Baseline distribution of stable copper isotope compositions of the brain and other organs in mice

Copper (Cu) stable isotopes are useful for understanding pathways and tracing changes in Cu homeostasis, such as those induced by various diseases (e.g. liver cirrhosis, numerous forms of cancer, and neurodegenerative diseases). However, this utility relies on a baseline understanding of the natural distribution of Cu isotopes between organs of healthy organisms, which is not well-known at present. Here, the distribution of natural Cu isotopes in the brain, liver, red blood cells, plasma, kidneys, and muscle of 14 mice (7 males and 7 females) from three different genetic backgrounds is assessed. We show that the Cu isotopic composition of most mouse organs is isotopically distinct from one another. The most striking feature is the heavy isotope enrichment of the kidney (delta Cu-65 = 1.65 +/- 0.06 parts per thousand, 2SE), brain (delta Cu-65 = 0.87 +/- 0.03 parts per thousand, 2SE) and liver (delta Cu-65 = 0.71 +/- 0.24 parts per thousand, 2SE) compared to blood components, i.e. red blood cells (RBCs) (delta Cu-65 = 0.30 +/- 0.06 parts per thousand, 2SE), and plasma (delta Cu-65 = -0.61 +/- 0.08 parts per thousand, 2SE), with delta Cu-65 being the per mil deviation of the Cu-65/Cu-63 ratio from the NIST SRM 976 standard. Differences in genetic background do not appear to affect the isotopic distribution of Cu. Interestingly, male and female mice appear to have different Cu concentrations and isotopic compositions in their brain, plasma, muscle, and RBC. By demonstrating that organs have distinct isotopic compositions, our study reinforces the notion that Cu stable isotopes can be used to trace changes in homeostasis in diseases affecting Cu distribution, such as Alzheimer's disease, liver cancer, and possible chronic kidney failure.