Genes for gestational iron loading?

Abstract

In a recent report,1Bensaid M. Fruchon S. Mazeres C. Bahram S. Roth M.P. Coppin H. Multigenic control of hepatic iron loading in a murine model of hemochromatosis.Gastroenterology. 2004; 126: 1400-1408Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar Bensaid et al present data from a genetic mapping study on the polygenic inheritance of hepatic iron levels in HFE-deficient mice. The study design consisted of breeding mice homozygous for a targeted disruption (knockout or −/−) of the HFE gene that had been extensively back-crossed on to the C57BL/6 (B) and the DBA/2 (D) backgrounds. Normal HFE replete B and D mice are known to differ markedly in hepatic iron levels,2Gerhard G.S. Kaufmann E.J. Wang X. Erikson K.M. Abraham J. Grundy M. Beard J.L. Chorney M.J. Genetic differences in hepatic lipid peroxidation potential and iron levels in mice.Mech Ageing Dev. 2002; 123: 167-176Crossref PubMed Scopus (17) Google Scholar a difference that Bensaid et al show is maintained in HFE nullizygotes. A backcross strategy was used to breed the disrupted HFE allele on to the B and D genetic backgrounds. The resulting B and D HFE −/− mice were then bred to produce BXD F1 and F2 HFE −/− homozygotes. Based upon the data presented in Figure 1, the F1 mice were severely iron overloaded as expected. However, this result has potentially significant implications for the interpretation of the iron overload phenotype in the F2 progeny. With iron overload and presumed elevated transferrin saturation in the blood, the potential for substantial gestational transfer of iron from F1 mother to F2 fetus could occur. This would result in F2 mice that were born with increased iron stores. In human hereditary hemochromatosis, most HFE mutant homozygotes are born to mothers who are heterozygous and not iron overloaded. The chance of a homozygous HFE C282Y woman carrying a homozygous fetus is less than 1/20 (1/10 incidence of heterozygous father x 1/2 chance of inheritance of mutant allele). In addition, women of reproductive age who are homozygous may not yet be significantly iron overloaded, may be subfertile,3Bradley R.J. Rosen M.P. Subfertility and gastrointestinal disease ‘unexplained’ is often undiagnosed.Obstet Gynecol Surv. 2004; 59: 108-117Crossref PubMed Scopus (31) Google Scholar or may already be treated. One report measured the iron status of an infant born to a treated hemochromatotic mother.4Baynes R.D. Meyer T.E. Bothwell T.H. Lamparelli R.D. Maternal and fetal iron measurements in a hemochromatotic pregnancy.Am J Hematol. 1991; 36: 48-49Crossref PubMed Scopus (3) Google Scholar The cord blood samples of the infant had elevated transferrin saturation (88%) and a raised ferritin concentration (250.2 μg/L). The mother had elevated transferrin saturation (66%) but normal ferritin level (91.6 μg/L). In another study,5O’Brien K.O. Zavaleta N. Abrams S.A. Caulfield L.E. Maternal iron status influences iron transfer to the fetus during the third trimester of pregnancy.Am J Clin Nutr. 2003; 77: 924-930PubMed Google Scholar the amount of isotopic iron found in the circulation of human neonates was shown to be significantly related to maternal iron absorption following maternal oral dosing. These results imply that elevated maternal blood iron levels during pregnancy may result in increased iron transfer to the fetus. Maternal age may have also affected iron levels. The ages of the BXD F1 HFE −/− homozygotes used for breeding the F2 mice may have varied, resulting in F1 female mice with potentially widely different degrees of iron overload due to age effects. Thus, each F2 litter may have developed in widely disparate maternal iron environments. A related point is the age at which hepatic iron levels were determined in the F2 mice. Since the mice were only 7 weeks old at the time of sacrifice, the amount of iron acquired during the approximately 3 weeks spent in utero could represent a substantial portion of the total iron stored. The subsequent 3 weeks in which the pups presumably fed on breast milk until weaning may also have had an impact on iron levels. Iron intake or supplementation does not seem to have a major impact on the iron levels in breast milk of normal individuals,6Vuori E. Makinen S.M. Kara R. Kuitunen P. The effects of the dietary intakes of copper, iron, manganese, and zinc on the trace element content of human milk.Am J Clin Nutr. 1980; 33: 227-231PubMed Google Scholar, 7Arnaud J. Prual A. Preziosi P. Cherouvrier F. Favier A. Galan P. Hercberg S. Effect of iron supplementation during pregnancy on trace element (Cu, Se, Zn) concentrations in serum and breast milk from Nigerian women.Ann Nutr Metab. 1993; 37: 262-271Crossref PubMed Scopus (35) Google Scholar but little data is available on the iron content of breast milk in patients with hemochromatosis. A potential evolutionary explanation for the continued high prevalence of HFE mutations rests upon increased iron transfer during both gestation and lactation.8Jankovic G.M. Petrovic M.D. Colovic M.D. Milosevic R.A. Janosevic S. Trpinac D.P. Increased transplacental and breast milk iron delivery in hereditary hemochromatosis an evolutionary enigma resolved?.Am J Hematol. 1991; 38: 153-155Crossref PubMed Scopus (2) Google Scholar The variables impacting hepatic iron levels in the phenotypic extremes of the large F2 population selected for genotyping may therefore be very different than those affecting adult patients with hereditary hemochromatosis or mice derived from HFE heterozygotes. We argue that the modifier loci identified in their study may need to be considered in a different physiological light, which, nonetheless, may provide insight into the contribution of genetic variation on iron metabolism during and after gestation. Multigenic control of hepatic iron loading in a murine model of hemochromatosisGastroenterologyVol. 126Issue 5Preview: Hereditary hemochromatosis is a common disorder of iron homeostasis characterized by increased dietary iron absorption and progressive iron accumulation, mainly in the liver. Most patients are homozygous for the C282Y mutation in the HFE gene. However, not all individuals carrying the hemochromatosis-predisposing genotype in the general population become iron loaded. Genetic modifiers have been shown to influence disease penetrance, but their number and chromosomal locations remain unknown, and their identification is hampered by complex interactions with environmental factors. Full-Text PDF ReplyGastroenterologyVol. 127Issue 6PreviewIn their response to our article, “Multigenic control of hepatic iron loading in a murine model of hemochromatosis,” Gerhard and Chorney raise an interesting issue for discussion. They suggest that the increased iron stores found in the Hfe−/− F2 progeny could result from gestational transfer of iron from iron-overloaded Hfe−/−F1 mothers. The genetic loci we mapped would then control susceptibility to gestational iron loading rather than modulate hepatic iron loading in response to Hfe disruption. Full-Text PDF