Iron Deficiency Anaemia in Newborn sla Mice: a Genetic Defect of Placental Iron Transport

Abstract

Newborn mice with X-linked anaemia (gene symbol sla) have lower haemoglobin levels at birth than normal and carrier mice but there is considerable overlap. Serial observations showed that the haemoglobin values of segregating male mice separate into a bimodal distribution of 42 d of age, and 50 d values were used to assign genotypes retrospectively. The anaemia in newborn sla mice is attributable to iron deficiency, since their total body iron is lower than in normal newborn mice, while their birth weights are almost identical. Haemoglobin levels at birth in normal, anaemic and carrier mice are also influenced by the mother's genotype and phenotype, and the haemoglobin value was progressively lower according to the sla gene dose of the mother. Materno-fetal iron transfer was examined by labelling pregnant carrier females with radioiron in various ways. When given as single or intermittent doses by injection no clearcut differences emerged in apparent iron transfer to anaemic as compared to non-anaemic fetuses. However, when radioiron was administered continuously in food a significant reduction in iron transfer to anaemic fetuses was demonstrated. The sla gene is already known to have a major effect in reducing iron transport in the small intestine. The present studies provide evidence of an analogous defect in placental iron transport.

Multi-Copper Oxidases and Human Iron Metabolism

“…While hephaestin is mainly expressed in the intestine, this protein has recently been found in the placenta, heart, brain and pancreas [122,125,126,127,128]. In placenta hephaestin has been suggested to facilitate iron transfer between mother and fetus [129], whereas in heart, brain and pancreas ferroxidase activity of hephaestin can protect these tissues from Fe(II) toxicity.…”

“…Young sla mice have severe anemia with symptoms decreasing with age [137]. Anemia of newborn mice may be explained by insufficient iron feeding of the fetus due to decreased ferroxidase activity of hephaestin in the placenta [129]. While ceruloplasmin is unable to compensate for hephaestin function in placental iron efflux [133,138], it can promote iron export from enterocytes [139].…”

Positional cloning of zebrafish ferroportin1 identifies a conserved vertebrate iron exporter

“…Sex-linked anaemia (sla) mice have a defect in basolateral iron transport in the duodenum as deduced from ferrokinetic studies and the presence of abnormal iron deposits in duodenal enterocytes 16 . Analogous to weh mutants, the sla mouse has a defect in transport of maternal iron to the embryonic circulation 17 . The sla phenotype is due to a mutation in the membrane-bound multicopper ferroxidase gene, hephaestin 18 .…”

The placenta: the forgotten essential organ of iron transport

“…75 Hemoglobin levels in sla pups is usually decreased compared with that in wild-type pups, though there is some overlap in the phenotypes. 76 Placental transfer of maternally injected radioiron in the second half of pregnancy was not different between sla and wild-type mice, although sla pups accumulated less radioiron given in the maternal diet throughout pregnancy. 76 It is worth pointing out that the sla allele of Heph retains partial ferroxidase activity, 77 so the minimally perturbed placental iron transfer in sla pups may underrepresent the degree to which Heph is important for placental iron transport.…”

“…76 Placental transfer of maternally injected radioiron in the second half of pregnancy was not different between sla and wild-type mice, although sla pups accumulated less radioiron given in the maternal diet throughout pregnancy. 76 It is worth pointing out that the sla allele of Heph retains partial ferroxidase activity, 77 so the minimally perturbed placental iron transfer in sla pups may underrepresent the degree to which Heph is important for placental iron transport. A third ferroxidase in the placenta has been described by Danzeisen et al, 78 who detected an intracellular, membrane-bound protein in BeWo cells that exhibited ceruloplasmin-like oxidase activity and reacted with a ceruloplasmin antibody.…”