Progress 02/08/11 to 02/07/16
Outputs
Progress Report Objectives (from AD-416): 1. Determine the biochemical and molecular basis for the species specificity of fumonisins using animal models. 2. Determine the dietary �no observed effect� and �lowest observed effect levels� for neural tube defect induction and determine the dose- response thresholds for elevation in sphingolipid biomarkers in blood spots and fumonisins in urine using animal models. 3. Determine the relationship between fumonisin consumption, urinary fumonisin (exposure biomarker) and changes in sphingolipids in blood spots (effect biomarker) in human populations consuming corn. 4. Determine the specific mechanism(s) by which fumonisins are readily taken up by corn plant roots and yet have limited translocation into above ground vegetative tissues. 5. Determine the effectiveness of alkaline cooking for reducing the toxic potential of fumonisin-contaminated whole kernel corn. Approach (from AD-416): 1. Conduct dose-response studies to determine the minimum oral dose of FB1 that disrupts sphingolipid metabolism and induces toxicity (increased apoptosis) in rat kidney and mouse liver. 2. Conduct dose-response studies in susceptible mouse strains to determine the thresholds for changes in biomarkers of exposure and effect and induction of neural tube defects. 3. Conduct epidemiological studies to identify humans consuming large amounts of corn-based foods in communities where FB is infrequently detected and frequently detected and sample and analyze urine (FBs) and blood spots (sphingolipids). 4. Conduct dose response studies to determine FB1 affects on plant transpiration and levels of sphingoid bases and their 1-phosphates in roots and aerial tissues in FB1-sensitive and -insensitive genotypes of corn. 5. Utilize FB-contaminated whole kernel corn to determine the processing conditions that maximize FB1 reduction using chemical analysis and in vivo animal bioassays. Over the life of this project, the research has documented the cellular effects of fumonisin, including elevation of the fats known as sphingoid base 1-phosphates. Two manuscripts have been published and a third accepted showing that one of the biochemical targets of sphinganine 1- phosphate and the structurally similar drug FTY720-P is an enzyme known as histone deacetylase, which is found in the nucleus of cells. This enzyme acetylates proteins known as histones which are associated with DNA that modulate gene expression. Changes in histone acetylation consequently affect the expression of genes that control many aspects of embryonic development. This is important because human exposure to other compounds that inhibit the histone deacetylase enzyme during pregnancy can cause birth defects known as neural tube defects (NTDs) in mice, and we have shown that both FTY720 and fumonisin B1 can also cause the same birth defect. Accumulation of nuclear sphingoid base 1-phosphates and reduction in histone deacetylase activity leading to increased acetylation of specific histones in the DNA represents a plausible mechanism for fumonisin induction of NTDs in humans. The information from in vivo mouse studies and in vitro studies in mouse and human neural progenitor cells are supportive of this possible impact of fumonisins. Additionally, our finding that consumption of corn contaminated with high levels of fumonisin B1 is correlated with elevated sphinganine 1- phosphate in Guatemalan women, a country with a high incidence of NTD, provides further evidence supporting the hypothesis that consumption of corn-based diets containing high levels of fumonisin B1 could be a possible risk factor for NTDs in humans. A manuscript describing for the first time the in vivo metabolism of fumonisin B1 to ceramide like compounds has been published. The findings show that bioavailability of fumonisin B1 is higher than previously shown with significant amounts of the metabolites, relative to parent compound, accumulating in liver. Characterizing metabolism and the biological activity of the metabolites is needed to better understand mechanisms of action and improve risk assessments. A manuscript has been published documenting the complexity of the interaction between folate sufficiency, NTD induction, and fumonisin exposure. Additional in vivo mouse studies on the interactions between folate in the diet and induction of neural tube defects in LM/Bc and SWV mice are in progress to explore the physiological/biochemical basis for the apparent paradoxical effects of folate sufficiency on fumonisin- induced NTDs in our mouse model and determine how dietary factors affect dose response for neural tube defect induction. Dose response of LM/Bc mice to oral (gavage) fumonisin B1 exposure was established and a dose level not causing neural tube defects or (< 10 mg/ kg body weight) and little to no evidence of liver toxicity was reported in a published manuscript. Data from rat feeding studies using uncooked and cooked Fusarium (F.) verticillioides culture materials as a dietary fumonisin source were provided to the FAO/WHO Joint Expert Committee for Food Additives for analysis of dose-response and setting a recommended maximum tolerated daily intake of fumonisins. Four manuscripts have been published reporting experiments showing that humans consuming diets containing high levels of fumonisin have significantly higher levels of sphingolipid metabolites (sphinganine 1- phosphate) in their blood. The results are consistent with the hypothesis that dietary intake of high levels of fumonisin contaminated corn results in disruption of sphingolipid metabolism in humans. Disruption of sphingolipid metabolism underlies all animal diseases known to be caused by fumonisin, including neural tube defects in mice. Results were provided to the Secretary of Food Security and Nutrition (SESAN) in Guatemala in 2014 along with data on both fumonisin and aflatoxin occurrence in Guatemalan corn. As a result of this work, a plan of action has been developed by SESAN and others to minimize both aflatoxin and fumonisin exposure. The results were also shared with the scientists at the U.S. Agency for International Development (USAID) Guatemala. Additional human fumonisin biomarker-based studies have been done in collaboration with Oakland University, Centro de Investigaciones en Nutrici�n y Salud (CIENSA), Michigan State University, and the University of Georgia. The Oakland University study is focused in the Department of Huehuetenango (Guatemala), the CIENSA study is focused on the Departments of Guatemala and Alta Verapaz (Guatemala), the Michigan State University study is focused on Nepal and Tanzania, and the University of Georgia study is focused in Texas. Additional human fumonisin biomarker-based studies, funded by the Bill and Melinda Gates Foundation, to study the role of mycotoxins in childhood growth retardation and enteric disease are in progress. Samples from Tanzania have been analyzed for urinary fumonisin B1 and the data supplied to the collaborators. Manuscripts have been published describing the physiological responses and molecular/cellular mechanisms that confer sensitivity/insensitivity to fumonisin B1 (FB1) in maize seedlings. The data provides a better understanding of the dynamics of mycotoxin movement and accumulation during fungal infection of the corn plant. Also, the possible suppression of fumonisin B1 production by fumonisin B1-insensitive maize genotypes may be a trait for targeted breeding efforts for reduced mycotoxin accumulation since preventing establishment of F. verticillioides root infections may reduce subsequent infection and fumonisin accumulation in aerial parts of the plant (leaves, stems, and perhaps ears). Alkaline cooking (nixtamalization) conditions leading to significant (80% or more) reduction of fumonisin levels in whole kernel corn were determined. A manuscript has been published demonstrating the effectiveness of the alkaline cooking for reducing fumonisin toxicity by means of a rat feeding bioassay has been published. Sources of corn suitable for further studies on nixtamalization have been identified for use in future studies incorporated into a new, approved project plan. Accomplishments 01 Fumonisin exposure in women linked to inhibition of an enzyme that is a key event in farm and laboratory animal diseases. Fumonisin B1 (FB1) is a toxic chemical produced by molds. The molds that produce fumonisin are common in corn. Consumption of contaminated corn by farm animals has been shown to be the cause of disease. Fumonisin has been hypothesized to be an environmental risk factor for diseases in humans in countries where corn is a dietary staple and infection with the mold is likely. In order to determine if fumonisin contributes to disease in humans, methods were developed to measure changes in the urine and blood levels of chemicals that are indicators of changes indicative of pre-disease states in animal studies. The human studies have focused on populations in Guatemala where corn is a dietary staple. Intake of fumonisin in these populations can be very high. Corn, urine and blood were sampled from over 1,500 women and the results show that fumonisin intake and changes in a unique class of fats (sphingoid base 1- phosphates) in the blood are correlated in a manner that mimics the effects of fumonisin in laboratory animals. The findings are consistent with the hypothesis that fumonisin inhibits the same enzyme in humans as it does in farm and laboratory animals consuming diets high in fumonisin. These findings are the basis for development of biomarker- based studies in humans designed to identify possible human diseases where fumonisin could be a contributing factor and will provide an incentive to reduce fumonisin exposure in developing countries where corn is a dietary staple. These studies were conducted as part of collaborations between USDA-TMRU (Athens, GA), Centro de Investigaciones en Nutrici�n y Salud in Guatemala, Creighton University and Duke University. 02 Human fumonisin biomarker-based studies have been completed in collaboration with Oakland University, Centro de Investigaciones en Nutrici�n y Salud (CIENSA), and Michigan State University. The Oakland University study in 104 women was focused in the Department of Huehuetenango (Guatemala), the CIENSA study in >300 women focused on the Departments of Guatemala and Alta Verapaz (Guatemala), the Michigan State University study focused on Nepal (50 children, 2-3 yr) and Tanzania (94 children, 2-3 yr). The study in Huehuetenango included the analysis of both urinary FB1 and sphingolipid biomarkers in blood. The results provided additional evidence for a link between fumonisin exposure and disruption of sphingolipid metabolism in humans. The study in Nepal only looked at urinary FB1 exposure biomarkers and showed that there is very little exposure to fumonisin in the sampled cohort of Nepalese children (1 positive sample). The study in Tanzania also involved only children and showed that fumonisin exposure was quite common (75 positive samples) with sometimes clear evidence of high levels of exposure (54 children exceeded the FAO/WHO provisional maximum tolerable daily intake of 2 �g/kg bw/day).
Impacts
(N/A)
Publications
- Mitchell, N.J., Riley, R.T., Egner, P.A., Groopman, J.D., Wu, F. 2016. Chronic aflatoxin exposure in children living in Bhaktapur, Nepal: Extension of the MAL-ED study. Journal of Exposure Science and Environmental Epidemiology. doi:10.1038/jes.2015.87.
- Gardner, N., Riley, R.T., Showker, A.J., Voss, K.A., Sachs, A., Maddox, J., Gelineau-Van Waes, J. 2015. Elevated Nuclear and Cytoplasmic FTY720- Phosphate in Mouse Embryonic Fibroblasts Suggests the Potential for Multiple Mechanisms in FTY720-Induced Neural Tube Defects. Toxicological Sciences. 150(1):161-168.
- Haschek, W.M., Voss, K.A. 2013. Mycotoxins. Book Chapter. pgs. 1187-1258.
- Jackson, L.S., Voss, K.A., Ryu, D. 2012. Effects of different extrusion conditions on the chemical and toxicological fate of fumonisin B1 in maize: a review. World Mycotoxin Journal. 5(3):251-260.
- Riley, R.T., Torres, O., Matute, J., Gregory, S., Ashley-Koch, A., Showker, A.J., Mitchell, T.R., Voss, K.A., Maddox, J., Gelineau-Van Waes, J. 2015. Evidence for fumonisin inhibition of ceramide synthase in humans consuming maize-based foods and living in high exposure communities in Guatemala. Molecular Nutrition and Food Research. 59(11):2209-2224.
- Gardner, N., Riley, R.T., Showker, A.J., Voss, K.A., Sachs, A., Maddox, J., Gelineau-Van Waes, J. 2016. Elevated Nuclear Sphingoid Base-1-Phosphates and Decreased Histone Deacetylase Activity after Fumonisin B1 Treatment in Mouse Embryonic Fibroblasts. Journal of Toxicology and Applied Pharmacology. 298:56-65.
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Progress 10/01/14 to 09/30/15
Outputs
Progress Report Objectives (from AD-416): 1. Determine the biochemical and molecular basis for the species specificity of fumonisins using animal models. 2. Determine the dietary �no observed effect� and �lowest observed effect levels� for neural tube defect induction and determine the dose- response thresholds for elevation in sphingolipid biomarkers in blood spots and fumonisins in urine using animal models. 3. Determine the relationship between fumonisin consumption, urinary fumonisin (exposure biomarker) and changes in sphingolipids in blood spots (effect biomarker) in human populations consuming corn. 4. Determine the specific mechanism(s) by which fumonisins are readily taken up by corn plant roots and yet have limited translocation into above ground vegetative tissues. 5. Determine the effectiveness of alkaline cooking for reducing the toxic potential of fumonisin-contaminated whole kernel corn. Approach (from AD-416): 1. Conduct dose-response studies to determine the minimum oral dose of FB1 that disrupts sphingolipid metabolism and induces toxicity (increased apoptosis) in rat kidney and mouse liver. 2. Conduct dose-response studies in susceptible mouse strains to determine the thresholds for changes in biomarkers of exposure and effect and induction of neural tube defects. 3. Conduct epidemiological studies to identify humans consuming large amounts of corn-based foods in communities where FB is infrequently detected and frequently detected and sample and analyze urine (FBs) and blood spots (sphingolipids). 4. Conduct dose response studies to determine FB1 affects on plant transpiration and levels of sphingoid bases and their 1-phosphates in roots and aerial tissues in FB1-sensitive and -insensitive genotypes of corn. 5. Utilize FB-contaminated whole kernel corn to determine the processing conditions that maximize FB1 reduction using chemical analysis and in vivo animal bioassays. Our research has well documented the cellular effects of fumonisin, including elevation of the fats known as sphingoid base 1-phosphates. Two new manuscripts have been prepared and one has been submitted showing that one of the biochemical targets of sphinganine 1-phosphate and the structurally similar drug FTY720-P is an enzyme known as histone deacetylase, which is found in the nucleus of cells. This enzyme acetylates proteins known as histones which are associated with DNA that modulate gene expression. Changes in histone acetylation consequently affect the expression of genes that control many aspects of embryonic development. This is important because human exposure to other compounds that inhibit the histone deacetylase enzyme during pregnancy can cause birth defects known as neural tube defects (NTDs) in mice, and we have shown that both FTY720 and fumonisin B1 can also cause the same birth defect. Accumulation of nuclear sphingoid base 1-phosphates and reduction in histone deacetylase activity leading to increased acetylation of specific histones in the DNA represents a plausible mechanism for fumonisin induction of NTDs in humans. The information from in vivo mouse studies and in vitro studies in mouse and human neural progenitor cells are supportive of this possible impact of fumonisins. Additionally, our finding that consumption of corn contaminated with high levels of fumonisin B1 is correlated with elevated sphinganine 1- phosphate in Guatemalan women, a country with a high incidence of NTD, provides further evidence supporting the hypothesis that consumption of corn-based diets containing high levels of fumonisin B1 could be a possible risk factor for NTDs in humans. A manuscript describing for the first time the in vivo metabolism of fumonisin B1 to ceramide like compounds has been published. The findings show that bioavailability of fumonisin B1 is higher than previously shown with significant amounts of the metabolites, relative to parent compound, accumulating in liver. Characterizing metabolism and the biological activity(ies) of the metabolites is needed to better understand mechanisms of action and improve risk assessments. Objective 2: A manuscript has been published documenting the complexity of the interaction between folate sufficiency, NTD induction, and fumonisin exposure. Ongoing and future studies will explore the physiological/biochemical basis for the apparent paradoxical effects of folate sufficiency on fumonisin-induced NTDs in our mouse model. Objective 3: Two manuscripts have been published and one is in press showing that humans consuming diets containing high levels of fumonisin have significantly higher levels of sphingolipid metabolites (sphinganine 1-phosphate) in their blood. The results are consistent with the hypothesis that dietary intake of high levels of fumonisin contaminated corn results in disruption of sphingolipid metabolism in humans. Disruption of sphingolipid metabolism is the proximate cause of all the animal diseases known to be caused by fumonisin, including neural tube defects in mice. These results were provided to the Secretary of Food Security and Nutrition (SESAN) in Guatemala in 2014 along with data on both fumonisin and aflatoxin occurrence in Guatemalan corn. As a result of this work, a plan of action has been developed by SESAN and others to minimize both aflatoxin and fumonisin exposure. The results were also shared with the scientists at the US Agency for International Development (USAID) Guatemala. Additional human fumonisin biomarker-based studies are in progress in collaboration with Oakland University, Centro de Investigaciones en Nutrici�n y Salud (CIENSA), Michigan State University, and the University of Georgia. The Oakland University study is focused in the Department of Huehuetenango (Guatemala), the CIENSA study is focused on the Departments of Guatemala and Alta Verapaz (Guatemala), the Michigan State University study is focused on Nepal and Tanzania, and the University of Georgia study is focused in Texas. Objective 4: Manuscripts have been published describing the physiological responses and molecular/cellular mechanisms that confer sensitivity/insensitivity to fumonisin B1 (FB1) in maize seedlings. The data provides a better understanding of the dynamics of mycotoxin movement and accumulation during fungal infection of the corn plant. Also, the possible suppression of fumonisin B1 production by fumonisin B1- insensitive maize genotypes may be a trait for targeted breeding efforts for reduced mycotoxin accumulation since preventing establishment of F. verticillioides root infections may reduce subsequent infection and fumonisin accumulation in aerial parts of the plant (leaves, stems, and perhaps ears). Objective 5: Suitable corn for further studies on nixtamalization has not been available. Previously, nixtamalization conditions leading to significant (80% or more) reductions of fumonisin levels in whole kernel corn were determined and the effectiveness of the cooking conditions for reducing fumonisin toxicity demonstrated in a rat feeding bioassay have been reported in a published manuscript. Accomplishments 01 Fumonisin exposure in women linked to inhibition of an enzyme that is a key event in farm and laboratory animal diseases. Fumonisin B1 (FB1) is a toxic chemical produced by molds. The molds that produce fumonisin are common in corn. Consumption of contaminated corn by farm animals has been shown to be the cause of disease. Fumonisin has been hypothesized to be an environmental risk factor for diseases in humans in countries where corn is a dietary staple and infection with the mold is likely. In order to determine if fumonisin contributes to disease in humans, methods were developed to measure changes in the urine and blood levels of chemicals that are indicators of changes indicative of pre-disease states in animal studies. The human studies have focused on populations in Guatemala where corn is a dietary staple. Intake of fumonisin in these populations can be very high. Corn, urine and blood were sampled from over 1500 women and the results show that fumonisin intake and changes in a unique class of fats (sphingoid base 1- phosphates) in the blood are correlated in a manner that mimics the effects of fumonisin in laboratory animals. The findings are consistent with the hypothesis that fumonisin inhibits the same enzyme in humans as it does in farm and laboratory animals consuming diets high in fumonisin. These findings are the basis for development of biomarker-based studies in humans designed to identify possible human diseases where fumonisin could be a contributing factor and will provide an incentive to reduce fumonisin exposure in developing countries where corn is a dietary staple. These studies were conducted as part of a collaboration between USDA-TMRU (Athens, GA), Centro de Investigaciones en Nutrici�n y Salud in Guatemala, Creighton University and Duke University.
Impacts
(N/A)
Publications
- Harrer, H., Humpf, H., Voss, K.A. 2015. In vivo formation of N-acyl- fumonisin B1. Mycotoxin Research. 31(1):33-40.
- Voss, K.A., Riley, R.T., Gelineau-Van Waes, J. 2014. Fumonisin B1 induced neural tube defects were not increased in LM/Bc mice fed folate-deficient diet. Molecular Nutrition and Food Research. 58(6):1190-1198.
- Riley, R.T., Showker, A.J., Lee, C.M., Zipperer, C.E., Mitchell, T.R., Voss, K.A., Zitomer, N.C., Torres, O., Matute, J., Gregory, S.G., Ashley- Koch, A.E., Maddox, J.R., Gardner, N., Gelineau-Van Waes, J. 2015. A Blood Spot Method for Detecting Fumonisin-Induced Changes in Putative Sphingolipid Biomarkers in LM/Bc Mice and Humans. Journal of Food Additives & Contaminants. 32(6):934-949.
- Torres, O., Matute, J., Gelineau-Van Waes, J., Maddox, J.R., Gregory, S.G., Ashley-Koch, A.E., Showker, A.J., Voss, K.A., Riley, R.T. 2015. Human health implications from co-exposure to aflatoxins and fumonisins in maize- based foods in Latin America: Guatemala as a case study. World Mycotoxin Journal. 8(2):143-159.
- Riley, R.T., Miller, D.J. 2014. The Statement that Some Ochratoxins are �.. classified as human carcinogens� is Not Accurate. Toxicological Sciences. 143(1):1-2.
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Progress 10/01/13 to 09/30/14
Outputs
Progress Report Objectives (from AD-416): 1. Determine the biochemical and molecular basis for the species specificity of fumonisins using animal models. 2. Determine the dietary �no observed effect� and �lowest observed effect levels� for neural tube defect induction and determine the dose- response thresholds for elevation in sphingolipid biomarkers in blood spots and fumonisins in urine using animal models. 3. Determine the relationship between fumonisin consumption, urinary fumonisin (exposure biomarker) and changes in sphingolipids in blood spots (effect biomarker) in human populations consuming corn. 4. Determine the specific mechanism(s) by which fumonisins are readily taken up by corn plant roots and yet have limited translocation into above ground vegetative tissues. 5. Determine the effectiveness of alkaline cooking for reducing the toxic potential of fumonisin-contaminated whole kernel corn. Approach (from AD-416): 1. Conduct dose-response studies to determine the minimum oral dose of FB1 that disrupts sphingolipid metabolism and induces toxicity (increased apoptosis) in rat kidney and mouse liver. 2. Conduct dose-response studies in susceptible mouse strains to determine the thresholds for changes in biomarkers of exposure and effect and induction of neural tube defects. 3. Conduct epidemiological studies to identify humans consuming large amounts of corn-based foods in communities where FB is infrequently detected and frequently detected and sample and analyze urine (FBs) and blood spots (sphingolipids). 4. Conduct dose response studies to determine FB1 affects on plant transpiration and levels of sphingoid bases and their 1-phosphates in roots and aerial tissues in FB1-sensitive and -insensitive genotypes of corn. 5. Utilize FB-contaminated whole kernel corn to determine the processing conditions that maximize FB1 reduction using chemical analysis and in vivo animal bioassays. Objective 1: Studies have been initiated to identify the subcellular localization of sphingoid bases and sphingoid base-1-phosphates in mice that are susceptible or resistant to fumonisin-disruption of sphingolipid metabolism and induction of neural tube defects (NTD). Towards this end, our collaborator at Creighton University developed a mouse embryonic fibroblast cell line from fumonisin susceptible and resistant mouse strains. The results show that the bioactive sphingoid base-1-phosphates (Sa1P) are present at much higher concentration in the nucleus than in the cytoplasm and that the levels are highest in the susceptible strain. The protein target of the elevated nuclear Sa1P appears to be histone deacetylase. This is important because human exposure to the histone deacetylase inhibitor, valproic acid, during pregnancy has been shown to cause NTDs. Accumulation of nuclear Sa1P, coupled with a reduction in histone deacetylase activity therefore represents a plausible mechanism for fumonisin induction of NTDs. The metabolism of fumonisin B1 (FB1) by an animal species was demonstrated for the first time using rats as a model species. The metabolites consist of FB1 combined with a fatty acid, yielding structures which resemble physiologically important ceramides found in liver and kidney. The amount of metabolites in these tissues represents only a small portion of the FB1 dose, but it accounted for about half of the total FB1 plus metabolites recovered from the liver. Understanding the metabolic fate of fumonisins is needed to improve confidence in risk assessments and regulatory advisories. Objective 2: We are conducting further studies on how folate concentration in the diet affects induction of NTD by FB1. In mice, blood folate was modulated by varying the length of time that mice were fed a folate deficient diet. Consistent with earlier findings, the folate deficient diet did not increase or offered some protection against NTD induction by FB1 when fed for up to two weeks before mating. No NTDs were found in viable fetuses from females fed the deficient diet five weeks before mating, however, in contrast to other studies, consumption of the folate deficient diet before mating enhanced embryo death. The findings confirm that NTD induction by FB1 in this mouse model is complicated and that, in addition to folate, other undefined factors, possibly including sphingolipid status of the animals, are involved. The results show that nutritional factors may significantly influence the no effect and lowest observed effect levels for NTD induction by FB1. Objective 3: Studies were completed which confirm that humans consuming diets containing high levels of fumonisin have significantly higher levels of sphingolipid metabolites (sphinganine 1-phosphate) in their blood. The levels of these sphingolipid metabolites are significantly correlated with the levels of fumonisin B1 in the urine. The results are consistent with the hypothesis that dietary intake of high levels of fumonisin contaminated corn results in disruption of sphingolipid metabolism in humans. Disruption of sphingolipid metabolism is the proximate cause of all the animal diseases known to be caused by fumonisin, including neural tube defects in mice. These results were provided to the Secretary of Food Security and Nutrition (SESAN) in Guatemala along with data on both fumonisin and aflatoxin occurrence in Guatemalan corn. As a result of this work, a plan of action has been developed by SESAN and others to minimize both aflatoxin and fumonisin exposure. The results were also shared with the scientists at the U.S. Agency for International Development Guatemala. Objective 4: The manuscript describing the results of the studies using the experimental system which was developed to assess the physiological responses and molecular/cellular mechanisms that confer sensitivity/ insensitivity to FB1 in maize seedlings was published. The data provides a better understanding of the dynamics of mycotoxin movement and accumulation during fungal infection of the corn plant. Also, the possible suppression of FB1 production by FB1-insensitive maize genotypes may be a trait for targeted breeding efforts for reduced mycotoxin accumulation. Objective 5: Additional studies to optimize the nixtamalization process to determine the minimum processing procedures (i.e. number and volume of rinses) needed to significantly reduce fumonisins in the corn and achieve a significant protective effect against fumonisin toxicity are pending the availability of suitably contaminated corn. Accomplishments 01 Biomarker-based studies in humans provide incentive to reduce mycotoxin exposure in developing countries. Studies were completed which confirm that humans consuming diets containing high levels of fumonisin have significantly higher levels of sphingolipid metabolites (sphinganine 1- phosphate) in their blood when compared to low fumonisin exposure groups. The levels of sphingolipid metabolites in the blood were significantly correlated with fumonisin B1 in the urine. The results are consistent with the hypothesis that dietary intake of high levels of fumonisin contaminated corn results in disruption of sphingolipid metabolism in humans. Disruption of sphingolipid metabolism is the proximate cause of all the animal diseases known to be caused by fumonisin, including neural tube defects in mice. The incidence of neural tube defects is high in countries where corn is a dietary staple and is likely to be contaminated with high levels of fumonisin and aflatoxin. The results of our biomarker-based studies were provided to the Secretary of Food Security and Nutrition (SESAN) in Guatemala and also other government agencies and non-governmental organizations (Catholic Relief Services Guatemala) along with data on both fumonisin and aflatoxin co-occurrence in Guatemalan corn. As a result of this work, a plan of action has been developed by SESAN and others (World Food Programme) to minimize both aflatoxin and fumonisin exposure in Guatemala. The results were also shared with the U.S. Agency for International Development and USDA Foreign Agricultural Service in Guatemala. These studies were conducted as part of a collaboration between USDA-ARS Toxicology and Mycotoxin Research Unit (Athens, Georgia), Centro de Investigaciones en Nutrici�n y Salud in Guatemala, Creighton University and Duke University.
Impacts
(N/A)
Publications
- Voss, K.A., Riley, R.T. 2013. Fumonisin toxicity and mechanism of action: overview and current perspectives. Food Safety. 1(1):49-69. doi: 10.14252/ foodsafetyfscj.2013006.
- Torres, O., Matute, J., Gelineau-Van Waes, J., Maddox, J.R., Gregory, S.G., Ashley-Koch, A.E., Showker, A.J., Zitomer, N.C., Voss, K.A., Riley, R.T. 2014. Urinary fumonisin B1 and estimated fumonisin intake in women from high and low exposure communities in Guatemala. Molecular Nutrition and Food Research. 58(5):973-983. doi: 10.1002/mnfr.201300481.
- Baldwin, T.T., Zitomer, N.C., Mitchell, T.R., Zimeri, A., Bacon, C.W., Riley, R.T., Glenn, A.E. 2014. Maize seedling blight induced by Fusarium verticillioides: accumulation of fumonisin B1 in leaves without colonization of the leaves. Journal of Agricultural and Food Chemistry. 62:2118-2125. doi: 10.1021/jf5001106.
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Progress 10/01/12 to 09/30/13
Outputs
Progress Report Objectives (from AD-416): 1. Determine the biochemical and molecular basis for the species specificity of fumonisins using animal models. 2. Determine the dietary �no observed effect� and �lowest observed effect levels� for neural tube defect induction and determine the dose- response thresholds for elevation in sphingolipid biomarkers in blood spots and fumonisins in urine using animal models. 3. Determine the relationship between fumonisin consumption, urinary fumonisin (exposure biomarker) and changes in sphingolipids in blood spots (effect biomarker) in human populations consuming corn. 4. Determine the specific mechanism(s) by which fumonisins are readily taken up by corn plant roots and yet have limited translocation into above ground vegetative tissues. 5. Determine the effectiveness of alkaline cooking for reducing the toxic potential of fumonisin-contaminated whole kernel corn. Approach (from AD-416): 1. Conduct dose-response studies to determine the minimum oral dose of FB1 that disrupts sphingolipid metabolism and induces toxicity (increased apoptosis) in rat kidney and mouse liver. 2. Conduct dose-response studies in susceptible mouse strains to determine the thresholds for changes in biomarkers of exposure and effect and induction of neural tube defects. 3. Conduct epidemiological studies to identify humans consuming large amounts of corn-based foods in communities where FB is infrequently detected and frequently detected and sample and analyze urine (FBs) and blood spots (sphingolipids). 4. Conduct dose response studies to determine FB1 affects on plant transpiration and levels of sphingoid bases and their 1-phosphates in roots and aerial tissues in FB1-sensitive and -insensitive genotypes of corn. 5. Utilize FB-contaminated whole kernel corn to determine the processing conditions that maximize FB1 reduction using chemical analysis and in vivo animal bioassays. Objective 1: When fumonisin (FB) inhibits ceramide biosynthesis in rats and mice, the biochemical responses in target organs are different. In rat, the lipid sphinganine accumulates and is metabolized to its 1- phosphate, which accumulates in kidney to high levels. Accumulation of this metabolite is the cause of the renal toxicity in rats. In mouse liver/kidney there is accumulation of 1-deoxysphinganine. We believe 1- deoxysphinganine is an important biochemical effector of liver toxicity in mice. These results provide evidence for the species and target organ specificity and will provide insight into the human targets. Objective 2: We are conducting studies on the role of dietary folate in induction of neural tube defects (NTD) in mouse. Studies confirm NTD induction by fumonisin B1 (FB1) is reduced in NTD-sensitive LM/Bc mice when fed folate deficient diets for five weeks prior to mating. The protection is associated with an 80 percent reduction of maternal red blood cell folate in mice fed the deficient diet. Based on our earlier work on interactions between folate and FB1, the finding is counterintuitive and suggests the activity of folate in this mouse model with FB1 treatment is much more complicated than previously believed. Objective 3: A survey of fumonisin (FB) contamination in corn in Guatemala was completed. Corn samples (640) were analyzed for FB and aflatoxins (AFB). High levels of AFB and FB were detected in corn from the Pet�n. High levels of FB, but not AFB, were detected in the Chiquimula and Santa Rosa and very low levels of FB and AFB were detected in the Sacatep�quez. Blood (n=390) and urine (n=390), as well as corn (n=30) for human consumption, were analyzed from Sacatep�quez, Chiquimula, and Santa Rosa. Analysis of the urinary FB biomarker confirmed low exposure in Sacatep�quez and high exposure in Chiquimula and Santa Rosa. The sphingolipid biomarkers in blood are being analyzed. Objective 4: An experimental system was developed to assess the physiological responses and molecular/cellular mechanisms that confer sensitivity/insensitivity to fumonisin B1 (FB1) in maize. Utilizing mutant strains of Fusarium verticillioides, we demonstrated that FB1 accumulates in leaves of the susceptible cultivar Silver Queen without colonization of aerial tissues. Wild-type F. verticillioides colonized leaves and accumulated FB1. Thus, in plant-fungal interactions with the susceptible cultivar, a mechanism for FB1 accumulation exists apart from fungal colonization of leaf. Insensitive inbreds, B73 and W23, accumulate very little FB1 in the leaves when inoculated with wild type, suggesting these maize genotypes are more insensitive, in part, due to less accumulation of FB1. They may suppress FB1 production by the fungus. Further study comparing maize genotypes will identify mechanistic differences. Objective 5: Studies to optimize the nixtamalization process, that will determine the minimum processing procedures (i.e., number and volume of rinses) needed to achieve a significant protective effect and define fumonisin concentrations or other factors limiting reductions, are pending the identification of a suitable source of corn. Accomplishments 01 Survey of Guatemalan maize reveals high levels of aflatoxins and fumonisins in some departamentos (equivalent to counties in the U.S.A.). A total of 640 corn samples from all 22 departamentos of Guatemala were analyzed for both fumonisins and aflatoxins. Very high levels of aflatoxins and fumonisins were detected in corn from the Departamento of Pet�n. High levels of fumonisins, but not aflatoxins, were also detected in the Departamentos of Chiquimula and Santa Rosa and very low levels of fumonisins and aflatoxins were detected in the highland Departamento of Sacatep�quez. Human urine (n=390), as well as corn (n=30) for human consumption, were collected and analyzed from Sacatep�quez (low fumonisin exposure), Chiquimula (high fumonisin exposure), and Santa Rosa (high fumonisin exposure). Analysis of the urinary fumonisin exposure biomarker confirmed low exposure in Sacatep�quez and high exposure in Chiquimula and Santa Rosa. The results of this study will allow us to validate the usefulness of mechanism-based biomarkers. This is important because the ability to predict the level of fumonisin intake that disrupts sphingolipid metabolism in humans is a necessary first step towards identifying any role for fumonisin exposure in human disease. This study was conducted in collaboration with the Centro de Investigaciones en Nutrici�n y Salud in Guatemala (CIENSA), Creighton University, and Duke University. 02 Dietary folate modulates neural tube defect induction in LM/Bc mouse model. Dietary folate modulates the induction of neural tube defects by fumonisin B1 in the sensitive LM/Bc mouse model. Consumption of folate deficient diet, beginning five weeks before mating, reduced maternal red blood cell folate concentrations by about 80 percent, compared to mice consuming folate replete diet, and did not significantly reduce the number of phenotypically normal fetuses in each litter. It also protected against neural tube defect induction by fumonisin B1, as fewer litters of folate deficient females had neural tube defects and, within these litters, fewer fetuses had neural tube defects. Modulation of neural tube defect induction by fumonisin B1 likely involves interactions between sphingolipid and folate metabolic pathways. 03 Spores are necessary for systemic colonization of corn, yet fumonisins can accumulate independently of the fungus. The mycotoxigenic fungus Fusarium verticillioides produces fumonisins that are accumulated in the vegetative tissues of the corn plant, as well as in the developing kernels. To demonstrate systemic movement of the fumonisins in seedlings, we showed that infection by the fungus is necessary for accumulation of the fumonisins in the leaves. Interestingly, fumonisin B1 is preferentially accumulated compared to fumonisin B2 or B3. Furthermore, exposing seedling roots to fumonisin B1 alone does not result in movement of the toxin to the leaves since infection is required. Yet, the fungus does not need to be locally present in order for fumonisin to accumulate. By utilizing mutants incapable of producing spores, we showed that spores are necessary for systemic colonization, since mutants inoculated on seed were not able to colonize the stem or leaves of the corn plant, but the non-infected leaves still accumulated fumonisins. These data will allow us to better understand the dynamics of mycotoxin movement and accumulation during fungal infection of the corn plant.
Impacts
(N/A)
Publications
- Gelineau-Van Waes, J., Rainey, M.A., Maddox, J.R., Voss, K.A., Sachs, A.J., Gardner, N.M., Wilberding, J.D., Riley, R.T. 2012. Increased sphingoid base-1-phosphates and failure of neural tube closure after exposure to fumonisin or FTY720. Birth Defects Research Part A: Clinical and Molecular Teratology. 94(10):790-803.
- Riley, R.T., Voss, K.A., Showker, A.J., Torres, O., Matute, J., Maddox, J. R., Rainey, M., Gardner, N.M., Sachs, A., Gregory, S.G., Ashley-Koch, A.E., Krupp, D., Gelineau-Van Waes, J. 2012. Development of biomarkers to assess fumonisin exposure and birth defects. In: Binder, E.M., editor. Proceedings of the World Nutrition Forum, October 10-13, 2012, Marina Bay, Singapore. p. 249-256.
- Pitt, J.I., Wild, C.P., Gelderblom, W., Miller, J., Riley, R.T., Wu, F., Bann, R.A. 2012. Improving public health through mycotoxin control. Lyon, France: International Agency for Research on Cancer. Publication No. 158. 162 p.
- Bondy, G.S., Mehta, R., Caldwell, D., Coady, L., Armstrong, C., Savard, M., Miller, J., Chomyshyn, E., Bronson, R., Zitomer, N.C., Riley, R.T. 2012. Effects of long term exposure to the mycotoxin fumonisin B1 in p53 heterozygous and p53 homozygous transgenic mice. Food and Chemical Toxicology. 50(10):3604-3613. DOI: 10.1016/j.fct.2012.07.024.
- Voss, K.A., Riley, R.T., Moore, N.D., Burns, T.D. 2013. Alkaline cooking (nixtamalisation) and the reduction in the in vivo toxicity of fumonisin- contaminated corn in a rat feeding Bioassay. Food Additives & Contaminants: Part A. 30(8):1415-1421. DOI: 10.1080/19440049.2012.712064.
- van der Westhuizen, L., Shephard, G.S., Gelderblom,, W.A., Torres, O., Riley, R.T. 2013. Fumonisin biomarkers in maize eaters and implications for human disease. World Mycotoxin Journal. DOI: 10.3920/WMJ2013.1589.
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Progress 10/01/11 to 09/30/12
Outputs
Progress Report Objectives (from AD-416): 1. Determine the biochemical and molecular basis for the species specificity of fumonisins using animal models. 2. Determine the dietary �no observed effect� and �lowest observed effect levels� for neural tube defect induction and determine the dose- response thresholds for elevation in sphingolipid biomarkers in blood spots and fumonisins in urine using animal models. 3. Determine the relationship between fumonisin consumption, urinary fumonisin (exposure biomarker) and changes in sphingolipids in blood spots (effect biomarker) in human populations consuming corn. 4. Determine the specific mechanism(s) by which fumonisins are readily taken up by corn plant roots and yet have limited translocation into above ground vegetative tissues. 5. Determine the effectiveness of alkaline cooking for reducing the toxic potential of fumonisin-contaminated whole kernel corn. Approach (from AD-416): 1. Conduct dose-response studies to determine the minimum oral dose of FB1 that disrupts sphingolipid metabolism and induces toxicity (increased apoptosis) in rat kidney and mouse liver. 2. Conduct dose-response studies in susceptible mouse strains to determine the thresholds for changes in biomarkers of exposure and effect and induction of neural tube defects. 3. Conduct epidemiological studies to identify humans consuming large amounts of corn-based foods in communities where FB is infrequently detected and frequently detected and sample and analyze urine (FBs) and blood spots (sphingolipids). 4. Conduct dose response studies to determine FB1 affects on plant transpiration and levels of sphingoid bases and their 1-phosphates in roots and aerial tissues in FB1-sensitive and -insensitive genotypes of corn. 5. Utilize FB-contaminated whole kernel corn to determine the processing conditions that maximize FB1 reduction using chemical analysis and in vivo animal bioassays. Objective 1: Rat liver and kidney were analyzed and confirmed that deoxysphinganine (DSa) is not detected in rat tissue. Analysis of mouse liver and kidney confirmed that DSa is produced in large amounts in animals treated with fumonisin B1 (FB1). These results provide evidence for the species and target organ specific responses in rats and mice with regards to the consequences of ceramide synthase inhibition. Objective 2: A study was conducted in collaboration with Creighton University to determine the oral dose of FB1 for induction of maternal toxicity, elevation in urinary FB1, and elevated sphingoid bases and sphingoid base 1-phosphates in maternal kidney, liver, and blood. This study showed that elevation in sphingoid base 1-phosphates in blood spots was correlated with subtle evidence of liver toxicity. Doses of FB1 of less than 10 mg/kg body weight per day for 4 days, induced little or no evidence suggestive of disrupted sphingolipid metabolism or liver toxicity. Follow-up studies were initiated to confirm or not results showing that neural tube defect induction by FB1 was significantly reduced in mice fed folate deficient diets. Follow-up confirmation is needed due to the unexpected and, based on earlier understandings of interactions between folate and fumonisins, counterintuitive findings of an earlier study. Objective 3: Biomarkers for FB exposure are being used in Institutional Review Board (IRB) approved studies in humans in collaboration with Guatemalan scientists. Approximately 1,200 urine and blood spot samples and 90 maize samples have been collected and analyzed from three locations in rural Guatemala. The results show that FB1 in urine is closely correlated with the level of FB in the maize collected from each locality and the urinary FB1 is significantly correlated with evidence indicating elevated levels of sphingoid base 1-phosphates in blood spots. At the request of the Guatemalan Ministry of Health (MOH) a modified human subjects' protocol was submitted and approved. A request was made to the NIH National Institute of Child Health & Human Development to modify the study design so as to identify two new sampling locations to be used to validate the findings thus far. This request was approved. Objective 4: Studies were conducted to determine if water uptake and transpiration in corn plants are modulated during the plant-Fusarium interaction. Transpiration may be negatively impacted by accumulation of sphingoid base 1-phosphates. We developed a growth chamber assay to address transpiration responses in plants treated with either FB alone or with F. verticillioides. Treatment with abscisic acid (ABA) plus FB1 resulted in reduced accumulation of FB1 in seedling roots compared to seedlings treated only with FB1. FB1 alone and infection with F. verticillioides both had a moderate effect on transpiration. Objective 5: An in vivo bioassay was conducted and showed that nixtamalization (alkaline cooking followed by three fresh water rinses) of whole kernel corn, as practiced in households and industry, significantly reduces the amount of measurable FB1 and, consequently, the toxicity of FB in the corn. Accomplishments 01 Evidence for fumonisin-induced disruption of sphingolipid metabolism. Studies conducted in Guatemala, in collaboration with the Centro de Investigaciones en Nutricion y Salud in Guatemala (CIENSA), Creighton University, and Duke University show that fumonisin exposure, based on t levels of urinary fumonisin B1, is significantly correlated with the lev of sphingoid base 1-phosphates in blood spots and the increase in the sphinganine 1-phosphate to sphingosine 1-phosphate ratio. This finding consistent with the hypothesis that high levels of fumonisin exposure in humans can lead to disruption of sphingolipid metabolism through inhibition of ceramide synthase. This is significant because every anim disease known to be caused by fumonisin has been shown to be closely correlated with, and preceded by, evidence of disruption of sphingolipid metabolism. The findings also provide a research tool for assessing the threshold for disruption of sphingolipid metabolism in humans and for designing epidemiological studies to evaluate the potential of fumonisin exposure as a contributing factor to human disease. 02 Alkaline processing of maize unequivocally reduces fumonisin toxicity in maize-based foods. Detoxification of fumonisin-contaminated, whole kern corn by nixtamalization was for the first time demonstrated using a well characterized rat feeding bioassay. The study combined cooking and rinsing (three times) under conditions that are relevant to households a industry. Unlike earlier in vitro experiments, the in vivo approach unequivocally demonstrated the absence of any significant toxicity that could be attributed to unknown fumonisin by-products remaining in the cooked corn.
Impacts
(N/A)
Publications
- Voss, K.A., Riley, R.T., Jackson, L.S., Jabloski, J.E., Bianchini, A., Bullerman, L.B., Hanna, M.A., Ryu, D. 2011. Extrusion cooking with glucose supplementation of fumonsin-contaminated corn grits protects against nephrotoxicity and disrupted sphingolipid metabolism in rats. Molecular Nutrition and Food Research. 55:S312-S320. DOI: 10.1002/mnfr.201100067.
- Callihan, P., Zitomer, N., Stoeling, M., Kennedy, P., Lynch, K.R., Riley, R.T., Hooks, S.B. 2012. Distinct generation, pharmacology, and distribution of sphingosine 1-phosphate and dihydro-sphingosine 1- phosphate in human neural progenitor cells. Neuropharmacology. 62:988-996.
- Jackson, L.W., Jablonski, J.E., Bullerman, L.B., Bianchini, A., Hanna, M.A. , Voss, K.A., Hollub, A.D., Ryu, D. 2011. Reduction of fumonisin B1 in corn grits by twin-screw extrusion. Journal of Food Science. 76(6):150-155.
- Riley, R.T., Torres, O., Showker, A.J., Zitomer, N.C., Matute, J., Voss, K. A., Gelineau-van Waes, J., Maddox, J.R., Gregory, S.G., Ashley-Koch, A.E. 2012. The kinetics of urinary fumonisin B1 excretion in humans consuming maize-based diets. Molecular Nutrition and Food Research. 56:1445-1455.
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Progress 10/01/10 to 09/30/11
Outputs
Progress Report Objectives (from AD-416) 1. Determine the biochemical and molecular basis for the species specificity of fumonisins using animal models. 2. Determine the dietary �no observed effect� and �lowest observed effect levels� for neural tube defect induction and determine the dose- response thresholds for elevation in sphingolipid biomarkers in blood spots and fumonisins in urine using animal models. 3. Determine the relationship between fumonisin consumption, urinary fumonisin (exposure biomarker) and changes in sphingolipids in blood spots (effect biomarker) in human populations consuming corn. 4. Determine the specific mechanism(s) by which fumonisins are readily taken up by corn plant roots and yet have limited translocation into above ground vegetative tissues. 5. Determine the effectiveness of alkaline cooking for reducing the toxic potential of fumonisin-contaminated whole kernel corn. Approach (from AD-416) 1. Conduct dose-response studies to determine the minimum oral dose of FB1 that disrupts sphingolipid metabolism and induces toxicity (increased apoptosis) in rat kidney and mouse liver. 2. Conduct dose-response studies in susceptible mouse strains to determine the thresholds for changes in biomarkers of exposure and effect and induction of neural tube defects. 3. Conduct epidemiological studies to identify humans consuming large amounts of corn-based foods in communities where FB is infrequently detected and frequently detected and sample and analyze urine (FBs) and blood spots (sphingolipids). 4. Conduct dose response studies to determine FB1 affects on plant transpiration and levels of sphingoid bases and their 1-phosphates in roots and aerial tissues in FB1-sensitive and -insensitive genotypes of corn. 5. Utilize FB-contaminated whole kernel corn to determine the processing conditions that maximize FB1 reduction using chemical analysis and in vivo animal bioassays. This report is the first for the project which replaces 6612-42000-038- 00D; terminated 02/07/2011. Objectives 1 and 2: Study was conducted in collaboration with Creighton University in female mice to determine the oral doses for a larger study to determine the threshold for fumonisin B1 (FB1)-induction of neural tube defects (NTD), maternal toxicity, urinary FB1 and sphingoid bases and sphingoid base 1-phosphates in maternal kidney, liver, blood and in the embryos. We showed that elevation in urinary FB1 and elevated sphingoid base 1-phosphates in red blood cells (blood spots) was detected at doses that did not induce NTDs in mice. NTDs were-induced at all doses > 5 mg/kg body weight per day. The elevation in FB1 in urine (exposure biomarker) and sphinganine 1-phosphate in blood spots (mechanism biomarker) was dose-dependent. Elevation in 1-deoxysphingoid bases was easily detected in mouse liver but was not detected in the liver or kidney of male rats. Objective 2: We showed that NTD induction by intraperitoneal injection of FB1 was significantly reduced in mice fed folate deficient diets beginning five weeks prior to pregnancy. In groups fed folate sufficient diets, fifteen and 90 percent of litters from mice given the low and high doses of FB1 had one or more NTD-affected fetuses. Corresponding values in the groups fed the folate deficient diet were zero and 36 percent. Objective 3: Biomarkers for FB exposure (urinary FB1) and effects (changes in sphingoid base 1-phosphates in blood spots) are being used in Independent Review Board approved studies in humans in collaboration with Guatemalan scientists through the Centro de Investigaciones en Nutricion y Salud in Guatemala (CIENSA). In the human studies approximately 450 urine and blood spot samples have been collected and analyzed from three locations in rural Guatemala. Maize samples (n=27) from the same locations have been collected and analyzed. The results show that FB1 in urine is correlated with the level of FB in the maize collected from each locality and the urinary FB1 is significantly correlated with evidence indicating elevated levels of sphingoid base 1-phosphates in blood spots. Objective 4: Studies are in progress to address our hypothesis that water uptake and transpiration processes in corn plants are modulated during the plant-Fusarium interaction. Plant transpiration may be negatively impacted by increased concentrations of sphingoid base 1- phosphates, which accumulate as a result of fumonisin inhibition of the corn plant�s ceramide synthase. Since such inhibition of ceramide synthase is dependent upon the concentration of FB that accumulates in the seedlings, we have developed growth chamber assays to address transpiration responses when the plant is treated with either FB alone or with F. verticillioides. These studies will address the potential negative physiological effects of FBs on corn growth and development. Objective 5: Institutional Animal Care and Use Committee approval was obtained, corn for use in experiment identified, and the protocol for cooking and bioassay was developed. Feeding trial is anticipated to begin in September. Accomplishments 01 Evidence for fumonisin-induced disruption of sphingolipid metabolism. Th studies conducted in Guatemala in collaboration with the Centro de Investigaciones en Nutricion y Salud in Guatemala (CIENSA), Creighton University and Duke University show for the first time that fumonisin exposure, based on the levels of urinary fumonisin B1, is significantly correlated with the level of sphingoid base 1-phosphates in blood spots and the increase in the sphinganine 1-phosphate to sphingosine 1-phospha ratio. This finding is consistent with the hypothesis that high levels o fumonisin exposure in humans can lead to disruption of sphingolipid metabolism through inhibition of ceramide synthase. This is a significan finding because every animal disease known to be caused by fumonisin has been shown to be closely correlated with and preceded by evidence of disruption of sphingolipid metabolism. The impact of this finding is tha it provides a research tool for assessing the threshold for disruption o sphingolipid metabolism in humans and for designing epidemiological studies to evaluate the potential of fumonisin exposure as a contributin factor to human disease.
Impacts
(N/A)
Publications
- Myung, K., Zitomer, N.C., Duvall, M., Glenn, A.E., Riley, R.T., Calvo, A.M. 2011. The conserved global regulator veA is necessary for symptom production and mycotoxin synthesis in maize seedlings by Fusarium verticillioides. Plant Pathology. (2012) 61:152-160. DOI: 10.1111/j.1365- 3059.2011.02504.x.
- Zitomer, N.C., Riley, R.T. 2011. Extraction and analyses of fumonisins and compounds indicative of fumonisin exposure in plant and mammalian tissues and cultured cells. In: Holst, O., editor. Microbial Toxins: Methods and Protocols. New York, NY: Humana Press. 739:171-185.
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