Iron Metabolism and Absorption Studies in the X‐linked Anaemia of Mice

Abstract

The X-linked anaemia of mice (gene symbol, sla) is hypochromic and microcytic, and the stainable iron stores are reduced. Chemical estimates of total body iron content and serum iron concentration show low values and the total serum iron binding capacity is elevated in anaemic mice. Rapid plasma iron clearance and increased iron utilization provide further confirmation of iron deficiency in anaemic animals. Alterations in activity of haem-containing enzymes have been sought in the heart, liver and kidney of anaemic mice, and slightly decreased activity found only in kidney cytochrome oxidase.The blood volume of mice with X-linked anaemia is increased in spite of decreased red cell mass, and thus the anaemia is in part due to dilution. The cause of the increased blood volume has not been elucidated, but it may be related to splenic enlargement. In contrast to iron depleted humans and experimental animals, mice with X-linked anaemia show impaired rather than increased intestinal iron absorption, indicating that the anaemia is a consequence of iron malabsorption. The defect in iron absorption may be an isolated one, since evidence of impaired retention of orally administered radio-iodinated tciolein, radio-zinc, radio-copper and radio-cobalt has not been found. It is suggested that the genetically-determined defect in the intestinal mucosa of mice with X-linked anaemia may be due to deficiency of either an enzyme or a carrier substance necessary for the normal transfer of iron from the intestinal mucosal cell to the plasma.The X-linked anaemia of mice is inherited as a recessive trait. The mutation arose in a mixed stock of mice following radiation, and the locus was shown to be near Tabby (Ta) and Brindled (Mo") on the X chromosome (Falconer & Isaacson, 1962). The gene symbol is sla, standing for sex-linked anaemia. The anaemia is hypochromic and microcytic (Grewal, 1962;Bannerman & Pinkerton, 1967). In young hemizygous male (sla/ -) and homozygous female (sla/sla) animals the haemoglobin concentration is generally between 5 and 8 g / I m ml. Spontaneous improvement may occur with age, and a rapid rise in haemoglobin and haematocrit follows

Systemic regulation of Hephaestin and Ireg1 revealed in studies of genetic and nutritional iron deficiency

“…21,37 Despite the recovery in hemoglobin levels, sla mice continue to be severely iron deficient as shown in this and previous studies. 38 In our study, sla mice have even lower liver iron levels than wild-type mice on an iron-deficient diet. The sla mouse therefore represents a unique model in which cellular iron levels are increased in the intestinal enterocytes yet systemic iron levels are low.…”

“…These results are consistent with previous reports that also show the persistent iron deficiency in sex-linked anemia. 38 …”

Hephaestin is a ferroxidase that maintains partial activity in sex-linked anemia mice

“…44 The severity of the anemia decreases with age, 45 although the animals remain iron deficient. 9,46 Despite this defect, sla mice absorb sufficient iron for normal development and reproduction. Previously, we suggested that either Hp is not absolutely required for intestinal iron transport 25 or that additional ferroxidases such as ceruloplasmin could compensate.…”

Intestinal hephaestin potentiates iron absorption in weanling, adult, and pregnant mice under physiological conditions

“…Sla and Heph (whole-body) KO mice are anemic during the rapid postnatal growth period, and intestinal iron absorption is impaired 15,28,29 ; however, the specific contribution of intestinal Heph at this developmental stage has not been established. Various physiological parameters and iron absorption were thus assessed in weanling mice of both sexes and genotypes.…”