Response to: DEA in consumer products is safe [2]

We thank Dr. Bailey for providing the perspective of the Cosmetic, Toiletry, and Fragrance Association. In our paper we reported that the developing mouse hippocampus was sensitive to dermally administered diethanolamine (DEA) during pregnancy. We used 80 mg/kg/d DEA in these experiments, and we estimated that this exposure was approximately 10-fold higher than likely human exposure. The message of our paper was that, for the first time, DEA was observed to have effects on brain development, and until we know more about this effect it would be prudent for pregnant women to minimize their exposure. Dr. Bailey disputes this, arguing that human skin is less permeable, that the DEA now commonly used in cosmetics is conjugated to a fatty acid, and that humans are not very susceptible to choline deficiency

Diet-gene interactions underlie metabolic individuality and influence brain development: Implications for clinical practice derived from studies on choline metabolism

One of the underlying mechanisms for metabolic individuality is genetic variation. Single nucleotide polymorphisms (SNPs) in genes of metabolic pathways can create metabolic inefficiencies that alter the dietary requirement for, and responses to, nutrients. These SNPs can be detected using genetic profiling and the metabolic inefficiencies they cause can be detected using metabolomic profiling. Studies on the human dietary requirement for choline illustrate how useful these new approaches can be, as this requirement is influenced by SNPs in genes of choline and folate metabolism. In adults, these SNPs determine whether people develop fatty liver, liver damage and muscle damage when eating diets low in choline. Because choline is very important for fetal development, these SNPs may identify women who need to eat more choline during pregnancy. Some of the actions of choline are mediated by epigenetic mechanisms that permit 'retuning' of metabolic pathways during early life

People with fatty liver are more likely to have the PEMT rs7946 SNP, yet populations with the mutant allele do not have fatty liver [2]

We reported that individuals with nonalcoholic fatty liver were significantly more likely to have a single nucleotide polymorphism (SNP) in the gene encoding for phosphatidylethanolamine N-methyltransferase (PEMT). This SNP (rs7946, +5465 G → A) leads to a V175M substitution and is a loss of function mutation (1). Drs. Romeo, Cohen, and Hobbs conducted an interesting study further investigating our observation. They asked whether individuals with the mutant allele (A) were more likely to have fatty liver, and concluded that this is not the case

A grand challenge for nutrigenomics

The low hanging fruit in genetics research has mostly been harvested, and now the work of studying genes as part of systems biology is well underway. Metabolism and nutrition seem to be an ideal complex system in which to apply the knowledge and methods of genetics and genomics. Diet is perhaps the most important environmental factor we are exposed to. Nutritional factors are thought to be the cause of 30–60% of cancers (similar in magnitude to smoking; Doll, 1992), diabetes is a nutritional/metabolic disorder, we are all familiar with the cholesterol–cardiovascular disease relationship, and obesity is a pressing nutritional problem, with a majority of Americans overweight and expanding rapidly (Ogden et al., 2007). If genetic scientists are looking for a complex system to step up to and address, what better choice? Hence, the developing discipline of nutrigenomics

Choline phospholipids: Signal transduction and carcinogenesis

Phospholipids act as vital elements in transmembrane signaling. Agonist- induced hydrolysis of phosphatidylinositides has been established as a major mechanism for transmitting messages into the interior of cells via protein phosphorylation cascades, ultimately regulating gene transcription. There is a growing body of evidence that choline phospholipids (phosphatidylcholine, sphingomyelin, and their metabolites) also are important mediators and modulators of transmembrane signaling. These functions may explain how choline phospholipids influence normal physiological processes as well as a diverse group of pathological processes

1,2-sn-Diacylglycerol accumulates in choline-deficient liver. A possible mechanism of hepatic carcinogenesis via alteration in protein kinase C activity?

Choline deficiency is associated with triacylglycerol accumulation in the liver, and is the only nutritional state known to trigger hepatic cancer spontaneously. In two different experiments, rats were pair-fed for 6 weeks with control (0.2% choline), or choline-deficient (CD) (0.002% choline) diets. Hepatic choline and phosphocholine declined in CD animals to 54% and 16% of control levels, respectively. In control livers, 1,2-sn-diacylglycerol (1,2-sn-DAG) concentration was (in nmol/g wet wt) 144 (± 25; mean ± SE); while in CD livers it was 792 (± 140) in the first experiment. In the second experiment the values were 375 (± 26) and 1147 (± 74), respectively. 1,2-sn-DAG, a precursor of triacylglycerol, is an endogenous activator of protein kinase C (PKC). PKC is the presumed site of action of the tumor-promoting phorbol esters. We suggest that the 1,2-sn-DAG accumulating in CD liver could bind PKC, altering its activity, and thus contribute to the carcinogenic effect of CD diets

Deletion of one allele of Mthfd1 (methylenetetrahydrofolate dehydrogenase 1) impairs learning in mice

The MTHFD1 gene encodes for methylenetetrahydrofolate dehydrogenase 1, an enzyme that has an important role in folate-mediated one-carbon metabolism. In people, a single nucleotide polymorphism of this gene (1958G > A; rs2236225) is associated with increased risk for bipolar disorder and schizophrenia, neural tube and other birth defects. Mice homozygous for a loss of Mthfd1 via a gene-trap mutation are not viable, and heterozygotes, though they appear healthy, have metabolic imbalances in the folate- and choline-mediated 1-carbon metabolic pathways. In this study, we evaluated cognitive function in Mthfd1gt/+ male and female mice using a behavioral battery composed of eight different tests. We found that these mice display impaired cue-conditioned learning, while other behaviors remain intact

Dietary modulation of the epigenome

Epigenetics is the study of heritable mechanisms that can modify gene activity and phenotype without modifying the genetic code. The basis for the concept of epigenetics originated more than 2,000 yr ago as a theory to explain organismal development. However, the definition of epigenetics continues to evolve as we identify more of the components that make up the epigenome and dissect the complex manner by which they regulate and are regulated by cellular functions. A substantial and growing body of research shows that nutrition plays a significant role in regulating the epigenome. Here, we critically assess this diverse body of evidence elucidating the role of nutrition in modulating the epigenome and summarize the impact such changes have on molecular and physiological outcomes with regards to human health

Perspectives from the symposium: The Role of Nutrition in Infant and Toddler Brain and Behavioral Development

This symposium examined current trends in neuroscience and developmental psychology as they apply to assessing the effects of nutrients on brain and behavioral development of 0-6-year-olds. Although the spectrum of nutrients with brain effects has not changed much in the last 25 years, there has been an explosion in new knowledge about the genetics, structure and function of the brain. This has helped to link the brain mechanistic pathway by which these nutrients act with cognitive functions. A clear example of this is linking of brain structural changes due to hypoglycemia versus hyperglycemia with cognitive functions by using magnetic resonance imaging (MRI) to assess changes in brain-region volumes in combination with cognitive test of intelligence, memory and processing speed. Another example is the use of event-related potential (ERP) studies to show that infants of diabetic mothers have impairments in memory from birth through 8 months of age that are consistent with alterations in mechanistic pathways of memory observed in animal models of perinatal iron deficiency. However, gaps remain in the understanding of how nutrients and neurotrophic factors interact with each other in optimizing brain development and function

Trimethylamine N-Oxide, the Microbiome, and Heart and Kidney Disease

Trimethylamine N-oxide (TMAO) is a biologically active molecule and is a putative promoter of chronic diseases including atherosclerosis in humans. Host intestinal bacteria produce its precursor trimethylamine (TMA) from carnitine, choline, or choline-containing compounds. Most of the TMA produced is passively absorbed into portal circulation, and hepatic flavin-dependent monooxygenases (FMOs) efficiently oxidize TMA to TMAO. Both observational and experimental studies suggest a strong positive correlation between increased plasma TMAO concentrations and adverse cardiovascular events, such as myocardial infarction, stroke, and death. However, a clear mechanistic link between TMAO and such diseases is not yet validated. Therefore, it is debated whether increased TMAO concentrations are the cause or result of these diseases. Here, we have tried to review the current understanding of the properties and physiological functions of TMAO, its dietary sources, and its effects on human metabolism. Studies that describe the potential role of TMAO in the etiology of cardiovascular and other diseases are also discussed