Investigating the role of transferrin in the distribution of iron, manganese, copper, and zinc

Abstract

The essential role of transferrin in mammalian iron metabolism is firmly established. Integral to our understanding of transferrin, studies in hpx mice, a model of inherited transferrin deficiency, have demonstrated that transferrin is essential for iron delivery for erythropoiesis and in the regulation of expression of hepcidin, a hormone that inhibits macrophage and enterocyte iron efflux. Here we investigate a potential role for transferrin in the distribution of three other physiologic metals, manganese, copper and zinc. We first assessed metal content in transferrin-rich fractions of wild-type mouse sera and demonstrate that while both iron and manganese cofractionate predominantly with transferrin, the absolute levels of manganese are several orders of magnitude lower than those of iron. We next measured metal content in multiple tissues in wild-type and hpx mice at various ages. Tissue metal imbalances were severe for iron and minimal to moderate for some metals in some tissues in hpx mice. Measurement of metal levels in a transferrin-replete yet hepcidin-deficient and iron-loaded mouse strain suggested that the observed imbalances in tissue copper, zinc and manganese levels were not all specific to hpx mice or caused directly by transferrin deficiency. Overall, our results suggest that transferrin does not have a primary role in the distribution of manganese, copper or zinc to tissues and that that the abnormalities observed in tissue manganese levels are not attributable to a direct role for transferrin in manganese metabolism but rather to an indirect effect of transferrin deficiency on hepcidin expression and/or iron metabolism.

Variance components of short-term biomarkers of manganese exposure in an inception cohort of welding trainees

“…Mn is known to complex with other substances in the plasma for transport [29, 30]. Animal studies have found that these plasma transporters used by Mn are also used by other metals such as iron, copper, or zinc [31–33]. Thus, co-exposures to these metals could explain some of the within-subject variation in MnP levels due to the competition for transporter binding.…”

Influence of iron metabolism on manganese transport and toxicity

“…Mice with decreased circulating Tf display reduced 54 Mn uptake as well as reduced steady-state levels of Mn in the liver 90, 91 , indicating that the Tf-TfR system is important for tissue distribution of Mn. Tf-mediated transport of Mn requires normal function of DMT1, as evidenced by the finding that b/b rats have impaired uptake of Tf-bound Mn, but not free Mn in serum 45 .…”

The use of hypotransferrinemic mice in studies of iron biology

“…Over the past several decades, this mouse line has been used in a multitude of studies. While some have focused on aberrant uptake or distribution of metals such as manganese, aluminum, gallium, cadmium, copper and zinc (Dickinson et al 1996; Radunović et al 1997; Takeda et al 1998; Raja et al 2006; Herrera et al 2014), most studies have employed this mouse model to study transferrin-dependent and -independent pathways of iron metabolism. As such, we will focus on transferrin and iron in this review.…”