Human exposure to mercury (Hg) compounds is a well recognized global problem. Organic Hg in fish and vaccines affects both developed and undeveloped countries, but inorganic Hg comes from distinct sources in undeveloped (artisanal gold mining, electronics recycling) and developed (dental restorations) countries.
Commonly overlooked is the fact that organic and inorganic forms of Hg differ in their toxicity. Inorganic mercury (ionic Hg2+) is neurotoxic (brain, nerves), nephrotoxic (kidney), hepatotoxic (liver), cardiotoxic (heart) and immunotoxic (autoimmune disorders), but organic mercurials (methylmercury, ethylmercury) cause only neurotoxicity and reproductive toxicity. As with many environmental toxicants, signs and symptoms can be quite varied, presenting a real challenge to correct diagnosis. Consequently, society’s efforts to protect against Hg are usually paradoxical. Why are the 40 micrograms of methylmercury in a typical can of tuna considered safe to eat, although swallowing 40 micrograms of pure methylmercury (6X the adult safe dose) would cause serious neuro-degeneration? Why do utility companies spend billions per year to scrub traces of inorganic Hg from coal, while the FDA holds it is safe to have grams of Hg metal in dental fillings in our mouths for decades?
As basic researchers in cell biology, toxicology and metallobiology we know that Hg is toxic in all its forms and that genetics influences how its toxicity is manifest in any individual. Current remedies are not Hg-specific and interfere with beneficial metal metabolism. To treat Hg exposure effectively (while minimizing side effects) requires precise knowledge of the most susceptible molecular targets of Hg damage and of how our cells succeed or fail to reverse that damage. Identification of the molecular targets most vulnerable to organic or inorganic Hg will enable design of focused nutritional and/or pharmaceutical interventions that augment our body’s natural detoxification systems.
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Why This Project Matters
Discovering the direct effects of Hg on the chromosome as a basis for biomarkers and therapies
Chromosomal DNA has been known for over 60 years to be the master code of life. However, for almost half that time we’ve also known that from the time we are conceived natural biochemical processes continuously “annotate” our genes in response to our environment. These annotation processes sculpt one’s own unique “epigenome” by adding small chemical groups such as methyls to the DNA itself and to the proteins (called histones) that support and maintain the DNA in the structures we call chromosomes.
These natural chemical annotations alter the timing and the intensity at which the underlying DNA-encoded genes are expressed. Ideally, these ancient, highly conserved patterns of DNA and protein modification occur in an orderly way and are manifest in how our cells divide and assemble in embryogenesis, how we learn as children, mature as adults and decline in old age. Some environmental signals known to affect this annotation process include our early diet and how we are stimulated in infancy. However, since the Industrial Revolution, exposure to not-so-benign environmental signals such as toxic chemicals has become very prevalent. The science of “epigenetics” has just begun to consider how environmental pollution can disturb the normal patterns of these chromosomal annotations and what health outcomes result.
Our project goes to the heart of this issue by examining the effects on genome annotation of one of the most pervasive and disruptive environmental toxicants, the heavy metal mercury (Hg). Our three parallel questions are: (a) what molecular changes do inorganic and organic Hg make in histone methylation in the fungus Neurospora crassa, a well-established model system for epigenetics research; (b) what molecular changes do inorganic and organic Hg make in histone methylation in neuronal cell cultures and in genetically metal-sensitive mice; and (c) which histone modifying proteins are most vulnerable to binding Hg and could serve as biomarkers to diagnose Hg exposure. This work will illuminate the genetic basis of susceptibility to Hg toxicity, provide biomarkers to diagnose clinically relevant Hg molecular damage and inform the design of pharmaceutical and nutritional interventions to enhance and monitor recovery compatible with the body’s natural metal detoxification processes.
To accomplish this work we will need to measure the Hg content in many hundreds of experimental samples ranging from a few microliters of pure proteins to milligrams of fungal or neuronal cells to grams of mouse organs. Public and private fee-for-service laboratories charge $40-$75 per sample. However, in the last decade robust multiuser instruments have emerged for rapid, precise quantification of total Hg from many different specimen types. Their prices average ~ $36,000 with per-sample costs <$1. Since this is a new collaboration an expenditure of this scale is beyond our current resources. Through generous donations from a dental professional association (www.iaomt.org) and the Departments of Microbiology and of Environmental Health Sciences we have already raised $22,500 and hope to raise the remaining funds needed through this campaign.
Help us raise the remaining $13,500 to optimize diagnosis of and recovery from Hg exposure.
Meet The Researchers
Zachary Lewis (Microbiology): Zack’s group focuses on understanding chromatin-modifying enzymes and how they impact eukaryotic gene transcription and genome stability. He and his students study the control and function of two conserved histone methyltransferases, KMT1 and PRC2, using the classic bread mold model system, Neurospora crassa. These proteins are highly conserved in mammals where they are critical for multicellular development; their dysfunction is linked to cancer and to the developmental anomalies of Weaver syndrome. Although these and other chromatin-associated proteins have many potential Hg-binding sites, our work will be the first systematic epigenetic assessment of the effects of mercurials on their activity. Follow Zack on Twitter | firstname.lastname@example.org
Xiaozhong (John) Yu (Environmental Health Sciences): John’s group examines how specific environmental exposures affect human diseases at the macro (epidemiology) and micro (molecular) levels, with emphasis on discovering new molecular and biochemical markers of exposure, effect, and susceptibility. John and his students have applied this toxicogenomic approach to discover interactions of genetic and environmental factors and have identified common and unique signatures of metal-induced responses during neurogenesis in metal-sensitive and non-sensitive mice. His team developed a systems- based quantitative GO-Quant approach to efficiently examine dose- and time-response in a pathway-based manner. Learn more about the Yu Lab | email@example.com
Anne Summers (Microbiology): Anne’s group uses a bacterial model to understand the molecular biology of Hg toxicity and recovery from it. She and her students have employed genetic, biochemical and biophysical methods to uncover t h e structure and function of a dedicated set of genes conferring inorganic and organic Hg resistance in many bacteria. Recently Anne and her collaborators devised a novel mass spectrometry method to identify over 300 proteins that are damaged when growing bacterial cells are exposed to mercurials. They have also reported major differences in global gene expression between inorganic and organic Hg exposure. Learn more about Anne | firstname.lastname@example.org
All collaborators have received notable professional recognition as invited speakers and members of grant review panels and journal editorial boards as well as sustained public and private research support throughout their careers.
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Contact Johnie Tucker | email@example.com | 706.542.6007
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