In this proposal we will examine how diethanolamine (DEA) effects the development of the hippocampus in the fetal mouse, and thereby could alter the onset of diminished memory function (senile dementia) in later adult life. DEA is used in the synthesis of fatty acid condensates that are present in many consumer products, including shampoos and cosmetics. DEA is structurally similar to choline, a methyl donor and an important endogenous precursor in the synthesis of phospholipids and acetylcholine. DEA competes with choline for tissue uptake and incorporation into phospholipids and mice treated with DEA become choline deficient. Maternal dietary choline intake during late pregnancy modulates mitosis and apoptosis in progenitor cells of the fetal hippocampus and septum and alters the differentiation of neurons in fetal hippocampus and causes significant and irreversible changes in hippocampal function in the adult animal, including altered long term potentiation and altered memory. We propose to test the hypotheses that exposure to DEA during pregnancy diminishes progenitor cell proliferation and increases apoptosis in the fetal hippocampus in a manner similar to that which we previously described in choline deficiency. If the hypothesis is confirmed, it would be possible to propose extensive studies on the structural, biochemical and functional effects of DEA on brain development and its effects on memory.
The specific aims of the proposal are 1) Determine whether DEA applied dermally to the pregnant mouse dam alters progenitor cell proliferation and apoptosis in the embryonic mouse hippocampus; 2) Determine whether DEA induced changes noted in Aim 1 can be prevented by choline supplementation and 3) Determine whether DEA induces changes in brain regions other than the hippocampus. Our proposal meets all required elements of PAR-03-121 including: sound mechanistic foundation for fetal programming of adult memory function; study of an environmental agent DEA to which there is known significant human exposure; use of gene expression profiling in fetus and adult; specific adult onset disease (senile dementia); and a focus on a required emphasis area (brain/nervous system); demonstrated expertise in developmental biology/toxicology and disease pathophysiology and gene expression profiling.
|Craciunescu, Corneliu N; Niculescu, Mihai D; Guo, Zhong et al. (2009) Dose response effects of dermally applied diethanolamine on neurogenesis in fetal mouse hippocampus and potential exposure of humans. Toxicol Sci 107:220-6|
|Niculescu, Mihai D; Wu, Renan; Guo, Zhong et al. (2007) Diethanolamine alters proliferation and choline metabolism in mouse neural precursor cells. Toxicol Sci 96:321-6|
|Sanders, Lisa M; Zeisel, Steven H (2007) Choline: Dietary Requirements and Role in Brain Development. Nutr Today 42:181-186|
|Zeisel, Steven H (2007) Nutrigenomics and metabolomics will change clinical nutrition and public health practice: insights from studies on dietary requirements for choline. Am J Clin Nutr 86:542-8|
|Zeisel, Steven H; Niculescu, Mihai D (2006) Perinatal choline influences brain structure and function. Nutr Rev 64:197-203|
|Niculescu, Mihai D; Craciunescu, Corneliu N; Zeisel, Steven H (2006) Dietary choline deficiency alters global and gene-specific DNA methylation in the developing hippocampus of mouse fetal brains. FASEB J 20:43-9|
|da Costa, Kerry-Ann; Kozyreva, Olga G; Song, Jiannan et al. (2006) Common genetic polymorphisms affect the human requirement for the nutrient choline. FASEB J 20:1336-44|
|Zeisel, Steven H (2006) The fetal origins of memory: the role of dietary choline in optimal brain development. J Pediatr 149:S131-6|
|Craciunescu, Corneliu N; Wu, Renan; Zeisel, Steven H (2006) Diethanolamine alters neurogenesis and induces apoptosis in fetal mouse hippocampus. FASEB J 20:1635-40|
|Zeisel, Steven H (2006) Betaine supplementation and blood lipids: fact or artifact? Nutr Rev 64:77-9|
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