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Extramural Papers of the Month

By Jerry Phelps
October 2007

Supplementation Counteracts Bisphenol A-Induced Epigenetics Changes

Recent research by NIEHS grantee Randy Jirtle and his research team shows that epigenetic changes induced by bisphenol A lead to problems with fertility and breast and prostate cancer in rat pups whose mothers were fed the compound in their diets. In addition, the team found that maternal dietary supplementation with folic acid or genestein reversed the epigenetic effects in the offspring.

Bisphenol A is a compound found in many types of plastic products including water and soft drink bottles, the liners of metal food cans, dental sealants, adhesives and many other plastics that humans come in contact with. Over time, small amounts of the compound leach out of the containers and into the food or beverage. Previous research has established that bisphenol A causes epigenetic changes through hypomethylation.

The Jirtle lab showed that epigenetic patterning during early stem cell development is sensitive to bisphenol A exposure. The addition of either methyl donor, folic acid or genestein, stopped the hypomethylating effect of bisphenol A. The authors conclude that their study's results support the inclusion of epigenetic effects of chemicals into risk assessments. The study also supports further investigation into possible dietary supplements that might counteract the adverse effects of environmental agents on the epigenome.

Citation: Dolinoy DC, Huang D, Jirtle RL ( Exit NIEHS 2007. Maternal nutrient supplementation counteracts bisphenol A-induced DNA hypomethylation in early development. Proc Natl Acad Sci U S A. 2007 104(32):13056-61.

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Loss of Norepinephrine Causes Parkinson-Like Tremor in Mice

Parkinson's disease is a chronic neurodegenerative disease that is characterized by the loss of dopamine-producing neurons in the substantia nigra region of the brain. There is also a simultaneous loss of norepinephrine-producing neurons in a region called the locus coeruleus. Administration of methyl phenyl tetrahydropyridine (MPTP) to laboratory animals is a common model for Parkinson's disease; however, MPTP does not cause the motor deficits seen in humans with Parkinson's disease.

NIEHS-supported investigators tested mice to determine whether the loss of norepinephrine neurons was necessary for the motor deficits seen in Parkinson's disease. They used transgenic mice that totally lack norepinephrine altogether.

The researchers detected no motor deficits in control mice treated with MPTP - despite an 80 percent reduction in the number of dopamine-producing cells. On the other hand, the norepinephrine-lacking mice exhibited motor deficits in most tests, along with other movement disorders, despite having normal dopamine levels. The researchers were able to reverse the motor effects by supplementation with a norepinephrine precursor and determined that increased levels of norepinephrine protected dopamine-producing neurons from MPTP toxicity.

This study suggests that loss of locus coeruleus neurons contributes to the motor deficits seen in Parkinson's disease and implies that administration of norepinephrine-like drugs could have dual therapeutic effects.

Citation: Rommelfanger KS, Edwards GL, Freeman KG, Liles LC, Miller GW, Weinshenker D. ( Exit NIEHS 2007. Norepinephrine loss produces more profound motor deficits than MPTP treatment in mice. Proc Natl Acad Sci U S A. 104(34):13804-13809.

VEGF Polymorphisms Associated with Higher Mortality in ARDS

Endothelial cell injury is an important factor in predicting the outcome of patients with acute respiratory distress syndrome (ARDS), a lung injury characterized by damage to the alveoli and increased pulmonary vascular permeability. Vascular endothelial growth factor (VEGF) is known to play a critical role in endothelial cell death and angiogenesis.

David Christiani and colleagues at the Harvard School of Public Health investigated the impacts of polymorphisms in the VEGF gene on the clinical outcomes of ARDS. They found three variations of the gene in 1,253 intensive care patients with risk factors for ARDS; 394 of these patients later developed the syndrome. Two of the polymorphisms were associated with increased mortality from ARDS, with risk increased two to four fold. Plasma VEGF levels were significantly lower, by more than half, in patients with the two at-risk polymorphisms as compared to the other gene variation.

The research team pointed out that this is a small study, which needs to be replicated, along with studying other functional VEGF variations before any definitive conclusions can be made. However, they concluded that at least two VEGF polymorphisms are associated with increased mortality from ARDS and that their findings may lead to the discovery of new treatments for ARDS.

Citation: Zhai R, Gong MN, Zhou W, Thompson TB, Kraft P, Su L, Christiani DC. 2007 ( NIEHS. Genotypes and haplotypes of the VEGF gene are associated with higher mortality and lower VEGF plasma levels in patients with ARDS. Thorax 62(8):718-722.

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Chromatin Remodeling Complex and DNA Damage Checkpoint Responses

NIEHS-supported scientists at the University of Texas M. D. Anderson Cancer Center have found that a signaling pathway and a chromatin remodeling pathway interact in response to DNA damage. The team suggests that this finding could open an entirely new category of targets for attacking cancer.

In response to DNA damage, checkpoint genes temporarily halt cellular division while DNA repair genes mobilize. The ATM/ATR kinases are known to regulate DNA repair and checkpoint pathways by phosphorylating other proteins involved in DNA damage control. The group found that one of these phosphorylated proteins is a subunit of the chromatin remodeling complex called INO80. Additional experiments showed that the activated protein regulates checkpoint pathways, but not DNA repair pathways.

Chromatin remodeling results in greater access to DNA so that repair machinery can attach and fix the damaged DNA strands. The team discovered that the les4 subunit of the INO80 remodeling complex is activated by the ATM/ATR kinases, a necessary step for certain cellular checkpoints to work properly. Mutation of les4 phosphorylation sites did not significantly affect DNA repair processes, but did influence DNA damage checkpoint responses. These findings establish the chromatin remodeling complex and a component in the DNA damage signaling pathway that controls checkpoint responses.

Citation: Morrison AJ, Kim JA, Person MD, Highland J, Xiao J, Wehr TS, Hensley S, Bao Y, Shen J, Collins SR, Weissman JS, Delrow J, Krogan NJ, Haber JE, Shen X. ( NIEHS 2007. Mec1/Tel1 phosphorylation of the INO80 chromatin remodeling complex influences DNA damage checkpoint responses. Cell 130(3):499-511.

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