Administration of High Doses of Copper to Capuchin Monkeys Does Not Cause Liver Damage but Induces Transcriptional Activation of Hepatic Proliferative Responses1–3

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 × kg21 . d21) and adult (7.5 mg Cu × kg21 . d21) 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, TGFb, and NFk 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, TGFb and NFkB 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.Supported by Corporacio´n Chilena del Cobre (CTA/Cochilco), the International Copper Association in the form of unrestricted research grants, Fondecyt 1071083, Fondecyt 1070595, and FONDAP 15090007