Metabolism of Mycotoxins, Intracellular Functions of Vitamin B12, and Neurological Manifestations in Patients with Chronic Toxigenic Mold Exposures. A Review

This paper evaluates the possible reasons for consistent vitamin B12deficiency in chronic toxigenic mold exposures and the synergistic relationships with the possible mycotoxic effects on one-carbon metabolism that lead to the manifestations of clinical neuropathological symptomology. Vitamins are first defined in general and the nutritional sources of vitamin B12are evaluated in particular. Since patients with chronic exposures to toxigenic molds manifest vitamin B12deficiencies, the role of mycotoxins in vitamin B12metabolism is assessed, and since vitamin B12plays important biochemical roles in one-carbon metabolism, the synergistic effects with mycotoxins on humans are reviewed. An outline of the proposed mechanism by which mycotoxins disrupt or interfere with the normal functions of vitamin B12on one-carbon metabolism is proposed. The overall functions of vitamin B12as a source of coenzymes, in intracellular recycling of methionine, in methionine synthase reaction, in the prevention of chromosome breakage, in methylation, and in maintaining a one-carbon metabolic balance are reviewed. Signs, symptoms, and clinical neurological indications of vitamin B12deficiency are also cited. By implication and derivation, it is likely that the interruption of the structure and function of vitamin B12would in turn interfere with the one-carbon metabolism leading to the neurological manifestations. This review is an attempt to formulate a basis for an ongoing research investigation on the subject.

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Matrix metalloproteinases-2, -3 and tissue inhibitors of metalloproteinases-1, -2 in placentas from preterm pregnancies and their association with one-carbon metabolites

Reproduction ◽

10.1530/rep-12-0520 ◽

2013 ◽

Vol 145 (4) ◽

pp. 401-410 ◽

Cited By ~ 13

Author(s):

Deepali Sundrani ◽

Preeti Chavan-Gautam ◽

Hemlata Pisal ◽

Savita Mehendale ◽

Sadhana Joshi

Keyword(s):

Oxidative Stress ◽

Matrix Metalloproteinases ◽

Carbon Metabolism ◽

Preterm Labor ◽

Tissue Inhibitors Of Metalloproteinases ◽

Vitamin B ◽

Tissue Inhibitors ◽

One Carbon Metabolism ◽

The One ◽

And Oxidative Stress

Maternal nutrition is an important determinant of one-carbon metabolism and defects in the one-carbon metabolism may lead to poor obstetric outcomes. This study was designed to test the hypothesis that altered intake/metabolism of micronutrients (folic acid and vitamin B12) and docosahexaenoic acid (DHA) contributes to increased homocysteine and oxidative stress leading to altered levels of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in women delivering preterm. We have earlier reported increased vitamin B12, homocysteine, and oxidative stress along with reduced placental DHA in women delivering preterm. In this study, we further examine the placental levels of MMP2, MMP3, TIMP1, and TIMP2 in 75 women delivering at term and 73 women delivering preterm. Placental levels of MMPs and TIMPs were determined by ELISA. Placental MMP2 and MMP3 levels were higher (P<0.01) in women delivering preterm as compared with term. There was no difference in the placental TIMP1 and TIMP2 levels in women delivering preterm and at term. Further placental MMP2 and MMP3 levels were higher (P<0.01) in women with preterm labor as compared with those in labor at term, suggesting that MMPs may favor degradation of extracellular matrix in the placenta during preterm labor. Our study for the first time suggests a crucial role of micronutrients and MMPs in preterm birth. Future studies need to examine if epigenetic modifications through the one-carbon cycle contribute to increased levels of MMPs leading to preterm deliveries.

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Formate can differentiate between hyperhomocysteinemia due to impaired remethylation and impaired transsulfuration

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00345.2011 ◽

2012 ◽

Vol 302 (1) ◽

pp. E61-E67 ◽

Cited By ~ 25

Author(s):

Simon G. Lamarre ◽

Anne M. Molloy ◽

Stacey N. Reinke ◽

Brian D. Sykes ◽

Margaret E. Brosnan ◽

...

Keyword(s):

Carbon Metabolism ◽

Folate Metabolism ◽

Methionine Synthase ◽

Vitamin B ◽

Metabolomic Analysis ◽

Elevated Plasma ◽

H Nmr ◽

Transsulfuration Pathway ◽

One Carbon Metabolism ◽

The One

Formate can differentiate between hyperhomocysteinemia due to impaired remethylation and impaired transsulfuration. Am J Physiol Endocrinol Metab 301: E000–E000, 2011. First published September 20, 2011; 10.1152/ajpendo.00345.2011.—We carried out a1H-NMR metabolomic analysis of sera from vitamin B12-deficient rats. In addition to the expected increases in methylmalonate and homocysteine (Hcy), we observed an approximately sevenfold increase in formate levels, from 64 μM in control rats to 402 μM in vitamin B12-deficient rats. Urinary formate was also elevated. This elevation of formate could be attributed to impaired one-carbon metabolism since formate is assimilated into the one-carbon pool by incorporation into 10-formyl-THF via the enzyme 10-formyl-THF synthase. Both plasma and urinary formate were also increased in folate-deficient rats. Hcy was elevated in both the vitamin B12- and folate-deficient rats. Although plasma Hcy was also elevated, plasma formate was unaffected in vitamin B6-deficient rats (impaired transsulfuration pathway). These results were in accord with a mathematical model of folate metabolism, which predicted that reduction in methionine synthase activity would cause increased formate levels, whereas reduced cystathionine β-synthase activity would not. Our data indicate that formate provides a novel window into cellular folate metabolism, that elevated formate can be a useful indicator of deranged one-carbon metabolism and can be used to discriminate between the hyperhomocysteinemia caused by defects in the remethylation and transsulfuration pathways.

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Betaine: a key modulator of one-carbon metabolism and homocysteine status

Clinical Chemistry and Laboratory Medicine (CCLM) ◽

10.1515/cclm.2005.187 ◽

2005 ◽

Vol 43 (10) ◽

Cited By ~ 129

Author(s):

Per Magne Ueland ◽

Pål I. Holm ◽

Steinar Hustad

Keyword(s):

Carbon Metabolism ◽

Individual Variability ◽

Vitamin B ◽

Total Homocysteine ◽

Altered Metabolism ◽

One Carbon Metabolism ◽

And Gender ◽

Betaine Homocysteine Methyltransferase ◽

Plasma Total Homocysteine ◽

Homocysteine Methyltransferase

AbstractBetaine serves as a methyl donor in a reaction converting homocysteine to methionine, catalysed by the enzyme betaine-homocysteine methyltransferase. It has been used for years to lower the concentration of plasma total homocysteine (tHcy) in patients with homocystinuria, and has recently been shown to reduce fasting and in particular post-methionine load (PML) tHcy in healthy subjects.Betaine exists in plasma at concentrations of about 30μmol/L; it varies 10-fold (from 9 to 90μmol/L) between individuals, but the intra-individual variability is small. Major determinants are choline, dimethylglycine and folate in plasma, folic acid intake and gender.Recent studies have demonstrated that plasma betaine is a stronger determinant of PML tHcy than are vitamin BTo conclude, betaine status is a component of an individual's biochemical make-up with ramifications to one-carbon metabolism. Betaine status should be investigated in pathologies related to altered metabolism of homocysteine and folate, including cardiovascular disease, cancer and neural tube defects.

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Duality of Tocopherol Isoforms and Novel Associations with Vitamins Involved in One-Carbon Metabolism: Results from an Elderly Sample of the LifeLines Cohort Study

Nutrients ◽

10.3390/nu12020580 ◽

2020 ◽

Vol 12 (2) ◽

pp. 580

Author(s):

Camilo G. Sotomayor ◽

Isidor Minović ◽

Manfred L. Eggersdorfer ◽

Ineke J. Riphagen ◽

Martin H. de Borst ◽

...

Keyword(s):

Vitamin E ◽

Carbon Metabolism ◽

Serum Vitamin ◽

Elderly Subjects ◽

Vitamin Supplement ◽

Total Lipids ◽

Metabolism Pathway ◽

Age Related ◽

One Carbon Metabolism ◽

The One

Whether the affinity of serum vitamin E with total lipids hampers the appropriate assessment of its association with age-related risk factors has not been investigated in epidemiological studies. We aimed to compare linear regression-derived coefficients of the association of non-indexed and total lipids-indexed vitamin E isoforms with clinical and laboratory characteristics pertaining to the lipid, metabolic syndrome, and one-carbon metabolism biological domains. We studied 1429 elderly subjects (non-vitamin supplement users, 60–75 years old, with low and high socioeconomic status) from the population-based LifeLines Cohort and Biobank Study. We found that the associations of tocopherol isoforms with lipids were inverted in total lipids-indexed analyses, which may be indicative of overcorrection. Irrespective of the methods of standardization, we consistently found positive associations of α-tocopherol with vitamins of the one-carbon metabolism pathway and inverse associations with characteristics related to glucose metabolism. The associations of γ-tocopherol were often opposite to those of α-tocopherol. These data suggest that tocopherol isoforms and one-carbon metabolism are related, with beneficial and adverse associations for α-tocopherol and γ-tocopherol, respectively. Whether tocopherol isoforms, or their interplay, truly affect the one-carbon metabolism pathway remains to be further studied.

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Investigating whether vitamin B12 and folic acid supplementation slows cognitive decline

Impact ◽

10.21820/23987073.2018.3.82 ◽

2018 ◽

Vol 2018 (3) ◽

pp. 82-83

Author(s):

Timothy Chi-yui Kwok

Keyword(s):

Hong Kong ◽

Cognitive Decline ◽

Early Stage ◽

The Elderly ◽

Folic Acid Supplementation ◽

Vitamin B ◽

Ongoing Research ◽

University Of Oxford ◽

Mild Impairment ◽

And Function

Given the increase in average lifespans in countries around the world, diseases that afflict the elderly are a major focus for scientists. Uppermost among these is dementia, a broad term which includes many types of cognitive decline from mild impairment to severe conditions such as Alzheimer's disease. We lose brain volume and function as we age, and it is this atrophy of different parts of the brain that leads to loss of cognitive function. Although atrophy takes many different forms and thus results in a range of conditions, there are commonalities between each that might be targets for treatment. One area of research is the possibility of using large doses of B vitamins to lower levels of the amino acid homocysteine, which has been linked to many conditions including cardiovascular disease and dementia. This is the focus of Professor Timothy Kwok's ongoing research at the Chinese University of Hong Kong. Kwok is also a practising consultant geriatrician at the Prince of Wales Hospital in Hong Kong and has been inspired to pursue this field of inquiry by the need for simple and inexpensive treatments which could be made available to large numbers of elderly patients. He says: 'A trial at the University of Oxford showed that lowering homocysteine levels led to a significant reduction in the rate of brain atrophy. However, many questions remain unanswered and our current two-year trial will hopefully give further insights into the benefits or otherwise of vitamin B supplementation. If a causative link can be found between vitamin B supplementation and a slower rate of cognitive decline, this would be an inexpensive and safe way of treating people at the early stage of disease. In addition, these vitamins could potentially be given as a preventative treatment in older people who are not yet showing signs of cognitive impairment. As Kwok says: 'Dementia is a major cause of dependency in old age and has a big impact on the people affected, their families and scarce medical resources. If supplementation could prevent dementia in people with early symptoms, this simple intervention could make a huge difference to the quality of life of elderly people and reduce the burden of dementia on national health services.'

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Long-Term, Supplemental, One-Carbon Metabolism–Related Vitamin B Use in Relation to Lung Cancer Risk in the Vitamins and Lifestyle (VITAL) Cohort

Journal of Clinical Oncology ◽

10.1200/jco.2017.72.7735 ◽

2017 ◽

Vol 35 (30) ◽

pp. 3440-3448 ◽

Cited By ~ 44

Author(s):

Theodore M. Brasky ◽

Emily White ◽

Chi-Ling Chen

Keyword(s):

Lung Cancer ◽

Cancer Risk ◽

Carbon Metabolism ◽

Lung Cancer Risk ◽

Hazard Ratio ◽

B Vitamins ◽

Vitamin B ◽

Supplement Use ◽

One Carbon Metabolism

Purpose Inconsistent findings have been reported of a link between the use of one-carbon metabolism–related B vitamins and lung cancer risk. Because of the high prevalence of supplemental vitamin B use, any possible increased association warrants further investigation. We examined the association between long-term use of supplemental B vitamins on the one-carbon metabolism pathway and lung cancer risk in the Vitamins and Lifestyle (VITAL) cohort, which was designed specifically to look at supplement use relative to cancer risk. Methods A total of 77,118 participants of the VITAL cohort, 50 to 76 years of age, were recruited between October 2000 and December 2002 and included in this analysis. Incident, primary, invasive lung cancers (n = 808) were ascertained by prospectively linking the participants to a population-based cancer registry. The 10-year average daily dose from individual and multivitamin supplements were the exposures of primary interest. Results Use of supplemental vitamins B6, folate, and B12 was not associated with lung cancer risk among women. In contrast, use of vitamin B6 and B12 from individual supplement sources, but not from multivitamins, was associated with a 30% to 40% increase in lung cancer risk among men. When the 10-year average supplement dose was evaluated, there was an almost two-fold increase in lung cancer risk among men in the highest categories of vitamin B6 (> 20 mg/d; hazard ratio, 1.82; 95% CI, 1.25 to 2.65) and B12 (> 55µg/d; hazard ratio, 1.98; 95% CI, 1.32 to 2.97) compared with nonusers. For vitamin B6 and B12, the risk was even higher among men who were smoking at baseline. In addition, the B6 and B12 associations were apparent in all histologic types except adenocarcinoma, which is the type less related to smoking. Conclusion This sex- and source-specific association provides further evidence that vitamin B supplements are not chemopreventive for lung cancer and may be harmful.

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Maternal vitamin D deficiency impact on LCPUFA and pregnancy outcome associated with alterations in the one carbon metabolism

Nutrition Research ◽

10.1016/j.nutres.2020.11.009 ◽

2020 ◽

Author(s):

Anindita A. Nandi ◽

Nisha S. Wadhwani ◽

Karuna N. Randhir ◽

Shweta D. Madiwale ◽

Juilee S. Deshpande ◽

...

Keyword(s):

Vitamin D ◽

Vitamin D Deficiency ◽

Pregnancy Outcome ◽

Carbon Metabolism ◽

Maternal Vitamin ◽

One Carbon Metabolism ◽

The One

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Biochemical Impedance on Intracellular Functions of Vitamin B12 in Chronic Toxigenic Mold Exposures

The Scientific World JOURNAL ◽

10.1100/tsw.2007.113 ◽

2007 ◽

Vol 7 ◽

pp. 1649-1657 ◽

Cited By ~ 1

Author(s):

Ebere C. Anyanwu ◽

Ijeoma Kanu

Keyword(s):

Vitamin B12 ◽

Neurological Disorders ◽

Vitamin B12 Deficiency ◽

Methionine Synthase ◽

Neurological Manifestations ◽

Biochemical Processes ◽

B12 Deficiency ◽

Spinal Degeneration ◽

One Carbon Metabolism ◽

And Function

A majority of patients with neurological disorders with chronic exposures to toxigenic molds and mycotoxins has vitamin B12 deficiency that is unrelated to dietary insufficiency. Vitamin B12 is a source of coenzymes, and participates in intracellular recycling of methionine, and in methionine synthase reactions. The biochemical processes that lead to B12 depletion and deficiency are not fully understood. This paper examines and assesses various most likely biochemical reasons that could impede upon the normal intracellular functions of vitamin B12 that lead to neurological manifestations. By biochemical implications and derivations, it is most likely that mycotoxins interrupt the structure and function of vitamin B12 through reactive interference with the normal One-Carbon metabolism leading to the observed clinical neurological manifestations such as nerve damage and, demyelination, degeneration of PNS leading to paralysis, progressive peripheral neuropathy, and spinal degeneration.

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Genetic Variants in One-Carbon Metabolism Pathway Predict Survival Outcomes of Early-Stage Non-Small Cell Lung Cancer

Oncology ◽

10.1159/000509658 ◽

2020 ◽

Vol 98 (12) ◽

pp. 897-904

Author(s):

Sook Kyung Do ◽

Sun Ha Choi ◽

Shin Yup Lee ◽

Jin Eun Choi ◽

Hyo-Gyoung Kang ◽

...

Keyword(s):

Lung Cancer ◽

Carbon Metabolism ◽

Genetic Variants ◽

Early Stage ◽

Small Cell ◽

Survival Outcomes ◽

Small Cell Lung ◽

Metabolism Pathway ◽

One Carbon Metabolism ◽

The One

Background: This study was conducted to investigate the association between genetic variants in one-carbon metabolism and survival outcomes of surgically resected non-small cell lung cancer (NSCLC). Methods: We genotyped 41 potentially functional variants of 19 key genes in the one-carbon metabolism pathway among 750 NSCLC patients who underwent curative surgery. The association between genetic variants and overall survival (OS)/disease-free survival (DFS) were analyzed. Results: Among the 41 single-nucleotide polymorphisms (SNPs) analyzed, 4 SNPs (MTHFD1L rs6919680T>G and rs3849794T>C, MTR rs2853523C>A, and MTHFR rs4846049G>T) were significantly associated with survival outcomes. MTHFD1L rs6919680T>G and MTR rs2853523C>A were significantly associated with better OS (adjusted hazard ratio [aHR] = 0.73, 95% confidence interval [CI] = 0.54–0.99, p = 0.04) and worse OS (aHR = 2.14, 95% CI = 1.13–4.07, p = 0.02), respectively. MTHFD1L rs3849794T>C and MTHFR rs4846049G>T were significantly associated with worse DFS (aHR = 1.41, 95% CI = 1.08–1.83, p = 0.01; and aHR = 1.97, 95% CI = 1.10–3.53, p = 0.02, respectively). When the patients were divided according to histology, the associations were significant only in squamous cell carcinoma (SCC), but not in adenocarcinoma (AC). In SCC, MTHFD1L rs6919680T>G and MTR rs2853523C>A were significantly associated with better OS (aHR = 0.64, 95% CI = 0.41–1.00, p = 0.05) and worse OS (aHR = 2.77, 95% CI = 1.11–6.91, p = 0.03), respectively, and MTHFD1L rs3849794T>C and MTHFR rs4846049G>T were significantly associated with worse DFS (aHR = 1.73, 95% CI = 1.17–2.56, p = 0.01; and aHR = 2.78, 95% CI = 1.12–6.88, p = 0.03, respectively). Conclusions: Our results suggest that the genetic variants in the one-carbon metabolism pathway could be used as biomarkers for predicting the clinical outcomes of patients with early-stage NSCLC.

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