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Extramural Papers of the Month

By Jerry Phelps
August 2009

HLA-DR4 - Possible Risk Gene for Autism

NIEHS-sponsored scientists report the discovery of a gene that may be involved in autism. The gene, known as HLA-DR4, is unique in that it acts in the mothers of children with autism disorder instead of acting in the children themselves. There are reports of about 30 such maternally acting or teratogenic genes.

The team genotyped members of 31 families for HLA-DR4. Children with autism were tested using a standard diagnostic psychological exam to confirm their condition. The results of the study led to the conclusion that HLA-DR4 is indeed a teratogenic gene and support the possibility of an immune component in the pathogenesis of autism.

The authors concluded that the gene could contribute to a subset of autism cases by interacting with other risk alleles or environmental factors to perturb pathways affecting brain development. They called for additional studies to address the causes of the development of autism that could lead to new interventions to prevent and treat the disorder.

Citation: Johnson WG, Buyske S, Mars AE, Sreenath M, Stenroos ES, Williams TA, Stein R, Lambert GH ( Exit NIEHS. 2009. HLA-DR4 as a risk allele for autism acting in mothers of probands possibly during pregnancy. Arch Pediatr Adolesc Med 163(6):542-546.

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Endocrine Society Position Statement on Endocrine Disruptors

In its first ever position statement, the Endocrine Society released a report outlining the public health concerns about exposure to endocrine disrupting chemicals and proposed a series of recommendations for revising current and generating new public-health related policies. The report states that the Society is concerned that the public may be at risk for exposure to endocrine disruptors because potential health effects are being overlooked in developing guidelines and regulations.

Endocrine disruptors are man-made compounds and substances in the environment that interfere with hormone production and action and metabolism, resulting in adverse health effects in a host of biological processes and systems in humans and wildlife. While stressing that it does not support alarmist action, the Society does support information dissemination on sources of exposure, potential health effects and preventive actions that can be taken to protect the American public from potential harm.

Recommendations in the report include centralized regulatory oversight of endocrine disrupting chemicals, policy development and research recommendations by a collaborative group of endocrinologists, toxicologists, epidemiologists and policy makers. The report also recommends the application of the precautionary principle to endocrine disrupting chemicals and the application of high-throughput research to test and identify many chemicals for endocrine disrupting activity.

Citation: Diamanti-Kandarakis E, Bourguignon JP, Giudice LC, Hauser R, Prins GS, Soto AM, Zoeller RT, Gore AC ( Exit NIEHS. 2009. Endocrine-disrupting chemicals: An Endocrine Society scientific statement. Endocr Rev 30(4):293-342.

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Bisphenol A Study Shows Reproductive Health Effects

New research results suggest that bisphenol A (BPA) significantly affects reproductive health at levels that are the same or lower than those currently considered to be too low to produce adverse effects. The research was conducted by Heather B. Patisaul, Ph.D., an NIEHS Outstanding New Environmental Scientist grantee.

BPA is a chemical used to harden many plastics in everyday food and beverage containers such as baby bottles, food can liners, water bottles and many other products. It is widely suspected of being an endocrine disrupting chemical.

The research team exposed female laboratory rats to 50 micrograms per kilogram of body weight in their first four days of life. The rats developed puberty earlier than their unexposed litter mates, significant ovarian malformations and premature loss of estrus. The dose is significant on a policy level because the EPA considers 50 micrograms per kilogram to be the human no-effect level.

Many states and municipalities have banned BPA totally or in products designated for children. Canada has announced plans to completely ban the chemical and has labeled it a toxin. Currently, there are bills in the U.S. House of Representatives and the Senate to ban the chemical in all food and beverage containers. This research may add evidence to support banning the chemical or restricting its use.

Citation: Patisaul HB, Adewale HB ( Exit NIEHS. 2009. Long-term effects of environmental endocrine disruptors on reproductive physiology and behavior. Front Behav Neurosci 3:10. [Epub ahead of print.] doi:10.3389/neuro.08.010.2009.

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New Method May Accelerate Drug Discovery for Parkinson's

A multi-center collaborative research effort partially funded by NIEHS has developed a rapid, inexpensive drug-screening method that could be used by drug developers to target Parkinson's as well as other debilitating diseases. The technique uses yeast to screen potential compounds, cutting the testing time to a few weeks.

Drug discovery is a long, difficult process requiring identification and synthesis of potential compounds, screening of compounds with expensive assays and definition of the structure of the compounds. Typically at the end of this months-long process, less than one per cent of the original compounds are deemed worthy of further testing in living cells.

The new method takes advantage of cyclic peptides that are capable of targeting the protein-protein interactions found in almost all cellular processes. Cyclic peptides are able to bind to proteins in smaller spaces where traditional drugs cannot. Using a yeast model of Parkinson's, the research team identified two cyclic peptides that were able to prevent dopaminergic neuron loss in the model. Once these peptides were sequenced, the team found that only the first four amino acids were necessary for the peptide to work. This four amino acid motif is similar to some important biochemical structures including molecules with oxidation or reduction properties and molecules that bind to metals.

Citation: Kritzer JA, Hamamichi S, McCaffery JM, Santagata S, Naumann TA, Caldwell KA, Caldwell GA, Lindquist S ( Exit NIEHS. 2009. Rapid selection of cyclic peptides that reduce α-synuclein toxicity in yeast and animal models. Nat Chem Biol, doi:10.1038/nchembio.193.

(Jerry Phelps is a program analyst in the NIEHS Division of Extramural Research and Training. Each month, he contributes summaries of extramural papers to the Environmental Factor.)

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