (2 female, 2 males) that did not receive additional copper (YC). We periodically assessed clinical, blood biochemical, and liver histological indicators and at 36 mo the hepatic mRNA abundance of MT2a, APP, DMT1, CTR1, HGF, TGFβ, and NFκΒ only in adult monkeys. After 36 mo, the liver copper concentration was 4-5 times greater in treated monkeys relative to controls. All monkeys remained healthy with normal routine serum biochemical indices and there was no evidence of liver tissue damage. Relative mRNA abundance of HGF, TGFβ and NFκB was significantly greater in ACu than in AC monkeys. In conclusion, capuchin monkeys exposed to copper at doses up to 50 times the current upper level enhanced expression of genes related to inflammation and injury without clinical, blood biochemical, or histological evidence of liver damage.
Institute of Nutrition and Food Technology, Universidad de Chile, Santiago, Chile. maraya@inta.cl
Magdalena
M
Araya
Héctor
H
Núñez
Leonardo
L
Pavez
Miguel
M
Arredondo
Marco
M
Méndez
Felipe
F
Cisternas
Fernando
F
Pizarro
Walter
W
Sierralta
Ricardo
R
Uauy
Mauricio
M
González
D000284:Administration, Oral; D000375:Aging; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002428:Cebus; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005942:Gluconates / Q000008:administration & dosage* / Q000032:analysis / Q000633:toxicity*; D006197:Hair / Q000737:chemistry; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008111:Liver Function Tests; D008297:Male; D023421:Models, Animal; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology*
D015415:Biomarkers; D005942:Gluconates; D012333:RNA, Messenger