Jay Gandolfi

Continued funding for Liver/kidney on-a-chip for environmental toxicology studies

 

Investigators

Jay Gandolfi, Ph.D.
Research Professor
Center for Toxicology

Terrence Monks, Ph.D.
Head
Pharmacology and Toxicology

 

 

Jeong- Yeol Yoon, Ph.D.
Agric & Biosystems Engr-Res

 

Amount of funding received:

20,000

Description:

MMA(III), Gene Expression, and Cellular Transformation

Relevance to Swehsc : 

Arsenic is a ubiquitous toxicant to the Southwestern population due to exposure via drinking water, dust, and ingestion.  Arsenic is a known human carcinogen causing cancer at various sites and has a multitude of toxic effects.  The mechanism(s) of action for arsenic to cause its carcinogenic/toxic effect from exposure at environmentally relevant levels is unclear and is a major thrust of this RFG and the entire SWEHSC.  Establishing “safe” levels of exposure to arsenic is imperative to properly protect the susceptible Southwestern population.

Cluster of Efforts: 

Investigators: 

  • Bernard Futscher, PhD
  • A. Jay Gandolfi, PhD
  • Walter Klimecki, DVM, PhD
  • Catharine Smith, PhD
Milestones: 
  • We discovered that exposing human cells to levels of arsenic often found in real world situations, such as in drinking water from wells, produces new pathologic epigenetic landscapes that participate in the malignant transformation of human cells.  Specifically, we found that arsenical-mediated malignant transformation produces long range epigenetic changes in the cancer cell genome that disrupt normal structure and function, and more importantly that these epigenetic changes are common to multiple types of arsenical-induced cancers.  Importantly, this type of long range epigenetic damage that we saw arise in laboratory models of arsenic-induced malignant cancer are also an epigenetic hallmark also seen in “real world” cancers derived from cancer patients, including cancers of the bladder, prostate, lung , and breast.  Overall, these results indicate that arsenicals epigenetically target common regions of the genome across multiple cancer types.  Furthermore these results strongly implicate the destruction of the cell’s epigenetic landscape as a critical carcinogenic mechanism of action of environmental arsenicals. 
  • Disruption in energy metabolism was observed by measuring changes in carbohydrate metabolism in the BEAS-2B lung cell line.  This work helped establish a novel hypothesis that decreased levels of carbohydrate metabolites such as acetate and succinate will result in changes in carbohydrate-dependent changes in protein post-translational modification.  A pilot project has been initiated between Drs. Klimecki and Smith (RFG3) to investigate mitochrondrial protein acetylation in response to arsenic exposure.

UA Science Internship Pairs High School Students, Research Mentors

News Date: 
June 3, 2013 :00am

Each year many SWEHSC researchers host high school students in their laboratories. Facility managers assits them process their samples and understand their data. SWEHSC members teach them about toxicology and environmental health. The program was designed by the SWEHSC Outreach Core and is conducted in collaboration with the BIO5 Instutue. Read more about this year's program

Research

The SWEHSC plays an important role in stimulating collaborative interactions among researchers. This is evidenced by a significant number of new, funded research projects, as well as a notable number of planned initiatives involving collaborations. The SWEHSC promotes and enhances collaborative research within and between the members through Research Focus Groups.

The themes of the three Research Focus Groups are seen below.

Personal exposure measurement device development

Relevance to Swehsc : 

Studies in environmentally-exposed populations frequently suffer from poorly estimated individual exposures. Estimates such as average duration-weighted exposure levels are blunt instruments that obscure the sizeable fraction of individual exposures that deviate from the average.

Cluster of Efforts: 

Investigators/Funding: Tao (RFG1), Gandolfi (RFG1) ES010606

Milestones: 
  • This project aims to design and build a wearable personal monitoring device that updates exposure levels to a database via a Bluetooth connection to the user's cell phone.
  • Prototype built that reliably measures benzene levels and transmits them through Bluetooth connection.
  • Minimal interference from humidity and perfumes.
  • Dr. Tao has established collaborations with SWEHSC colleagues in the College of Public Health (Drs. Burgess and Beamer, RFG 2), resulting in a recently submitted collaborative grant to NIOSH to utilize this system to assess exposures to volatile pollutants for emergency workers. ES010606

 

Human Genetics of arsenic biotransformation

Relevance to Swehsc : 

Individual variation in the efficiency of metabolic arsenic methylation is one of the most consistently reported predictors of disease risk in arsenic-exposed human populations. Defining the genetic and environmental determinants of arsenic methylation efficiency should establish easily measured biomarkers of increased susceptibility in an exposed population.

        

Cluster of Efforts: 

Investigators/Funding: Klimecki (RFG1), Gandolfi (RFG1), Billheimer (IHSFC-Biostats) NIEHS/ES004940 (Superfund Component Project)

Milestones: 
  • This epidemiology project is studying about 800 arsenic-exposed subjects from our geographical region, residing in Northern Sonora, Mexico. Demographic and questionnaire data, urine (for arsenic metabolite determination) and buccal swabs (for genetic variant testing) are being collected.
  • A detailed characterization of chromosome 10 surrounding AS3MT,the key arsenic metabolic gene, revealed an extraordinarily large region of linkage disequilibrium (LD) that spans nearly 400,000 bases at very high LD, potentially confounding genetic association studies of arsenic metabolism.
  • Replicating the first published genetic association of AS3MT with arsenic metabolism (our report), intronic variants in AS3MT were shown to be associated with more efficient arsenic methylation, however this is complicated by the occurrence of these variants within the extremely large cluster of linked polymorphisms that spans 5 genes.
  • Quantitative ascertainment of ancestry using a set of 90 ancestry informative marker SNPs suggests that arsenic methylation efficiency is positively correlated with the fraction of indigenous ancestry in mestizo populations. NIEHS/ES004940 (Superfund Component Project)

 

Modification of the epigenetic landscape by arsenic

Relevance to Swehsc : 

The absence of mechanistic explanations for the increased risk of cancers from arsenic exposure in humans confounds regulators and hinders progress in mitigation of risk in exposed populations. A growing body of data suggests that one key mechanism of arsenic may be the perturbation of epigenetic gene regulation.

Cluster of Efforts: 

Investigators/Funding: Futscher (RFG1), Gandolfi (RFG1), Klimecki (RFG1, IHSFC) NCI/CA015159

             

Milestones: 
  • This grant, awarded under a joint NIEHS/NCI RFA, studies the epigenetic status of both human cell lines exposed to arsenic, as well as exfoliated bladder cells from exposed human study participants exposed to arsenic at defined low and high levels of arsenic exposure. NCI/CA015159
  • Arsenic exposure to UROtsa cell lines alters the levels of siRNA species with defined involvement in epigenetic gene regulation
  • Genome-wide measurement of epigenetic marks on DNA from exfoliated bladder cells from arsenic-exposed people, analyzed by principal component analysis, result in segregation of the samples into clusters of low exposure and high exposure individuals, suggesting that the epigenetic landscape is modified by arsenic and that epigenetic signatures may be promising biomarkers of arsenic exposure and disease. NIEHS/ES004940, NCI/CA015159

 

Oral Folate, arsenic, and genetic polymorphisms: Impact on breast cancer

Relevance to Swehsc : 

Low circulating folate levels are associated with a higher prevalence of ER-negative breast cancer, as well as less efficient arsenic methylation -- a phenotype associated with increased disease risk for known arsenic associated cancers, including bladder and skin.

Cluster of Efforts: 

Investigators/Funding: Klimecki (RFG1), Gandolfi (RFG1), Lizbeth Lopez-Carrillo (INSP [Mexican National Public Health Institute]) USEPA STAG X-96948701

Jay Gandolfi Walt Klimecki

Milestones: 
  • This case control study of 2000 women from Northern Mexico will estimate folate consumption from diet, measure arsenic exposure biomarkers, and test genetic polymorphisms in folate metabolism and arsenic metabolism to explore a potential role for arsenic in the relationship between folate and breast cancer.
  • Subject accrual completed, urinary arsenic determinations ongoing, genetic analyses ongoing. NIEHS/ES004940 (Superfund Component Project)

 

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