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DERT Papers of the Month

By Jerry Phelps
January 2007

Tissue-Specific Functions of the Mammalian Clock Protein BMAL1

NIEHS grantee Christopher Bradfield has shown that expression of a clock gene known as BMAL1 in specific tissues is necessary for proper physiological function. Using mutant mice, Bradfield and colleagues determined that circadian rhythm was normalized only when the protein was produced in the brain, but normal activity and body weight also required expression in muscle tissue. These findings are consistent with the tissue-specific variation in circadian gene expression and suggest that central circadian clock components act differently in a variety of tissues in mammals at the molecular, cellular and systems levels.

Research into dioxin toxicology and the Ah receptor-ARNT signal transduction pathway led to the discovery of the family of proteins that BMAL1 is a part of - the PAS proteins. They act as both sensors of environmental cues and transmitters of these signals to the nuclei of cells. The recent explosion in the number of known members of the PAS family led to the discovery of sensors that are involved in responses to low atmospheric oxygen, tissue hypoxia, exposure to polycyclic aromatic pollutants and body rhythms.

Bradfield has been instrumental in the discovery of PAS proteins and the Ah receptor signaling pathway. Through his high productivity and exceptional grant writing skills, the grant that supports this work was converted to a prestigious Method to Extend Research In Time (MERIT) award.

Citation: McDearmon EL, Patel KN, Ko CH, Walisser JA, Schook AC, Chong JL, Wilsbacher LD, Song EJ, Hong HK, Bradfield CA, Takahashi JS. 2006. Dissecting the functions of the mammalian clock protein BMAL1 by tissue-specific rescue in mice. Science. 2006 Nov 24;314(5803):1304-8.

Sea Urchin Genome Sequenced

An international team of 240 scientists from 11 countries has successfully sequenced the genome of the sea urchin, adding to the list of organisms whose complete genomes have been unraveled. The effort took two years and included researchers supported by NIEHS. The importance of the effort is demonstrated in the remarkable genetic connections between the spiny echinoderm and humans. The team predicts that the complete DNA sequence will contribute valuable insight into human development processes.

The complete sequence is 814 million DNA bases, which is roughly one-quarter the size of the human genome, although it contains roughly the same number of genes (greater than 23,000). More than seven thousand of the genes are shared with humans, making sea urchins closer genetically to humans than other widely studied organisms. Genetically, sea urchins have the most complex innate immune system of any animal studied to date. Surprisingly, they carry genes related to many human diseases such as muscular dystrophy and Huntington's disease as well as genes associated with taste, smell, hearing and balance. Another surprising finding is that the eyeless creatures actually have genes associated with vision that are expressed in tissues in their feet.

Citation: Sea Urchin Genome Sequencing Consortium. 2006. The genome of the sea urchin Strongylocentrotus purpuratus. Science 314(5801):941-952.

Caution Advised in Genetics Research on Smoking

In a commentary in JAMA, NIEHS-supported scientist Chris Carlsten, along with a colleague at the University of Washington, warns that genetic testing and subsequent risk identification might not be good public health practice regarding cigarette smoking.

Carlsten cites two approaches where genetic testing might improve rates of getting smokers to successfully kick their habits. Genetic testing could be used to warn individuals at higher risk of lung cancer and subsequently increase their motivation to stop smoking. Also, genetic testing might identify candidates for more intensive cessation programs based on increased cancer risk or conceivably help determine more effective cessation approaches, such as drug therapy based on the genotypes of individual smokers. However, Carlsten points out that data currently available on genotype and risk are not necessarily highly motivating in modifying behavior. The data suggest that knowledge of small increases in risk of disease is insufficient in motivating smokers to quit. In addition, there is little evidence that nicotine therapy tailored to individual genotypes is effective.

For these reasons, as well as to reduce the risks of bystanders from second hand smoke inhalation,

Carlsten recommends the more standard, societal approaches for getting smokers to quit, including smoking bans in public areas, high taxes on tobacco products and government-sponsored anti-smoking campaigns.

Citation: Carlsten C, Burke W. 2006. Potential for genetics to promote public health: genetics research on smoking suggests caution about expectations. JAMA 296(20):2480-2482.

Neurodevelopmental Effects of Prenatal Pesticide Exposure

Inner-city children in New York City exposed in utero to high levels of the pesticide Dursban (chlorpyrifos) experienced delays in mental and psychomotor development compared to children with low prenatal exposure, according to a study funded by NIEHS and conducted by the Columbia Center for Children's Environmental Health. Highly exposed children with chlorpyrifos levels >6.17 picograms/gram of plasma scored on average 6.5 points lower on the Bayley Psychomotor Development Index and 3.3 points lower on the Bayley Mental Development Index at 3 years of age than children with lower exposures. These two tests are widely used developmental indicators used to diagnose developmental delay in young children.

Additionally, children born to mothers who had been exposed to high levels of the pesticide were five times more likely to have psychomotor delays and nearly 2.5 times more likely to have delayed mental development. Dursban was also marketed under the trade name Lorsban. It is a widely used insecticide, although indoor uses of the pesticide were banned in 2000. The chemical is still approved for many agricultural applications. Products used indoors that contained the pesticide included pet tick collars, termite sprays, and roach and ant control systems.

Dursban is an organophosphate insecticide. It works by disrupting acetylcholinesterase, the enzyme responsible for the breakdown of the neurotransmitter acetylcholine - a reaction necessary to allow a cholinergic neuron to return to its resting state after activation.

Citation: Rauh VA, Garfinkel R, Perera FP, Andrews HF, Hoepner L, Barr DB, Whitehead R, Tang D, Whyatt RW. 2006. Impact of prenatal chlorpyrifos exposure on neurodevelopment in the first 3 years of life among inner-city children. Pediatrics 118(6):e1845-1859.



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