Developmental iron deficiency dysregulates TET activity and DNA hydroxymethylation in the rat hippocampus and cerebellum

Iron deficiency (ID) during neurodevelopment is associated with lasting cognitive and socioemotional deficits, and increased risk for neuropsychiatric disease throughout the lifespan. These neurophenotypical changes are underlain by gene dysregulation in the brain that outlasts the period of ID; however, the mechanisms by which ID establishes and maintains gene expression changes are incompletely understood. The epigenetic modification 5-hydroxymethylcytosine (5hmC), or DNA hydroxymethylation, is one candidate mechanism because of its dependence on iron-containing TET enzymes. The aim of the present study was to determine the effect of fetal-neonatal ID on regional brain TET activity, Tet expression, and 5hmC in the developing rat hippocampus and cerebellum, and to determine whether changes are reversible with dietary iron treatment. Timed pregnant Sprague-Dawley rats were fed iron deficient diet (ID; 4 mg/kg Fe) from gestational day (G)2 to generate iron deficient anemic (IDA) offspring. Control dams were fed iron sufficient diet (IS; 200 mg/kg Fe). At postnatal day (P)7, a subset of ID-fed litters was randomized to IS diet, generating treated IDA (TIDA) offspring. At P15, hippocampus and cerebellum were isolated for subsequent analysis. TET activity was quantified by ELISA from nuclear proteins. Expression of Tet1, Tet2, and Tet3 was quantified by qPCR from total RNA. Global %5hmC was quantified by ELISA from genomic DNA. ID increased DNA hydroxymethylation (p=0.0105), with a corresponding increase in TET activity (p<0.0001) and Tet3 expression (p<0.0001) in the P15 hippocampus. In contrast, ID reduced TET activity (p=0.0016) in the P15 cerebellum, with minimal effect on DNA hydroxymethylation. Neonatal dietary iron treatment resulted in partial normalization of these changes in both brain regions. These results demonstrate that the TET/DNA hydroxymethylation system is disrupted by developmental ID in a brain region-specific manner. Differential regional disruption of this epigenetic system may contribute to the lasting neural circuit dysfunction and neurobehavioral dysfunction associated with developmental ID.

Dietary Iron

Iron metabolism differs from the metabolism of other metals in that there is no physiologic mechanism for iron excretion, it is unusual; approximately 90% of daily iron needs are obtained from an endogenous source, the breakdown of circulating RBCs. Additionally humans derive iron from their everyday diet, predominantly from plant foods and the rest from foods of animal origin. Iron is found in food as either haem or non-haem iron. Iron bioavailability has been estimated to be in the range of 14–18% for mixed diets and 5–12% for vegetarian diets in subjects with no iron stores. Iron absorption in humans is dependent on physiological requirements, but may be restricted by the quantity and availability of iron in the diet. Bioavailability of food iron is strongly influenced by enhancers and inhibitors in the diet. Iron absorption can vary from 1 to 40%. A range of iron bioavailability factors that depend on the consumption of meat, fruit, vegetables, processed foods, iron-fortified foods, and the prevalence of obesity. The methods of food preparation and processing influence the bioavailability of iron. Cooking, fermentation, or germination can, by thermal or enzymatic action, reduce the phytic acid and the hexa- and penta-inositol phosphate content. Thus improving bioavailability of non-haem iron. This chapter will elaborate the dietary iron sources and means of enhancing bioavailability.

Dietary Iron Consumption Estimates Among Women Of Reproductive Age In Kersa, Eastern Ethiopia: Cross-Sectional Study

Dietary iron inadequacy is a public health concern in developing countries. Women of reproductive age (WRA) are the most at risk for this micronutrient deficiency due to biological, socio-cultural, and dietary factors. This analysis aimed to assess estimated dietary intakes of iron (including heme and non-heme) and estimate bioavailability of dietary iron intake in Ethiopian women of reproductive age in Kersa district, Eastern Ethiopia. A total of 1140 randomly selected women from households in Kersa participated in this study. We used a non-quantitative food frequency questionnaire to assess total dietary iron consumption in WRA. Adjusted prevalence ratios (APRs) and 95% confidence intervals (CIs) were computed using modified Poisson regression to evaluate factors for inadequate dietary iron intake. The median usual iron consumption was 24.7 mg/d and 41.8 % of WRA were at risk for iron inadequacy. The following factors were associated with a greater likelihood for the risk of iron inadequacy: seasonal (APR 1.56; 95% CI 1.36-1.80) and part-time (APR 1.75; 95% CI 1.45-2.12) agricultural employment, market food source (APR 1.30; 95% CI 1.14-1.49), old age (APR 1.29; 95% CI 1.05-1.60) and low women’s dietary diversity (APR 2.34; 95% CI 1.88-2.91). Two-fifths of women had an inadequate dietary iron intake. Improving dietary diversity and food security, fortifying staple foods that have low iron bioavailability, and increasing animal-based foods and fruit consumption with meals would help to decrease the burden of iron dietary inadequacy and deficiency in WRA.

Persistence of anaemia among Samoan preschool age children: a longitudinal study

Objective: To characterise the prevalence and persistence of anaemia among Samoan children over a 2–3-year period. Design: Data were from two consecutive waves (2015 and 2017–2018) of the Ola Tuputupua’e ‘Growing up’ study. Anaemia (Hb < 11·0 or 11·5 g/dl for 2–4 and ≥ 5 years old, respectively) was considered ‘transient’ when it occurred at only one wave or ‘persistent’ if it was present at two consecutive waves. Child, maternal and household correlates of anaemia were examined using log-binomial and modified Poisson regressions. Setting: Eleven Samoan villages. Participants: Mother–child pairs (n 257) recruited in 2015 and reassessed in 2017–2018. Results: Anaemia prevalence was 33·9 % in 2015 and 28·0 % in 2017–2018; 35·6 % of cases identified in 2015 were persistent. Risk of anaemia at only one wave was lower among children who were older in 2015 (age 4 v. 2 years, adjusted relative risk (aRR) = 0·54, (95 % CI 0·35, 0·84), P = 0·007), had older mothers (≥ 40 v. 18–29 years, aRR = 0·61, (95 % CI 0·39, 0·95), P = 0·029) and had higher daily sodium intake (for every 100 mg/d, aRR = 0·97, (95 % CI 0·95, 0·99), P = 0·003) than children with no anaemia. Children whose anaemia persisted were more likely to have had a mother with anaemia (aRR = 2·13, (95 % CI 1·17, 3·89), P = 0·013) and had higher daily dietary iron intake (for every 10 mg/d, aRR = 4·69, (95 % CI 1·33, 16·49), P = 0·016) than those with no anaemia. Conclusions: Alongside broadly targeted prevention efforts, which are warranted given the moderate-high anaemia prevalence observed, specific attention should be paid to children with risk factors for persistent anaemia. Routine screening of children whose mothers have anaemia should be encouraged.

Risk of anaemia among women engaged in biomass-based fish smoking as their primary livelihood in the central region of Ghana: a comparative cross-sectional study

Background Fish smoking using biomass fuel is an important livelihood for women living in the coastal regions of Ghana and may contribute to anaemia risk. We assessed whether women who smoke fish as their primary livelihood are at increased risk of anaemia compared to women in other livelihoods in the Central Region of Ghana. Methods We conducted a comparative cross-sectional study of 330 randomly selected adult women (18–49 years) whose primary livelihood was either fish smoking (FSL) involving the burning of biomass fuel (n = 175) or other livelihoods (OL) not involving burning of firewood (n = 155). Data on participants’ recent diet were collected from a single, quantitative 24-h dietary recall and qualitative 7-day food frequency questionnaire of animal-source food (ASF) consumption. We further assessed participants’ haemoglobin concentration using the Urit 12 Hemocue system. We compared total iron intakes, the proportion of dietary iron from animal and plant sources, mean haemoglobin concentrations, and anaemia prevalence between FSL and OL women. Results Fish was the most frequently consumed ASF by both groups of women. Although OL women consumed more diverse ASFs in the past week compared with the FSL women (3.4 ± 1.2 vs. 2.7 ± 1.3; p < 0.001), the contribution of ASFs to total iron intake in the past day was greater for the FSL women (49.5% vs. 44.0%; p = 0.030). Estimated total dietary iron intake in the past day was generally low (5.2 ± 4.7 mg) and did not differ by group. The unadjusted prevalence of anaemia was 32 and 27.1% among the FSL and OL women, respectively (p = 0.33). After covariates adjustment, the FSL women had statistically higher anaemia prevalence (36.4% vs. 20.5%; p = 0.032) and 80% greater risk of being anemic (RR: 1.8; 95% CI: 1.1, 3.0) than the OL women. Conclusion Women who use biomass fuel to smoke fish as their primary livelihood had an increased risk of anaemia. Furthermore, the average 24-h dietary iron intake among both the FSL and OL women was below their daily iron requirement. Interventions to enhance women’s dietary iron intake and reduce their livelihood related biomass smoke exposure may be warranted in this population.

Fat specific adipose triglyceride lipase is necessary for iron-mediated lipolysis and lipid mobilization in response to negative energy balance

Maintenance of energy balance is essential for the overall health of an organism. In mammals, both negative and positive energy balance are associated with disease states. To maintain their energy balance within a defined homeostatic setpoint, mammals have evolved complex regulatory mechanisms that control energy intake and expenditure. Traditionally, studies have focused on understanding the role of macronutrient physiology in energy balance. In the present study, we examined the role of the essential micronutrient iron in regulating energy balance. Using a dietary model, we found that a short course of excess dietary iron caused a negative energy balance resulting in a severe whole body wasting phenotype. This disruption in energy balance was due to an iron dependent increase in energy expenditure caused by a heightened basal metabolic rate and activity level. Using a transgenic mouse model lacking adipose triglyceride lipase (ATGL) specifically in fat tissue, we found that to meet the increased energetic demands, dietary iron caused increased lipid utilization that required fat specific ATGL-mediated lipid mobilization and wasting of subcutaneous white adipose tissue deposits. When fed dietary iron, mice lacking fat-specific ATGL activity were protected from fat wasting, and developed a severe cachectic response that is necessary to meet the increased energetic demands caused by the dietary regimen. Our work highlights the multi-faceted role of iron regulation of organismal metabolism and provides a novel in vivo mechanism for micronutrient control of lipolysis that is necessary for regulating mammalian energy balance.

The Associations of Dietary Iron Intake and the Transferrin Receptor (TFRC) rs9846149 Polymorphism with the Risk of Gastric Cancer: A Case–Control Study Conducted in Korea

Background: A positive association between a high iron intake and colorectal cancer has been identified; however, the effect of dietary iron on gastric cancer (GC) remains unclear. Here, we investigate whether dietary iron is related to GC risk and whether the transferrin receptor (TFRC) rs9846149 polymorphism modifies this association. Methods: A case–control study was designed to assess this association among 374 GC patients and 754 healthy controls. A self-administered questionnaire was used to collect information on demographics, medical history and lifestyle. Dietary iron intake was assessed using a semi-quantitative food frequency questionnaire. TFRC rs9846149 was genetically analyzed using the Affymetrix Axiom Exom 319 Array platform. Results: A higher total dietary iron was significantly associated with decreased GC risk [OR = 0.65 (0.45–0.94), p for trend = 0.018]. A similar association was observed with nonheme iron [OR = 0.64 (0.44–0.92), p for trend = 0.018]. Individuals with a major allele of TFRC rs9846149 (CC/GC) and higher intake of total iron had a significantly lower GC risk than those with a lower intake [OR = 0.60 (0.41–0.88), p interaction = 0.035]. Conclusion: Our findings show the protective effects of total dietary iron, especially nonheme iron, against GC risk, and this association can be modified by TFRC rs9846149.