Background: In animal models, variations in early maternal care are associated with differences in hypothalamic-pituitary-adrenal (HPA) stress response in the offspring, mediated via changes in the epigenetic regulation of glucocorticoid receptor (GR) gene (Nr3c1) expression. Objective: To study this in humans, relationships between prenatal exposure to maternal mood and the methylation status of a CpG-rich region in the promoter and exon 1F of the human GR gene (NR3C1) in newborns and HPA stress reactivity at age 3 months were examined. Methods: The methylation status of a CpG-rich region of the NR3C1 gene, including exon 1F, in genomic DNA from cord blood mononuclear cells was quantified by bisulfite pyrosequencing in infants of depressed mothers treated with a serotonin reuptake inhibitor antidepressant (SRI) (n=33), infants of depressed non treated mothers (n=13) and infants of non depressed/non treated mothers (n=36). To study the functional implications of the newborn methylation status of NR3C1 in ...

Prenatal exposure to maternal depression, neonatal methylation of human glucocorticoid receptor gene (NR3C1) and infant cortisol stress responses

Arsenic Exposure and Toxicology: A Historical Perspective

The increasing utilization of heavy metals in modern industries leads to an increase in the environmental burden. Nickel represents a good example of a metal whose use is widening in modern technologies. As the result of accelerated consumption of nickel-containing products nickel compounds are released to the environment at all stages of production and utilization. Their accumulation in the environment may represent a serious hazard to human health. Among the known health related effects of nickel are skin allergies, lung fibrosis, variable degrees of kidney and cardiovascular system poisoning and stimulation of neoplastic transformation. The mechanism of the latter effect is not known and is the subject of detailed investigation. This review provides an analysis of the current state in the field.

Nickel essentiality, toxicity, and carcinogenicity.

https://www.cell.com/cell/pdf/S0092-8674%2815%2900186-5.pdf

Promoting Health and Longevity through Diet: From Model Organisms to Humans

Tissue concentrations of both homocysteine (Hcy) and cysteine (Cys) are maintained at low levels by regulated production and efficient removal of these thiols. The regulation of the metabolism of methionine and Cys is discussed from the standpoint of maintaining low levels of Hcy and Cys while, at the same time, ensuring an adequate supply of these thiols for their essential functions. S-Adenosylmethionine coordinately regulates the flux through remethylation and transsulfuration, and glycine N-methyltransferase regulates flux through transmethylation and hence the S-adenosylmethionine/S-adenosylhomocysteine ratio. Cystathionine beta-synthase activity is also regulated in response to the redox environment, and transcription of the gene is hormonally regulated in response to fuel supply (insulin, glucagon, and glucocorticoids). The H2S-producing capacity of cystathionine gamma-lyase may be regulated in response to nitric oxide. Cys is substrate for a variety of anabolic and catabolic enzymes. Its concentration is regulated primarily by hepatic Cys dioxygenase; the level of Cys dioxygenase is upregulated in a Cys-responsive manner via a decrease in the rate of polyubiquitination and, hence, degradation by the 26S proteasome.

SULFUR AMINO ACID METABOLISM: Pathways for Production and Removal of Homocysteine and Cysteine

DNA methylation is an important epigenetic mechanism of transcriptional control. DNA methylation plays an essential role in maintaining cellular function, and changes in methylation patterns may contribute to the development of cancer. Aberrant methylation of DNA (global hypomethylation accompanied by region-specific hypermethylation) is frequently found in tumor cells. Global hypomethylation can result in chromosome instability, and hypermethylation has been associated with the inaction of tumor suppressor genes. Preclinical and clinical studies suggest that part of the cancer-protective effects associated with several bioactive food components may relate to DNA methylation patterns. Dietary factors that are involved in one-carbon metabolism provide the most compelling data for the interaction of nutrients and DNA methylation because they influence the supply of methyl groups, and therefore the biochemical pathways of methylation processes. These nutrients include folate, vitamin B(12), vitamin B(6), methionine, and choline. However, looking at individual nutrients may be too simplistic. Dietary methyl (folate, choline, and methionine) deficiency in combination causes decreased tissue S-adeno-sylmethionine, global DNA hypomethylation, hepatic steatosis, cirrhosis, and ultimately hepatic tumorigenesis in rodents in the absence of carcinogen treatment. Other dietary components such as vitamin B(12), alcohol, and selenium may modify the response to inadequate dietary folate.

DNA methylation, cancer susceptibility, and nutrient interactions.

Selenium is an essential trace element for human health, and it has received considerable attention for its possible role as an anticarcinogenic agent. The purpose of the present study was to determine whether changes in the amount and the chemical form of selenium would affect DNA methylation and whether this effect would be modified by arsenic. Caco-2 cells, a human colon cancer cell line, were exposed to 0, 1 or 2 micromol supplemental selenite/L and 0, 1 or 2 micromol supplemental arsenite/L for 7 d. DNA isolated from Caco-2 cells not treated with selenite was significantly (P: < 0. 0001) hypomethylated compared with that from cells treated with 1 or 2 micromol selenite/L. DNA isolated from Caco-2 cells not treated with arsenite was significantly (P: < 0.0001) hypomethylated compared with DNA isolated from cells treated with 1 or 2 micromol arsenite/L. In addition, methylation of the p53 promoter region of Caco-2 cells decreased when cells were cultured in the absence of selenite and in the absence of arsenite. Sixty weanling male Fischer 344 rats were fed a torula yeast-based diet supplemented with 0, 0.1 or 2 mg selenium/kg diet as either selenite or selenomethionine in the presence or absence of 5 mg arsenic/kg diet as arsenite for 6 wk. Similar to the results with Caco-2 cells, rats fed selenium-deficient diets had significantly (P: < 0.0001) hypomethylated liver and colon DNA compared with rats fed 0.1 or 2.0 microg selenium/g diets as either selenite or selenomethionine. Thus, alterations in DNA methylation may be a potential mechanism, whereby deficient dietary selenium increases liver and colon tumorigenesis.

/pdf/dietary-selenium-and-arsenic-affect-dna-methylation-in-vitro-g896thqdd5.pdf

Dietary Selenium and Arsenic Affect DNA Methylation In Vitro in Caco-2 Cells and In Vivo in Rat Liver and Colon

Early studies on nickel essentiality with rats and goats indicated that nickel deprivation impaired reproductive performance. Nickel also has been found to influence cyclic nucleotide gated channels (CNG); these types of channels are important in sperm physiology. Thus, two experiments were conducted to test the hypothesis that nickel deficiency affects sperm physiology in a manner consistent with nickel having an essential function related to CNG channel functions. The experiments were factorially arranged with four treatment groups of eight weanling rats in each. In experiment 1, the treatments were supplemental dietary nickel of 0 and 1 mg/kg and Nω-nitro-l-arginine methyl ester (l-NAME, a nitric oxide synthase inhibitor) added to the drinking water (50 mg/100 mL) the last 3 wk of an 8-wk experiment. In experment 2, the treatments were supplemental dietary nickel at 0 and 1 mg/kg and supplemental dietary sodium chloride (NaCl) at 0 and 80 g/kg. The NaCl and l-NAME variables were included to act as stressors affecting CNG channel activity. The basal diet contained per kilogram about 27 µg of nickel and 1 g of sodium. After 8 wk in experiment 1 and 16 wk in experiment 2, urine while fasting and testes and epididymis in both experiments, and seminal vesicles and prostates in experiment 2 were harvested for analysis. Nickel deprivation significantly decreased spermatozoa motility and density in the epididymides, epididymal transit time of spermatozoa, and testes sperm production rate. Nickel deficiency also significantly decreased the weights of the seminal vesicles and prostate glands. Excessive NaCl had no effect on sperm physiology; however, it decreased prostate gland weights. The findings support the hypothesis that nickel has an essential function that possibly could affect reproductive performance in higher animals, perhaps through affecting a CNG channel function.

Nickel deficiency diminishes sperm quantity and movement in rats.

Several observations suggest a role for DNA methylation in cancer pathogenesis. Although both selenium and folate deficiency have been shown to cause global DNA hypomethylation and increased cancer susceptibility, the nutrients have different effects on one-carbon metabolism. Thus, the purpose of this study was to investigate the interactive effects of dietary selenium and folate. Weanling, Fischer-344 rats (n = 23/diet) were fed diets containing 0 or 2.0 mg selenium (as selenite)/kg and 0 or 2.0 mg folate/kg in a 2 x 2 factorial design. After 3 and 4 wk of a 12-wk experiment, 19 rats/diet were injected intraperitoneally with dimethylhydrazine (DMH, 25 mg/kg) and 4 rats/diet were administered saline. Selenium deficiency decreased (P < 0.05) colonic DNA methylation and the activities of liver DNA methyltransferase and betaine homocysteine methyltransferase and increased plasma glutathione concentrations. Folate deficiency increased (P < 0.05) the number of aberrant crypts per aberrant crypt foci, the concentration of colonic S-adenosylhomocysteine and the activity of liver cystathionine synthase. Selenium and folate interacted (P < 0.0001) to influence one-carbon metabolism and cancer susceptibility such that the number of aberrant crypts and the concentrations of plasma homocysteine and liver S-adenosylhomocysteine were the highest and the concentrations of plasma folate and liver S-adenosylmethionine and the activity of liver methionine synthase were the lowest in rats fed folate-deficient diets and supplemental selenium. These results suggest that selenium deprivation ameliorates some of the effects of folate deficiency, probably by shunting the buildup of homocysteine (as a result of folate deficiency) to glutathione.

/pdf/dietary-folate-and-selenium-affect-dimethylhydrazine-induced-32xnrw456m.pdf

Eric O. Uthus

Papers

DNA methylation, cancer susceptibility, and nutrient interactions.

Dietary Selenium and Arsenic Affect DNA Methylation In Vitro in Caco-2 Cells and In Vivo in Rat Liver and Colon

Nickel deficiency diminishes sperm quantity and movement in rats.

Dietary Folate and Selenium Affect Dimethylhydrazine-Induced Aberrant Crypt Formation, Global DNA Methylation and One-Carbon Metabolism in Rats

Mechanistic aspects of the interaction between selenium and arsenic.