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Environmental Factor

April 2011

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Extramural papers of the month

By Jerry Phelps
April 2011

SRP logo Research Brief

Resveratrol protects mother and fetus from immunotoxic effects of TCDD

A recent study by NIEHS grantees at the University of South Carolina School of Medicine found that administration of resveratrol protects the mother and developing fetus from the immunotoxic effects of dioxin. Resveratrol is a natural product found in grapes, red wine, nuts, berries, and other plants, and is also available as an over-the-counter supplement. It has anti-inflammatory properties and is touted as a natural treatment for autoimmune disorders.

Pregnant laboratory mice were injected once with 2,3,7,8- tetrachlorodibenzo-p-dioxin (TCDD) at 10 micrograms per kilogram body weight on gestation day 14. The pregnant mice also received resveratrol at 100 milligrams per kilogram body weight orally from gestation day 14 to 19.  The researchers observed that resveratrol protected the pregnant mice and their offspring from dioxin-induced thymic atrophy, apoptosis, and alterations in T-cell receptor expression. It also significantly reduced thymus expression of cytochrome P450-1A1. 

These findings demonstrate that, in laboratory animals, administration of resveratrol during pregnancy affords protection to the mother and the fetus from the toxicity induced by environmental pollutants that have their effects through activation of the aryl hydrocarbon receptor. Additional studies are needed before similar claims can be made for humans.

Citation: Singh NP, Singh US, Nagarkatti M, Nagarkatti PS.( Exit NIEHS 2011. Resveratrol (3,5,4'-trihydroxystilbene) protects pregnant mother and fetus from the immunotoxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin. Mol Nutr Food Res 55(2):209-219.

Human-induced pluripotent stem cells exhibit extensive epigenomic reprogramming

Reprogramming adult cells to regain their ability to differentiate into a variety of cells appears to leave indelible marks, report NIEHS-supported researchers. When the team scoured the epigenomes of induced pluripotent stem (iPS) cells, they found a consistent pattern of reprogramming errors. What's more, these incompletely reprogrammed hotspots were maintained when iPS cells were differentiated into a more specialized cell type, providing an iPS cell-specific signature, enabling the researchers to determine whether a cell was an iPS or an embryonic stem cell, simply by examining these hotspots. 

Reprogramming induces a complete reconfiguration of the DNA methylation pattern throughout the genome, returning it to an embryonic stem cell-like state. Overall, this process results in an iPS cell methylation pattern very similar to that of embryonic stem cells, but when the team looked further, they discovered significant differences. Their experiments revealed considerable variability between iPS cell lines, including a memory of their tissue of origin. Regardless of their individual history, iPS cells showed a common defect - hotspots near telomeres and centromeres that proved resistant to reprogramming.

These findings confirm that iPS cells, which by all appearances look and act like embryonic stem cells, differ in certain aspects from their embryonic cousins, emphasizing that further research will be necessary before they can be rightful substitutes for embryonic stem cells.

Citation: Lister R, Pelizzola M, Kida YS, Hawkins RD, Nery JR, Hon G, Antosiewicz-Bourget J, O'Malley R, Castanon R, Klugman S, Downes M, Yu R, Stewart R, Ren B, Thomson JA, Evans RM, Ecker JR.( Exit NIEHS 2011. Hotspots of aberrant epigenomic reprogramming in human induced pluripotent stem cells. Nature 471(7336):68-73.

Arsenic exposure may increase mortality from tuberculosis

According to scientists supported by NIEHS and the Superfund Research Program, increased mortality from pulmonary tuberculosis could be yet another serious outcome from exposure to arsenic in drinking water. These findings are from an ongoing study in Chile and, if confirmed in other arsenic-exposed populations, they will have important public health implications, since some of the largest arsenic-exposed populations are in developing countries with widespread tuberculosis.

Tuberculosis is a major public health problem worldwide, causing over 2 million deaths in the last year alone and 9 million new infections. Increased susceptibility to tuberculosis has been identified with a variety of other diseases and exposures. Likewise, arsenic in drinking water is a serious public health problem affecting many countries, with millions of people throughout the world exposed.

The findings constitute the first evidence relating arsenic exposure to tuberculosis. The researchers compared mortality rate ratios with time patterns of arsenic exposure, which increased abruptly in 1958 in a specific region in Chile and then started declining in 1971. Tuberculosis mortality rate ratios in men started increasing in 1968, 10 years after high arsenic exposure commenced. The peak male 5-year mortality rate ratio occurred during 1982-1986. The findings are biologically plausible in view of evidence that arsenic is an immunosuppressant and also a cause of chronic lung disease.

Citation: Smith AH, Marshall G, Yuan Y, Liaw J, Ferreccio C, Steinmaus C.( Exit NIEHS 2011. Evidence from Chile that arsenic in drinking water may increase mortality from pulmonary tuberculosis. Am J Epidemiol 173(4):414-420.

Tobacco smoke enhances the progression of diabetic nephropathy

Using a diabetic mouse model, researchers from the University of Alabama at Birmingham report that exposure to tobacco smoke worsens the progression of diabetic nephropathy, likely mediated by increased expression of profibrotic cytokines.

Diabetic nephropathy is the most common cause of end-stage renal disease in the U.S. It is characterized by proteinuria and irreversible changes, such as sclerosis, in the structure and function of the glomeruli, the filtering structures in the kidney. These changes effectively reduce the kidney's ability to filter waste and toxins from the blood by reducing the glomerular filtration surface. Cigarette smoking is now recognized as a risk factor in the progression of chronic kidney disease.

In the current study, the mice were exposed to tobacco smoke for eight weeks at roughly the same levels as those found in active smokers. Tobacco smoke exposure caused significant increases in mesangial expansion, accompanied by increases in expression of transforming growth factor beta and fibronectin, as compared to the control group mice that breathed regular air.

These studies demonstrate that smoking and exposure to environmental tobacco smoke may further the progression of diabetic nephropathy. The researchers conclude, based on this and previous research, that nicotine may be mediating these effects.

Citation: Obert DM, Hua P, Pilkerton ME, Feng W, Jaimes EA( Exit NIEHS. 2011. Environmental tobacco smoke furthers progression of diabetic nephropathy. Am J Med Sci 341(2):126-130.

(Jerry Phelps is a program analyst in the NIEHS Division of Extramural Research and Training.)

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