Iron deficiency and malaria have similar global distributions, and frequently co-exist in pregnant women and young children. Where both conditions are prevalent, iron supplementation is complicated by observations that iron deficiency anaemia protects against falciparum malaria, and that iron supplements increase susceptibility to clinically significant malaria, but the mechanisms remain obscure. Here, using an in vitro parasite culture system with erythrocytes from iron-deficient and replete human donors, we demonstrate that Plasmodium falciparum infects iron-deficient erythrocytes less efficiently. In addition, owing to merozoite preference for young erythrocytes, iron supplementation of iron-deficient individuals reverses the protective effects of iron deficiency. Our results provide experimental validation of field observations reporting protective effects of iron deficiency and harmful effects of iron administration on human malaria susceptibility. Because recovery from anaemia requires transient reticulocytosis, our findings imply that in malarious regions iron supplementation should be accompanied by effective measures to prevent falciparum malaria.

Background Liver metabolite levels have the potential to be key biomarkers of systemic metabolic dysfunction and overall health. However, for most conditions we do not know the extent to which genetic differences regulate susceptibility to metabolic responses. This limits our ability to detect and diagnose effects in heterogeneous populations. Objective Here, we investigated the extent to which naturally occurring genetic differences regulate maternal liver metabolic response to vitamin D deficiency, particularly during perinatal periods when such changes can adversely affect maternal and fetal health. Methods We used a panel of eight inbred Collaborative Cross mouse strains, each with a different genetic background (72 dams, 3–6 per treatment group, per strain). We identified robust maternal liver metabolic responses to vitamin D depletion before and during gestation and lactation using a vitamin D deficient (0 IU/kg vitamin D3, VDD) or sufficient diet (1000 IU/kg vitamin D3, VDS). We then identified VDD-induced metabolite changes influenced by strain genetic background. Results We detected a significant VDD effect by OPLS-DA (Q2 = 0.266, pQ2 = 0.002), primarily, altered levels of 78 metabolites involved in lipid, amino acid, and nucleotide metabolism (VIP ≥ 1.5). Metabolites in unsaturated fatty acid and glycerophospholipid metabolism pathways were significantly enriched (FDR < 0.05). VDD also significantly altered levels of putative markers of uremic toxemia, acylglycerols, and dipeptides. The extent of metabolic response to VDD was strongly dependent on genetic strain, ranging from robustly responsive to nonresponsive. Two strains (CC017/Unc and CC032/GeniUnc) were particularly sensitive to VDD, however, each strain altered different pathways. Conclusions These novel findings demonstrate that maternal VDD induces different liver metabolic effects in different genetic backgrounds. Strains with differing susceptibility and metabolic response to VDD represent unique tools to identify causal susceptibility factors and further elucidate the role of VDD-induced metabolic changes in maternal and/or fetal health for ultimately translating findings to human populations.

In utero exposure to vinclozolin (VIN), an antiandrogenic fungicide, is linked to multigenerational phenotypic and epigenetic effects. Mechanisms remain unclear. We assessed the role of antiandrogenic activity and DNA sequence context by comparing effects of VIN vs. M2 (metabolite with greater antiandrogenic activity) and wild-type C57BL/6 (B6) mice vs. mice carrying mutations at the previously reported VIN-responsive H19/Igf2 locus. First generation offspring from VIN-treated 8nrCG mutant dams exhibited increased body weight and decreased sperm ICR methylation. Second generation pups sired by affected males exhibited decreased neonatal body weight but only when dam was unexposed. Offspring from M2 treatments, B6 dams, 8nrCG sires or additional mutant lines were not similarly affected. Therefore, pup response to VIN over two generations detected here was an 8nrCG-specific maternal effect, independent of antiandrogenic activity. These findings demonstrate that maternal effects and crossing scheme play a major role in multigenerational response to in utero exposures.

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Introduction: Dystrophic cardiac calcinosis (DCC) is an age-related cardiomyopathy that involves myocardial injury, necrosis, and calcification. The genetic factors contributing to myocardial calcification are complex, and several loci for DCC have been identified. However, only 1 gene, Abcc6, has been cloned and confirmed to regulate DCC. Our current studies were designed to study the genetic architecture of DCC. Methods and Results: Recently, the Diversity Outbred (DO) population was developed from 8 inbred strains of mice. The DO mice are mosaics of 8 progenitor strains: C57BL6/J, A/J, NOD/ShiLtJ, NZO/HiLtJ, WSB/EiJ, CAST/EiJ, PWK/PhJ and 129S1/SvImJ. Our initial studies examined the effects of diet and genetic background on the development of DCC in the 8 progenitor strains. At 24 weeks of age, the hearts of mice from these 8 strains were collected, and a colorimetric assay was used to measure calcium levels in heart tissue. ANOVA tests indicated a significant effect (p < 0.05) of the underlying genetics on DCC. To identify genes and pathways contributing to DCC, we next performed QTL mapping using 300 DO mice. Our QTL mapping analysis was carried out using a genetic model that incorporates reconstructed haplotypes and accounts for population structure. We identify a significant (LOD 7.10) QTL on chromosome 6 (94.7 Mb - 97.3 Mb) associated with DCC. Detailed analysis identified the CAST/EiJ and PWK/PhJ founder alleles as the greatest genetic contributors to the chromosome 6 peak. Myocardial calcification involves a highly regulated process of mineralization similar to osteogenesis, and several of the positional candidates mediate calcification, including: Fam19a4, Fam19a1, Eogt, and Arl6ip5. Conclusions: This data identifies genes that may regulate the mineralization underlying both DCC and osteogenesis. They may yield new therapeutic targets for DCC and serve as indicators of atherosclerosis.