Dr. Mary Gamble's research focuses on nutritional biochemistry at both basic and applied levels. Her earlier work on retinoid metabolism included studies on proteins involved in retinoid transport and in the generation of transcriptionally active retinoic acid metabolites. Dr. Gamble's international research began with studies on vitamin A deficiency in the Republic of the Marshall Islands and in Brazil. Presently, she focuses primarily on nutrient/environment interactions, with her latest project determining nutritional influences on arsenic toxicity.
American Society for Nutrition Mary Swartz Rose Young Investigator Award, 2008
Calderone Award for Junior Faculty Development, 2007-2008
Selected Global Activities:
Nutritional Influences on Arsenic Toxicity
The largest known mass exposure to arsenic is presently occurring due to ground water contamination of well water throughout the Ganges-Brahmaputra Delta. There is a significant inter-individual variability in susceptibility to progression from arsenic exposure to clinical manifestations of arsenic toxicity (e.g. skin, lung, liver and bladder cancers). Several observational as well as biochemical studies have led to a prevalent hypothesis that nutritional status may account for a substantial portion of this variability, though no controlled clinical studies have addressed this important hypothesis.
Methylation of inorganic arsenic (InAs) has generally been considered to be a detoxification pathway. InAs and DNA are both methylated via one-carbon metabolism, a biochemical pathway which is dependent on folate for de novo generation of one-carbon groups, and also uses vitamins B12 and B6 as cofactors. The primary hypothesis of this proposal is that nutritional regulation of one-carbon metabolism, specifically folate availability, contributes substantially to the large inter-individual variability observed in InAs and DNA methylation, and thus progression from arsenic exposure to toxicity. These hypotheses have been tested in a randomized, controlled folic acid supplementation trial of adults chronically exposed to arsenic-contaminated drinking water in Bangladesh. These studies have also revealed complex interations between arsenic exposure, folate deficiency and DNA methylation that influence risk for development of arsenic-induced premalignant skin lesions.
Folic acid and creatine as therapeutic approaches for lowering blood arsenic
Arsenic (As) exposure affects more than 140 million people worldwide. Methylation of inorganic-arsenic (InAs) to methylarsonic- (MMA) and dimethylarsinic acids (DMA) relies on folate-dependent one-carbon metabolism and facilitates urinary arsenic (As) elimination. Our studies indicate that folate deficiency and hyperhomocysteinemia (HHcys) are associated with a reduced capacity to methylate As and are risk factors for As-induced skin lesions. Furthermore, folic acid (FA) supplementation significantly lowers blood As concentrations in individuals who are folate deficient.
However, several fundamental questions remain to be addressed: a) Does FA supplementation lower blood As concentrations in the general population? b) What is the optimal dose?, c) What is the time-course of the decline in blood As? d) Is there a rebound in blood As after the cessation of FA supplementation due to release of As from tissue stores? e) Can the ability of FA to lower blood As and homocysteine be enhanced by the addition of a novel new alternative approach: reduce methylation demand. The methylation of guanadinoacetate represents the final step in creatine biosynthesis. This reaction is the major consumer of methyl groups and every molecule of creatine synthesized ultimately generates a molecule of homocysteine. Furthermore, creatinine concentrations are a robust predictor of arsenic methylation. We will test the hypothesis that creatine supplementation, which downregulates endogenous creatine biosynthesis, will spare methyl groups, facilitate the methylation of other substrates - including As - and thereby lower blood As.
To answer all of these questions, we are conducting a randomized, double-blind, placebo controlled trial of FA (a comparison of two doses and durations), creatine, and creatine plus FA. Positive results of these interventions could have important therapeutic potential for ameliorating the long-term health consequences of As exposure for the many populations at risk.
One-carbon metabolism, oxidative stress and arsenic toxicity in Bangladesh
Two overarching themes of the biomedical research of our Superfund Basic Research Program addressed in this project relate to a) the metabolism of arsenic (As) and b) As-induced oxidative stress. In this project, we are expanding our studies which have begun to characterize the impact of nutritional regulation of one-carbon metabolism on the inter-individual variability in As methylation. Glutathione (GSH), a key component of the primary antioxidant defense mechanism, and the electron donor for As reduction, is synthesized from homocysteine, and this synthesis is regulated by intermediates of one-carbon metabolism. A great deal of basic research, including salient work from members of our group, points to the growing belief that As depletes glutathione (GSH) and induces oxidative stress. However, this has not been rigorously examined in human populations.
We are conducting a nested case-control study to identify modifiable risk factors ? e.g. oxidative stress and/or hyperhomocysteinemia ? related to increased susceptibility to As-induced skin lesions. We are also examining dose-response relationships between As exposure and oxidative stress. These studies have the potential to a) determine whether or not As induces oxidative stress and depletes GSH in humans, b) link As-induced oxidative stress and/or nutritional status to risk for premalignant skin lesions, and c) expand our understanding of the mechanisms underlying these processes. Such findings could have significant implications for the identification of targeted interventions for preventing As-toxicity.
Gamble MV, Ramakrishnan R, Palafox NA, Briand K, Berglund L, Blaner WS Retinol binding protein as a surrogate measure for serum retinol American Journal of Clinical Nutrition 73 594-601 2001
Gamble MV, Palafox NA, Dancheck B, Ricks MO, Briand K, Semba RD Relationship of vitamin A deficiency, iron deficiency, and inflammation to anemia among preschool children in the Republic of the Marshall Islands Eur J Clin Nutr 2004
Gamble MV, Liu X, Slavkovich V, Pilsner JR, Ilievski V, Factor-Litvak P, Levy D, Alam S, Islam M, Parvez F, Ahsan H, and Graziano JH Folic acid supplementation lowers blood arsenic American Journal of Clinical Nutrition 86 1202-1209 2007
Semba RD, Yuniar Y, Gamble MV, Natadisastra G, and Muhilal Assessment of vitamin A status of preschool children in Indonesia using plasma retinol-binding protein J Trop Pediatr 48 84-7 2002
Pilsner JR, Liu X, Ahsan H, Ilievski V, Slavkovich V, Levy D, Factor-Litvak P, Graziano JH, and Gamble MV Genomic methylation of peripheral blood leukocyte DNA: influences of arsenic and folate in Bangladeshi adults American Journal of Clinical Nutrition 86 1179-1186 2007
Gamble MV, Ramakrishnan R, Palafox NA, Briand K, Berglund L, Blaner WS Retinol binding protein as a surrogate measure for serum retinol: studies in vitamin A-deficient children from the Republic of the Marshall Islands Am J Clin Nutr 73 594-601 2001
Hall M, Gamble MV, Slavkovich V, Liu X, Levy D, Cheng Z, van Geen A, Yunus M, Rahman M, Pilsner JR, and Graziano JH Determinants of arsenic metabolism: Blood arsenic metabolites, plasma folate, cobalamin, and homocysteine concentrations in maternal-newborn pairs Environmental Health Perspectives 115 1503-1509 2007
van Bennekum AS, Wei S, Gamble MV, Vogel S, Piantedosi R, Gottesman M, Episkopou V and Blaner WS Biochemical basis for depressed serum retinol levels in transthyretin-deficient mice J Biol Chem 276 1107-1113 2001
Ahsan H, Chen Y, Kibriya MG, Slavkovich V, Parvez F, Jasmine F, Gamble MV, and Graziano JG Arsenic metabolism, genetic susceptibility and risk of pre-malignant skin lesions in Bangladesh Cancer epidemiology, biomarkers and prevention 16 1270-1278 2007
Filteau SM, Willumsen JF, Sullivan K, Simmank K, and Gamble M Use of the retinol-binding protein/transthyretin ratio for assessment of vitamin A status during the acute phase response Br J Nutr 83 513-520 2000