Copper toxicology, oxidative stress and inflammation using zebrafish as experimental model

Abstract

Copper is an essential micronutrient and a key catalytic cofactor in a wide range of enzymes. As a trace element, copper levels are tightly regulated and both its deficit and excess are deleterious to the organism. Under inflammatory conditions, serum copper levels are increased and trigger oxidative stress responses that activate inflammatory responses. Interestingly, copper dyshomeostasis, oxidative stress and inflammation are commonly present in several chronic diseases. Copper exposure can be easily modeled in zebrafish; a consolidated model in toxicology with increasing interest in immunity-related research. As a result of developmental, economical and genetic advantages, this freshwater teleost is uniquely suitable for chemical and genetic large-scale screenings, representing a powerful experimental tool for a whole-organism approach, mechanistic studies, disease modeling and beyond. Copper toxicological and more recently pro-inflammatory effects have been investigated in both larval and adult zebrafish with breakthrough findings. Here, we provide an overview of copper metabolism in health and disease and its effects on oxidative stress and inflammation responses in zebrafish models. Copper-induced inflammation is highlighted owing to its potential to easily mimic pro-oxidative and pro-inflammatory features that combined with zebrafish genetic tractability could help further in the understanding of copper metabolism, inflammatory responses and related diseases. Copyright © 2016 John Wiley & Sons, Ltd.

Cu(I) Disrupts the Structure and Function of the Nonclassical Zinc Finger Protein Tristetraprolin (TTP)

“…While under most cellular conditions Cu(I) levels are tightly controlled and free Cu(I) concentrations are very low, 62 several disease states are characterized by misregulation of cellular copper. 56,73,87–91 A clear understanding of Cu(I) binding to Zn(II)-metalloproteins is important in identifying putative targets for disruption by Cu(I) under conditions of copper misregulation. Previous work has shown that the ZF-based Sp1 transcription factor regulates the expression of multiple copper-binding proteins in response to fluctuations in copper concentrations, and it is hypothesized that the ZFs in Sp1 function as intracellular copper sensors via copper interaction at the zinc binding sites.…”

“…68,70–72 The two CCCH domains must be bound to zinc (or iron) and folded in order for the protein to bind to mRNA. 1,44 There is evidence that Cu(I) levels are elevated during inflammation, 73,74 suggesting that Cu(I) may target TTP and affect its function, making it a particularly relevant ZF to utilize for studies aimed at understanding how Cu(I) can target ZF sites. We prepared a single- and double-domain construct of TTP, called TTP-1D and TTP-2D, and measured the structural and, for TTP-2D, the functional affects of Cu(I) binding.…”

Can CuO nanoparticles lead to epigenetic regulation of antioxidant enzyme system?

“…(); Song et al ., ; Ahamed et al ., ). CuO NPs also exhibit neurotoxicity and genotoxicity in vivo , and ROS generation was suggested to be the reason for the induction in toxicity (Pereira et al ., ).…”

Serum Zn/Cu Ratio Is Associated with Renal Function, Glycemic Control, and Metabolic Parameters in Japanese Patients with and without Type 2 Diabetes: A Cross-sectional Study

“…Cu ion may also play a protective role in the accumulation of human islet amyloid peptide, which is the major component of amyloid deposits in pancreatic β-cells of type 2 diabetic patients; however, whether or not Cu have a protective role in the etiology of type 2 diabetes is not clarified (19, 20). Excess of Cu under inflammatory conditions trigger oxidative stress which are present in chronic diseases (21). On the other hand, increased Zn ion levels may provide a protective effect against Cu toxicity by competing for Cu binding sites (16).…”