Dietary Heme Iron Research Articles

Associations of dietary total, heme, non-heme iron intake with diabetes, CVD, and all-cause mortality in men and women with diabetes

BackgroundIron metabolism disorders significantly increase the risk of diabetes and its related complications by inducing oxidative stress, inflammation, insulin resistance, and disturbances in glucose and lipid metabolism. However, whether dietary iron intake can influence progression of diabetes remains unclear. The present study aims to investigate the relationship between total iron, heme iron, and non-heme iron intake and diabetes, CVD, and all-cause mortality among men and women with diabetes in the U.S. population. MethodsA total of 4416 adults with diabetes(2415 men and 2001 women) from the NHANES 2003–2014 were enrolled. Dietary information was collected by 24-h dietary recall during two nonconsecutive days. Dietary total iron intake was measured based on the dietary survey. Dietary heme iron intake was calculated based on its proportion in dietary total iron intake from each food. non-heme iron is the difference between total iron and heme iron. Diabetes, CVD, and all-cause mortality status were identified as main outcomes. Cox models and RCS analysis were performed to estimate the hazard ratios and 95%CIs. ResultsFor men, the participants with a higher dietary heme iron intake were associated with higher risks of CVD (HRheme iron = 1.61,95%CI:1.03–2.51) and all-cause mortality (HRheme iron = 1.42,95%CI:1.10–1.83). For women, participants in the highest quartile of dietary total/heme/non-heme iron intake had a higher diabetes mortality risk ((HRtotal iron = 2.33,95%CI:1.24–4.38; HRheme iron = 1.87,95%CI:1.00–3.49; HRnon-heme iron = 2.28,95%CI:1.19–4.39), compared to those in the lowest quartile. Additionally, the dose–response curve for the relationship between dietary non-heme iron intake and CVD mortality followed a reverse J-shape in women with diabetes. ConclusionsHigher dietary heme iron intake was associated with an increased CVD mortality risk in both men and women with diabetes. Additionally, higher dietary total, heme, and non-heme iron intake was linked to an increased risk of diabetes mortality among women with diabetes. Therefore, women with diabetes should pay more attention on the overconsumption of any type of dietary iron.

P1159 Gene and environment interactions in inflammatory bowel disease: a systematic review of human epidemiologic studies

Abstract Background Complex gene-environment interaction for Inflammatory Bowel Disease (IBD) remains elusive. This systematic review aims to summarize the current evidence of gene and environment interactions in IBD. Methods PubMed, EMBASE, Web of Science and Scopus were systematically searched from inception through July 20, 2022 to identify publications examining the interaction effect of genetic variants and environmental factors in IBD. Two investigators independently screened the title/abstract and full text according to the predefined criteria. All eligible studies were graded using STREGA guideline. The protocol was registered on PROSPERO (CRD42023443071). Results 4,305 publications were identified and screened, resulting in 36 eligible studies. 17 studies reported statistically significant interactions. The interaction effect of NOD2 and smoking was most frequently investigated and showed variant-specific interaction at rs2066847 regrading risk of Crohn’s disease (CD). Gene-smoking interactions were further identified in 1) other IBD risk genes (ATG16L1, IL23R, CALM3), as well as the IBD-genetic risk score (GRS), 2) detoxification genes (GSTP1 and ΗΜΟΧ1), 3) smoking-associated genes (CHRNA3, CHRNA5, PPP1R3C, BDNF), as well as the general smoking-GRS, and 4) the inflammation cytokine gene (IL-1β) using the candidate gene approach. Using the Illumina immune-focused Chip, another 64 smoking interacting variants were identified. Gene-diet interactions were reported across different nutritional measures, including the intake of fatty acids with CYP4F3 and FADS2, serum level of selenium with SEPHS1and SEPSECS, dietary intake of potassium with IL21, alcohol consumption with IL12B, dietary heme iron intake with FcgRIIA and serum level of 25-hydroxyvitamin D with VDR. No genome wide environment interaction studies (GWEIS) of IBD have been conducted to date, while this strategy holds great potential to unravel the missing heritability influenced by environment factors for IBD. Conclusion While past studies have increased insights into potential gene-environmental interactions in the pathophysiology of IBD, current evidence is limited and inconclusive due to lack of replication of presented results, and limited study power. Further research, including GWEIS and clinical trials, is needed for future recommendations on lifestyle and dietary modification, based on individual genetic backgrounds.

Iron and cancer: overview of the evidence from population-based studies.

Iron is an essential nutrient required for various physiological processes in the body. However, iron imbalance can potentially contribute to initiating and promoting cancer development. Epidemiological studies have investigated the relationship between dietary iron intake and the risk of different types of cancer, yet, not all studies have consistently shown a significant association between dietary iron and cancer risk. Also, studies have shown different effects of dietary heme and non-heme iron intake on cancer risk. While some epidemiological studies suggest a possible link between high dietary iron (mainly heme-iron) intake and increased cancer risk, the evidence remains inconsistent. Moreover, multiple iron biomarkers, which can mirror physiological iron status, have demonstrated varied correlations with the risk of cancer, contingent upon the specific biomarker analyzed and the type of cancer being investigated. Here, we have investigated the current evidence on the potential relationship between dietary iron intake on one hand, and iron biomarkers on the other hand, with the risk of developing different types of cancer, including breast, prostate, lung, pancreatic, colon, colorectal, and liver cancers. Further research is warranted to better understand the complex relationship between dietary iron, physiological iron and cancer development. Future research should account for factors that affect and interact with dietary iron and physiological iron levels, such as genetic susceptibility, overall diet quality, and lifestyle habits.

Dietary iron and the risk of lung cancer.

Animal models have suggested the carcinogenic effect of iron due to its oxidative potential. The lung is particularly vulnerable to oxidative stress. However, epidemiological studies investigating the association between dietary iron and the risk of lung cancer have reported inconclusive results. In this systematic review and meta-analysis, we aimed to clarify this association. Methods: We searched PubMed, Web of Science, Scopus and Google scholar for eligible articles published through May 2023 reporting the Relative Risk (RR), Hazard Ratio (HR) or Odds Ratio (OR) with 95% confidence interval (95% CI). Case-control and cohort studies that examined the relationship between dietary iron and lung cancer risk were included and review and meta-analyses articles, experimental studies, abstracts, letters to editor and studies with insufficient data were excluded. Finally, three case-control studies and 6 cohort studies were included. Random effect models were used to calculate the pooled results. Results: Nine studies (cases n=21,943, participants n=1,542,993) were included. There were no significant associations between the highest dietary total iron (heme and non-heme) (RR: 1.09, 95% CI: 0.78 to 1.51) or heme iron (RR: 1.01, 95% CI: 0.73 to 1.38) intake compared to the lowest intake with lung cancer risk. Null-associations were also observed in the subgroup analysis based on smoking status and lung cancer histology. However, in the subgroup of women (cases n=5074), heme iron was associated with a 14% increase in the risk of lung cancer (RR: 1.14, 95% CI: 1.01 to 1.29). Conclusions: The current results demonstrated that there is no significant relationship between dietary iron intake and the risk of lung cancer. However, a positive association was observed between dietary heme iron and the risk of lung cancer in women, which may require further investigation.

P11-061-23 Dietary Heme Iron Intake and the Risk of Type 2 Diabetes: An Analysis in the Context of Dietary Patterns

P11-061-23 Dietary Heme Iron Intake and the Risk of Type 2 Diabetes: An Analysis in the Context of Dietary Patterns

Establishing a Rat Model of Intestinal Heme-iron Absorption

Heme iron, derived from hemoglobin and myoglobin of animal products, is efficiently absorbed and utilized by humans. Despite extensive investigation over the last several decades, the exact mechanism(s) of heme-iron absorption and tissue utilization of absorbed heme are unclear. Mice are frequently used for investigation of iron biology; however, mice do not efficiently utilize dietary iron derived from heme, so development of alternative models is warranted. Rats could more efficiently utilize dietary heme iron, but this has not been rigorously tested. Our initial studies demonstrated that dietary heme (derived from porcine RBCs) could partially correct iron-deficiency anemia (IDA) in rats of one strain (rat strain 1), but not in 2 others. We hypothesized that a heme-iron diet would fully replete strain 1 rats with IDA, at a similar rate to a non-heme iron (NHI) diet. We utilized repletion diets containing 50, 75 or 100 ppm heme iron; a control diet contained 50 ppm NHI. Forty-two, three-week-old, female strain 1 rats were weaned onto a low-iron diet with 3-4 ppm NHI, and then after 2 weeks, rats were repleted with the different diets for 8 days. Rats were housed in overhanging wire bottom stainless steel cages during the low-iron feeding period to prevent coprophagia. Blood was collected from the tail vein at baseline and every 4 days thereafter to track correction of anemia. Outcomes showed that repletion of IDA rats with the 50-ppm heme-iron diet resolved the anemia; however, tissue iron depletion indicated that the rats remained iron deficient. Also, the rate of repletion was slightly slower as compared to rats repleted with the control (50 ppm NHI) diet. With higher dietary heme-iron levels, repletion was as fast, or even faster, than in control rats suggesting that a rat strain was identified that can efficiently assimilate dietary heme iron. Our studies support a role for rats as a genetic model to preferentially mimic human nutritional studies of iron and heme absorption. This investigation was funded by grant DK074867 from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (JFC, PI), and grant DK109717 from NIDDK and the Office of Dietary Supplements (to JFC, PI). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Dietary Iron Intake and New-Onset Hypertension: A Nationwide Cohort Study from China.

The relationship of dietary iron intake with the risk of hypertension remains uncertain. We aimed to investigate the prospective association between dietary iron intake and new-onset hypertension among Chinese adults. A nationwide cohort study. Using data from seven rounds of the China Health and Nutrition Survey (CHNS) from 1997 to 2015. A total of 12,245 participants without hypertension at baseline were included in this study. Dietary intake was measured by three consecutive 24-h dietary recalls combined with a household weighing inventory. The study outcome was new-onset hypertension, defined as systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg or diagnosed by physician or currently under antihypertensive treatment during the follow-up. During a median follow-up of 6.1 years, 4,304 (35.1%) participants developed hypertension. Overall, there was a U-shaped association between dietary total iron intake and new-onset hypertension (P for nonlinearity <0.001), with the lowest risk observed at 18.2-<22.1 mg/day (quintile 2-3). Similarly, a U-shaped association between dietary nonheme iron intake and new-onset hypertension was found (P for nonlinearity <0.001), with the lowest risk at 17.4-<21.3 mg/day (quintile 2-3). However, the association between dietary heme iron intake and new-onset hypertension followed a L-shape (P for nonlinearity <0.001), and a significantly lower risk of new-onset hypertension was found in participants with quintile 2-5 of dietary heme iron intake (adjusted HR, 0.75; 95% CI: 0.68, 0.82), compared with those in quintile 1 (<0.25 mg/day). The association between dietary iron and new-onset hypertension was nonlinear in Chinese adults, following a U-shape for total or nonheme iron intake, and a L-shape for heme iron intake.

Maternal heme-enriched diet promotes a gut pro-oxidative status associated with microbiota alteration, gut leakiness and glucose intolerance in mice offspring

Maternal environment, including nutrition and microbiota, plays a critical role in determining offspring's risk of chronic diseases such as diabetes later in life. Heme iron requirement is amplified during pregnancy and lactation, while excessive dietary heme iron intake, compared to non-heme iron, has shown to trigger acute oxidative stress in the gut resulting from reactive aldehyde formation in conjunction with microbiota reshape. Given the immaturity of the antioxidant defense system in early life, we investigated the extent to which a maternal diet enriched with heme iron may have a lasting impact on gut homeostasis and glucose metabolism in 60-day-old C3H/HeN mice offspring.As hypothesized, the form of iron added to the maternal diet differentially governed the offspring's microbiota establishment despite identical fecal iron status in the offspring. Importantly, despite female offspring was unaffected, oxidative stress markers were however higher in the gut of male offspring from heme enriched-fed mothers, and were accompanied by increases in fecal lipocalin-2, intestinal para-cellular permeability and TNF-α expression. In addition, male mice displayed blood glucose intolerance resulting from impaired insulin secretion following oral glucose challenge. Using an integrated approach including an aldehydomic analysis, this male-specific phenotype was further characterized and revealed close covariations between unidentified putative reactive aldehydes and bacterial communities belonging to Bacteroidales and Lachnospirales orders.Our work highlights how the form of dietary iron in the maternal diet can dictate the oxidative status in gut offspring in a sex-dependent manner, and how a gut microbiota-driven oxidative challenge in early life can be associated with gut barrier defects and glucose metabolism disorders that may be predictive of diabetes development.

Dietary Trace Element Intake and Risk of Breast Cancer: A Mini Review.

Trace elements are essentially required for various physiological and metabolic functions, and any disturbance in the trace elements homeostasis may result in the development of chronic diseases including breast cancer. Breast cancer is the most prevalent cancer type reported in women equally affecting both the high-income and low-income countries. This review therefore aimed to evaluate the impact of dietary trace element intake in relation to the incidence of breast cancer. We focused on five trace elements, thus emphasizing dietary selenium, zinc, iron, copper, and cadmium intake and risk of breast cancer. A systematic approach was applied to perform this review through entering a search term in PubMed and Scopus databases. A total of 24 articles were included after meeting the inclusion and exclusion criteria. Most of the studies regarding dietary iron intake showed a detrimental effect of increased dietary heme iron on breast cancer incidence risk. In addition, there is a limited evidence of high dietary intake of selenium and zinc to reduce the risk of breast cancer. Also, a few studies showed a relationship between high cadmium consumption and risk of breast cancer. More studies related to cadmium and copper exposure are needed to confirm this relationship. As a result, the findings of this review suggested that high dietary heme iron is a potential risk factor for breast cancer.

Chronic intestinal inflammation drives colorectal tumor formation triggered by dietary heme iron in vivo

The consumption of red meat is associated with an increased risk for colorectal cancer (CRC). Multiple lines of evidence suggest that heme iron as abundant constituent of red meat is responsible for its carcinogenic potential. However, the underlying mechanisms are not fully understood and particularly the role of intestinal inflammation has not been investigated. To address this important issue, we analyzed the impact of heme iron (0.25 µmol/g diet) on the intestinal microbiota, gut inflammation and colorectal tumor formation in mice. An iron-balanced diet with ferric citrate (0.25 µmol/g diet) was used as reference. 16S rRNA sequencing revealed that dietary heme reduced α-diversity and caused a persistent intestinal dysbiosis, with a continuous increase in gram-negative Proteobacteria. This was linked to chronic gut inflammation and hyperproliferation of the intestinal epithelium as attested by mini-endoscopy, histopathology and immunohistochemistry. Dietary heme triggered the infiltration of myeloid cells into colorectal mucosa with an increased level of COX-2 positive cells. Furthermore, flow cytometry-based phenotyping demonstrated an increased number of T cells and B cells in the lamina propria following heme intake, while γδ-T cells were reduced in the intraepithelial compartment. Dietary heme iron catalyzed formation of fecal N-nitroso compounds and was genotoxic in intestinal epithelial cells, yet suppressed intestinal apoptosis as evidenced by confocal microscopy and western blot analysis. Finally, a chemically induced CRC mouse model showed persistent intestinal dysbiosis, chronic gut inflammation and increased colorectal tumorigenesis following heme iron intake. Altogether, this study unveiled intestinal inflammation as important driver in heme iron-associated colorectal carcinogenesis.

Revisiting Iron Metabolism, Iron Homeostasis and Iron Deficiency Anemia.

Iron deficiency anemia (IDA) is one of the commonest clinical scenarios especially in children, women of childbearing age, and elders. The crux of this review was revisiting iron homeostasis, mechanism of iron absorption, causes, laboratory diagnosis, and management of IDA. This narrative review is compiled after a relevant literature search from electronic databases including, but not limited to, Google, Google Scholar, PMC, PubMed, Science Direct, and Scopus. The key words used for searching relevant literature include iron, iron deficiency, iron deficiency anemia, iron metabolism, hepcidin, transferrin, causes of iron deficiency anemia, and laboratory diagnosis of iron deficiency anemia. Reference hema-tology books were also consulted. According to the published literature, about one mg of iron is required daily which equals its loss, although the iron requirement increases in pregnancy and lactating mothers. Dietary non heme iron (oxidized Fe3+) is reduced to the ferrous (Fe2+) form by ferrireductase present in the brush border of duodenal enterocytes. Ferrous iron is absorbed in the brush border of duodenal enterocytes through a carrier protein, divalent metal transporter 1 (DMT1). Heme iron is absorbed by the duodenal enterocytes through a mechanism that is not well understood or a receptor yet to be discovered. Transferrin receptor helps in the internalization of iron in the cells. Hepcidin acts as a gatekeeper and controls iron absorption by enterocytes and macrophages. IDA may be caused by decreased intake of iron, increased iron requirements or loss of iron from the body. Iron deficiency anemia is the most common nutritional anemia that affects large numbers of people in developed as well as in developing countries. It is estimated that approximately 2 billion people around the world have IDA. Microcytosis with marked reduction in serum iron, decreased % saturation of transferrin, low ferritin, and reduced or even undetectable hepcidin are the laboratory features of IDA. In addition, total iron binding capacity and soluble transferrin receptors increase significantly in IDA. Management of IDA is incomplete if the underlying cause is not ruled out and left untreated.

Association between Habitual Dietary Iron Intake and Glucose Metabolism in Individuals after Acute Pancreatitis.

Dietary intake of iron is known to be associated with impaired glucose metabolism. However, its involvement in derangements of glucose metabolism after acute pancreatitis (AP) is not completely understood. The aim was to investigate the association between dietary iron intake and markers of glucose metabolism in individuals after an attack of AP. Fasting blood samples were collected to analyse markers of glucose metabolism (fasting plasma glucose (FPG) and haemoglobin A1c (HbA1c)). The EPIC-Norfolk food frequency questionnaire was used to determine the habitual intake of dietary iron (total, haem, and non-haem). Multivariable linear regression analyses were conducted and six statistical models were built to adjust for covariates. A total of 109 individuals after AP were studied in a cross-sectional fashion. Total iron (β (95% confidence interval) = −0.19 (−0.35, −0.05); p = 0.01 in the most adjusted model) and non-haem iron (β (95% confidence interval) = −0.19 (−0.33, −0.04); p = 0.03 in the most adjusted model) were significantly associated with FPG, consistently in all adjusted model. Total iron and non-haem iron did not have consistent significant associations with HbA1c. Dietary haem iron intake was not associated with either FPG or HbA1c. Habitual intake of dietary iron is inversely associated with FPG in individuals after an attack of AP and may be involved in the pathogenesis of new-onset diabetes after pancreatitis. Prospective longitudinal studies are now warranted to unveil the specific mechanism underlying the involvement of dietary iron.

Dietary iron and vitamins in association with mortality

Although disorders of iron metabolism are among the most common diseases and dietary intakes of vitamin A, B2, B6, C, E, and folic acid are known to affect the absorption or oxidation of iron, limited data are available on the association of dietary iron and these vitamins with mortality in the same population. Specifically, the holistic dietary vitamins intake and its combined effect with iron on mortality are unclear. The purpose of this study was to evaluate the association of dietary iron, holistic dietary vitamins, and their interactive effect with total and cause-specific mortality. We evaluated the effects of dietary total/heme/non-heme iron, vitamins, and their interaction on all-cause/cardiovascular disease (CVD)/cancer mortality among 14,826 US adults in the National Health and Nutrition Examination Survey (NHANES), a population-based nationally representative study. We developed a vitamin score to represent the holistic dietary intakes of vitamin A, B2, B6, C, E, and folic acid. A total of 2154 deaths occurred during a median follow-up of 9.3 years. Results from multivariate Cox proportional hazards models showed that higher vitamin score was associated lower risk of all-cause mortality (P-trend=0.027). Negative interactions between dietary heme iron and vitamin score were observed on all-cause/CVD mortality. Dietary higher vitamins combined with lower heme iron was associated with lower risk of all-cause and CVD mortality (HR (95% confidence intervals (CIs)): 0.80 (0.64-0.98) and 0.55 (0.31-0.98), respectively). Higher dietary vitamins combined with higher total/non-heme iron was associated with lower risk of CVD mortality (HR (95%CIs): 0.69 (0.48-0.99) and 0.70 (0.48-0.99), respectively). These results remained significant even excluding participants with iron supplementation. Our findings suggested that interactive effect of holistic dietary vitamins and iron play a protective role in decreasing all-cause and CVD mortality. Future studies, including cohort studies and clinical trials, are necessary to confirm these findings.

Dietary Iron Intake and Incident Type 2 Diabetes in Chinese Middle-Aged and Elderly Population: A Prospective Cohort Study

Abstract Objectives Excessive dietary iron intake may lead to iron overload and further induce pancreatic islet damage to increase risk of diabetes, which has a higher prevalence in middle-aged and elderly population. We aimed to explore the association between dietary iron intake and incident type 2 diabetes (T2D) in Chinese middle-aged and elderly population. Methods This study was based on the Guangzhou Nutrition and Health Study (GNHS), an on-going, community-based prospective cohort study that recruited participants aged 40–75 years from 2008. All participants were followed up every three years. 2765 participants free of diabetes were included in data analysis. Dietary iron intake was obtained by a validated food-frequency questionnaire at baseline. T2D was ascertained by self-reported diabetes medications, fasting glucose ≥7.0 mmol/L or glycosylated hemoglobin ≥6.5%. Cox proportional hazards models were used to estimate HRs and 95% CIs. Results We ascertained 209 incident diabetes cases during 13,634 person-years of observation. The mean ± SD intakes of dietary total iron, heme iron and nonheme iron among all participants were 20.40 ± 2.73 mg/d, 1.26 ± 0.62 mg/d and 19.14 ± 2.66 mg/d, respectively. The multivariate-adjusted HR and 95% CI for T2D for the highest quartile of heme iron intake compared with the lowest quartile was 2.11 (95% CI: 1.14–3.89, P-trend = 0.014). However, the association between total iron intake or a nonheme iron intake with T2D risk was no significant difference. The adjusted HR for T2D risk was 1.79 (95% CI:1.05–3.08, P-trend = 0.037) for heme iron intake from red meat, while no association was found for heme iron intake from poultry or fish. Conclusions Greater intake of heme iron, especially heme iron from red meat, was associated with higher risk of incident T2D in Chinese middle-aged and elderly population, while intakes of total iron and nonheme were not related to diabetes. Controlling heme iron intake, especially red meat intake, may be a target to prevent T2D in middle-aged and elderly population. Funding Sources The National Science Foundation of China; the National Science Foundation of Guangdong Province, China.

Dietary iron intake and risk of death due to cardiovascular diseases: A systematic review and dose-response meta-analysis of prospective cohort studies.

Many studies have investigated the association between dietary iron intake and death due to cardiovascular disease (CVD), but the results were inconsistent. We performed a dose-response meta- analysis to quantitatively assess the risk of CVD mortality with dietary intake of iron (total iron, heme iron, and non-heme iron). PubMed and Embase databases were searched for articles published up to February 21, 2019. Prospective cohort studies were included if reporting relative risks (RRs) and 95% confidence intervals (CIs) for risk of CVD mortality associated with dietary iron intake. Restricted cubic splines were used to model the dose-response association. We included eight articles (19 studies including 720,427 participants [46,045 deaths due to CVD]) in the meta-analysis. When comparing the highest versus lowest level of dietary heme iron intake, the pooled RR for CVD mortality was 1.19 (95% CI, 1.01-1.39). With a 1-mg/day increase in dietary heme iron intake, the pooled RR for death due to CVD, stroke, coronary heart disease, and myocardial infarction were 1.25 (95% CI, 1.17-1.33), 1.17 (1.04-1.32), 1.25 (0.70-2.22), and 1.17 (0.55-2.50) respectively. The association between dietary iron intake and CVD mortality was linear (pnonlinearity> 0.05). Higher dietary intake of heme iron was associated with a greater risk of CVD mortality. Reducing consumption of heme iron may help to prevent premature death due to CVD.

Iron intake, oxidative stress-related genes and breast cancer risk.

Iron has been suggested to contribute to breast cancer development through oxidative stress generation. Our study investigated associations between iron intake and breast cancer risk, overall and by menopausal and estrogen receptor/progesterone receptor (ER/PR) status, and modification by oxidative stress-related genetic polymorphisms (MnSOD, GSTM1 and GSTT1). A population-based case-control study (3,030 cases and 3,402 controls) was conducted in Ontario, Canada. Iron intake (total, dietary, supplemental, heme, nonheme) was assessed using a validated food frequency questionnaire. Odds ratios (OR) and 95% confidence intervals (CI) were estimated from multivariable logistic regression models. Interactions between iron intake and genotypes were assessed among 1,696 cases and 1,761 controls providing DNA. Overall, no associations were observed between iron intake and breast cancer risk. Among premenopausal women, total, dietary and dietary nonheme iron were positively associated with ER-/PR- breast cancer risk (all ptrend < 0.05). Among postmenopausal women, supplemental iron was associated with reduced breast cancer risk (OR>18 vs. 0 mg/day = 0.68, 95% CI: 0.51-0.91), and dietary heme iron was associated with an increased risk, particularly the ER-/PR- subtype (ORhighest vs. lowest quintile = 1.69, 95% CI: 1.16-2.47; ptrend = 0.02). Furthermore, GSTT1 and combined GSTM1/GSTT1 polymorphisms modified some of the associations. For example, higher dietary iron was most strongly associated with increased breast cancer risk among women with GSTT1 deletion or GSTM1/GSTT1 double deletions (pinteraction < 0.05). Findings suggest that iron intake may have different effects on breast cancer risk according to menopausal and hormone receptor status, as well as genotypes affecting antioxidant capacity.

Dietary Nonheme, Heme, and Total Iron Intake and the Risk of Diabetes in Adults: Results From the China Health and Nutrition Survey.

Excessive iron intake has been linked to diabetes risk. However, the evidence is inconsistent. This study examined the association between dietary heme and nonheme iron intake and diabetes risk in the Chinese population. We included 17,026 adults (8,346 men and 8,680 women) who were part of the China Health and Nutrition Survey (1991-2015) prospective cohort. Dietary intake was measured by three consecutive 24-h dietary recalls combined with a household food inventory. Diabetes cases were identified through a questionnaire. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% CIs. A total of 547 men and 577 women developed diabetes during 202,138 person-years of follow-up. For men, the adjusted HRs (95% CIs) for quintiles of nonheme iron intake were 1.00, 0.77 (0.58-1.02), 0.72 (0.54-0.97), 0.63 (0.46-0.85), and 0.87 (0.64-1.19) (P-nonlinearity = 0.0015). The corresponding HRs (95% CIs) for women were 1.00, 0.63 (0.48-0.84), 0.57 (0.43-0.76), 0.58 (0.43-0.77), and 0.67 (0.49-0.91) (P-nonlinearity < 0.0001). The dose-response curves for the association between nonheme iron and total iron intake and diabetes followed a reverse J shape in men and an L shape in women. No significant associations were observed between heme iron intake and diabetes risk. Total iron and nonheme iron intake was associated with diabetes risk, following a reverse J-shaped curve in men and an L-shaped curve in women. Sufficient intake of nonheme or total iron might be protective against diabetes, while excessive iron intake might increase the risk of diabetes among men.

Caveats for the Good and Bad of Dietary Red Meat.

Red meat and its constituents of heme iron or free iron have been the target of scrutiny related to their purported association to many chronic diseases. However, in contrast, red meat provides a rich source of nutrition. In 2007, Al Tappel hypothesized that the mechanistic explanation for the adverse impact of iron and heme iron could be the strong influence these substances have in initiating and promoting oxidative stress. Also, there is an emphasis on the importance of dietary antioxidants in the modulation of these adverse effects. The goal of this argumentative review is to provide an update of the importance of dietary red meat for health, and the hypothesis that oxidative stress initiated by dietary iron and heme iron may be related to chronic diseases, with a particular emphasis on recent research that impacts the paradigm. We also examine potential dietary changes that could substantially modify the potential adverse outcomes of chronic diseases initiated by heme iron mechanisms, e.g., consumption of antioxidant-rich fruits and vegetables.

Iron Consumption Is Not Consistently Associated with Fecundability among North American and Danish Pregnancy Planners

Infertility is an important public health problem with few known modifiable risk factors. Dietary factors including folic acid have been associated with improved fertility, but the association between iron and fertility is understudied. One study among US nurses found a 40% lower risk of ovulatory infertility with higher intake of nonheme iron and iron supplements. The aim of this study was to determine the extent to which iron intake from diet and supplements reported on structured questionnaires is associated with fecundability. We conducted parallel analyses that used data from 2 prospective cohort studies of pregnancy planners from Denmark (Snart Foraeldre; n=1693) and North America (PRESTO; n=2969) during 2013-2018. Follow-up comprised menstrual cycles at risk until pregnancy or censoring for fertility treatment, stopped trying to conceive, withdrawal, loss to follow-up, or 12 cycles of attempt. We used proportional probabilities regression models to estimate fecundability ratios (FRs) and 95% CIs, adjusting for confounders. We found little association between dietary heme iron intake and fecundability in either cohort. The FR for nonheme iron intake (≥11 mg/d compared with <9 mg/day) was 1.11 for Snart Foraeldre participants (95% CI: 0.92, 1.34) and 1.01 for PRESTO participants (95% CI: 0.89, 1.14). The FR for iron-containing supplements was 1.01 in Snart Foraeldre (95% CI: 0.90, 1.13) and 1.19 in PRESTO (95% CI: 1.03, 1.38). In PRESTO, but not Snart Foraeldre, stronger positive associations were found for nonheme iron intake and iron supplement use among women with heavy menses or short menstrual cycles. Overall, dietary intake of iron was not consistently associated with fecundability, although there was some evidence for a positive association among women with risk factors for iron deficiency. We also found a small positive association between supplemental iron intake and fecundability among North American, but not Danish, pregnancy planners.

The interaction of Hemin and Sestrin2 modulates oxidative stress and colon tumor growth

Several large epidemiological and animal studies demonstrate a direct correlation between dietary heme iron intake and/or systemic iron levels and cancer risk in several cancers including colorectal cancer (CRC). However, the precise mechanisms for how heme iron contributes to CRC and how cancer cells respond to heme iron-induced stress are still unclear. Previously we have shown that one of the stress-inducible proteins, Sestrin2 (SESN2), is a novel tumor suppressor in colon by limiting endoplasmic reticulum stress and mammalian target of rapamycin complex 1 (mTORC1) signaling and tumor growth. But the relationship between heme iron and SESN2, especially in the context of colon carcinogenesis, was not investigated previously. Here, we found that hemin dose-dependently increased SESN2 expression in an oxidative stress and nuclear factor (erythroid-derived 2)-like 2 (NFE2L2, NRF2)-dependent manner. Since SESN2 overexpression reduced hemin-induced oxidative stress, SESN2 could be an important target of NRF2 exerting antioxidant function. Indeed, expression of several oxidative stress responsive proteins such as NRF2 and its target genes was reduced by SESN2. Although we formerly reported that SESN2 expression was reduced after p53 mutation in colon tumors, mouse colon tumors, which have intact p53 and NRF2, induced SESN2 expression in response to iron stimulus. Although SESN2 overexpression decreased murine colon tumor cell growth both in vitro and in vivo, it rendered colon cancer cells more resistant to hemin-induced apoptosis and therefore promoted tumor growth during hemin treatment. Taken together, although SESN2 generally suppresses tumorigenesis, it can produce tumor-promoting role in iron-rich environment by suppressing oxidative stress-associated cancer cell death.