title: Sex differences and steroid modulation of cardiac iron in a mouse model of iron overload.
abstract: Iron cardiomyopathy is the leading cause of death in transfusional iron overload, and men have twice the mortality of women. Because the prevalence of cardiac iron overload increases rapidly during the second decade of life, we postulated that there are steroid-dependent sex differences in cardiac iron uptake. To test this hypothesis, we manipulated sex steroids in mice with constitutive iron absorption (homozygous hemojuvelin knockout); this model mimics the myocyte iron deposition observed in humans. At 4 weeks of age, female mice were ovariectomized (OVX) and male mice were castrated (OrchX). Female mice received an estrogen implant (OVX + E) or a cholesterol control (OVX), whereas male mice received an implant containing testosterone (OrchX + T), dihydrotestosterone (OrchX + DHT), estrogen (OrchX + E), or cholesterol (OrchX). All animals received a high-iron diet for 8 weeks. OrchX, OVX, and OVX + E mice all had similar cardiac iron loads. However, OrchX + E males had a significant increase in cardiac iron concentration compared with OrchX mice (P < 0.01), whereas the OrchX + T and OrchX + DHT groups only trended higher (P < 0.06 and P < 0.15, respectively). Hormone treatments did not impact liver iron concentration in either sex. When data were pooled across hormone therapies, liver iron concentration was 25% greater in males than females (P < 0.01). In summary, we found that estrogen increased cardiac iron loading in male mice, but not in females. Male mice loaded 25% more hepatic iron than female mice regardless of the hormone treatment.
authors.affiliation: Division of Pediatric Cardiology, Children's Hospital Los Angeles, Los Angeles, Calif.
authors.forename: Casey
authors.initials: C
authors.lastname: Brewer
authors.affiliation: Division of Pediatric Cardiology, Children's Hospital Los Angeles, Los Angeles, Calif.
authors.forename: Maya
authors.initials: M
authors.lastname: Otto-Duessel
authors.affiliation: Department of Cell and Neurobiology, Keck School of Medicine of the University of Southern California, Los Angeles, Calif.
authors.forename: Ruth I
authors.initials: RI
authors.lastname: Wood
authors.affiliation: Division of Pediatric Cardiology, Children's Hospital Los Angeles, Los Angeles, Calif. Electronic address: jwood@usc.edu.
authors.forename: John C
authors.initials: JC
authors.lastname: Wood
mesh_terms: D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D004195:Disease Models, Animal; D005260:Female; D019190:Iron Overload / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012737:Sex Factors
chemical_list: D017931:DNA Primers
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