TOPIC OF CONCERN - Genetic Susceptibility

Our Involvement | Research | Other Resources

About Genetic Susceptibility

Differences in genetic make-up affect the way we respond to environmental health risks, such as exposure to toxic chemicals like pesticides. People respond differently to substances in the environment. Some of these responses can be attributed to differences in our genetic make-up, which make us more or less sensitive to the substances around us. Researchers want to find out more about these genetic susceptibilities and to find ways to keep us all healthy.

Scientists at the DEOHS are conducting basic research on the ways that genetic and environmental factors combine to affect susceptibility to diseases and disorders including:

adverse reactions to drugs and chemicals
age
asthma
birth defects
cancer
occupational factors
Parkinson’s disease and other neurological disorders

Our Involvement

Faculty

Courses

ENV H 513 Basic Concepts in Pharmacogenetics and Toxicogenomics
ENV H 514 Environmental and Occupational Toxicology I
ENV H 515 Environmental and Occupational Toxicology II
ENV H 516 Environmental and Occupational Toxicology III
ENV H 517 Children's Environmental Health
ENV H 531 Neurotoxicology
ENV H 532 Reproductive and Developmental Toxicology
ENV H 533 Molecular Toxicology
ENV H 535 Inhalation Toxicology

Centers and Institutes

Services

News Coverage

Dave Eaton's May 25, 2006 distinguished faculty lecture, "Genes and Cancer-Causing Chemicals: Understanding Why Humans Are Not Just Big Rodents." Podcast , Feature Story (PDF download)

Genetics at the Community Level (Environmental Health Perspectives, August, 2005)

Genetics and Ethics (Environmental Health News, Spring-Summer, 2005)

Student Green Mapping (KPLU, June 6, 2005--link to MP3 file)

Mukilteo students brew up some fuel: They hope to persuade the school board to use biodiesel in school buses (The Herald, Everett, Washington, March 28, 2005)

Beyond the Bench: Tox-in-a-Box (Environmental Health Perspectives 113(3), March 2005)

Research

Graduate Students

Bekris Lynn (2005): Glutathione related enzyme gene polymorphisms and Type 1 Diabetes. Doctoral dissertation (Terrance Kavanagh)

Garry, Michael, PhD (2006): Differential response and susceptibility to oxidative stress in mouse lung fibroblasts heterozygous for phospholipid hydroperoxide glutathione peroxidase (GPx4) (Elaine Faustman)

Gribble, Elizabeth, PhD (2005): Cell cycle inhibition as a mode of abnormal development: The role of cell cycle checkpoint proteins and cyclin dependent kinase inhibitors in neurodevelomental toxicant defense (Elaine Faustman)

Hoeft Julia, MS (2001): A biologically based dose-response model for ethanol-induced developmental neurotoxicity (Elaine Faustman)

Kelada, Samir, PhD (2006): 5' and 3' region variability in the dopamine transporter gene (SLC6A3) and Parkinson's disease (Lucio Costa)

Walter, Betsy, MS (2005): Acute organophosphorus insecticide toxicity in developing humanized paraoxonase (hPON1-Q192R) transgenic mice (Lucio Costa)

Zhang, Xun, PhD (2006): Genetic and genomic approaches to the study of progression in mammary carcinogenesis (Helmut Zarbl)

Peer-reviewed Publications

Bekris LM, Shephard C, Peterson M, Hoehna J, Van Yserloo B, Rutledge E, Farin F, Kavanagh TJ, Lernmark A. Glutathione-s-transferase M1 and T1 polymorphisms and associations with type 1 diabetes age-at-onset. Autoimmunity. 2005 Dec;38(8):567-575.

Bekris LM, Kavanagh TJ, Lernmark A. Targeting type 1 diabetes before and at the clinical onset of disease. Endocr Metab Immune Disord Drug Targets. 2006 Mar;6(1):103-24.

Bekris LM, Viernes HM, Farin FM, Maier LA, Kavanagh TJ, Takaro TK. Chronic beryllium disease and glutathione biosynthesis genes. J Occup Environ Med. 2006 Jun;48(6):599-606.

Botta D, Shi S, White CC, Dabrowski MJ, Keener CL, Srinouanprachanh SL, Farin FM, Ware CB, Ladiges WC, Pierce RH, Fausto N, Kavanagh TJ. Acetaminophen-induced liver injury is attenuated in male glutamate cysteine ligase transgenic mice. J Biol Chem. 2006 Sep 29;281(39):28865-28875.

Cole TB, Walter BJ, Shih DM, Tward AD, Lusis AJ, Timchalk C, Richter RJ, Costa LG, Furlong CE. Toxicity of chlorpyrifos and chlorpyrifos oxon in a transgenic mouse model of the human paraoxonase (PON1) Q192R polymorphism. Pharmacogenet Genomics. 2005 Aug;15(8):589-598.

Corey LM, Baker C, Luchtel DL. Heart-rate variability in the apolipoprotein E knockout transgenic mouse following exposure to Seattle particulate matter. J Toxicol Environ Health A. 2006 May;69(10):953-965.

Costa LG. Current issues in organophosphate toxicology. Clin Chim Acta. 2006 Apr;366(1-2):1-13.

Costa LG, Cole TB, Furlong CE. Paraoxonase (PON1): from toxicology to cardiovascular medicine. Acta Biomed Ateneo Parmense. 2005;76 Suppl 2:50-57.

Costa-Mallen P, Costa LG, Checkoway H. Genotype combinations for monoamine oxidase-B intron 13 polymorphism and dopamine D2 receptor TaqIB polymorphism are associated with ever-smoking status among men. Neurosci Lett. 2005 Sep 9;385(2):158-162.

Costa-Mallen P, Kelada SN, Costa LG, Checkoway H. Characterization of the in vitro transcriptional activity of polymorphic alleles of the human monoamine oxidase-B gene. Neurosci Lett. 2005 Jul 22-29;383(1-2):171-175.

Costa L and Furlong C, editors, Paraoxonase (PON1) in Health and Disease: Basic and Clinical Aspects. Kluwer Academic Press, 2002.

Costa LG, Guizzetti M, Burry M, et al. Developmental neurotoxicity: do similar phenotypes indicate a common mode of action? A comparison of fetal alcohol syndrome, toluene embryopathy and maternal phenylketonuria. Toxicol Lett, 2002. 127(1-3):197-205.

Costa LG. The emerging field of ecogenetics. Neurotoxicology, 2000. 21(1-2):85-9.

Dabrowski MJ, Maeda D, Zebala J, Lu WD, Mahajan S, Kavanagh TJ, Atkins WM. Glutathione S-transferase P1-1 expression modulates sensitivity of human kidney 293 cells to photodynamic therapy with hypericin. Arch Biochem Biophys. 2006 May 15;449(1-2):94-103.

Eaton DL. Glutathione S-transferases as putative host susceptibility genes for cancer risk in agricultural workers. J Biochem Mol Toxicol. 2005;19(3):187-189.

Echeverria D, Woods JS, Heyer NJ, Rohlman D, Farin FM, Li T, Garabedian CE. The association between a genetic polymorphism of coproporphyrinogen oxidase, dental mercury exposure and neurobehavioral response in humans. Neurotoxicol Teratol. 2006 Jan-Feb;28(1):39-48.

Echeverria D, Woods JS, Heyer NJ, Rohlman DS, Farin FM, Bittner AC Jr, Li T, Garabedian C. Chronic low-level mercury exposure, BDNF polymorphism, and associations with cognitive and motor function. Neurotoxicol Teratol. 2005 Nov-Dec;27(6):781-796.

Faustman EM, Silbernagel SM, Fenske RA, et al. Mechanisms underlying children's susceptibility to environmental toxicants. Environ Health Perspect, 2000. 108 Suppl 1:13-21.

Furlong CE, Cole TB, Jarvik GP, Pettan-Brewer C, Geiss GK, Richter RJ, Shih DM, Tward AD, Lusis AJ, Costa LG. Role of paraoxonase (PON1) status in pesticide sensitivity: genetic and temporal determinants. Neurotoxicology. 2005 Aug;26(4):651-659. Review.

Furlong CE, Cole TB, Walter BJ, Shih DM, Tward A, Lusis AJ, Timchalk C, Richter RJ, Costa LG. Paraoxonase 1 (PON1) status and risk of insecticide exposure. J Biochem Mol Toxicol. 2005;19(3):182-183.

Gharib SA, Luchtel DL, Madtes DK, Glenny RW. Global gene annotation analysis and transcriptional profiling identify key biological modules in hypoxic pulmonary hypertension. Physiol Genomics. 2005 Jun 16;22(1):14-23.

Giordano G, Sanchez-Perez AM, Montoliu C, Berezney R, Malyavantham K, Costa LG, Calvete JJ, Felipo V. Activation of NMDA receptors induces protein kinase A-mediated phosphorylation and degradation of matrin 3. Blocking these effects prevents NMDA-induced neuronal death. J Neurochem. 2005 Aug;94(3):808-818.

Guo Y, Breeden LL, Fan W, Zhao LP, Eaton DL, Zarbl H. Analysis of cellular responses to aflatoxin B(1) in yeast expressing human cytochrome P450 1A2 using cDNA microarrays. Mutat Res. 2006 Jan 29;593(1-2):121-142.

Guo Y, Breeden LL, Zarbl H, Preston BD, Eaton DL. Expression of a human cytochrome p450 in yeast permits analysis of pathways for response to and repair of aflatoxin-induced DNA damage. Mol Cell Biol. 2005 Jul;25(14):5823-5833.

Heyer NJ, Bittner AC Jr, Echeverria D, Woods JS. A cascade analysis of the interaction of mercury and coproporphyrinogen oxidase (CPOX) polymorphism on the heme biosynthetic pathway and porphyrin production. Toxicol Lett. 2006 Feb 20;161(2):159-166.

Ho HK, White CC, Fernandez C, Fausto N, Kavanagh TJ, Nelson SD, Bruschi SA. RNrf2 activation involves an oxidative-stress independent pathway in tetrafluoroethylcysteine-induced cytotoxicity. Toxicol Sci. 2005 Aug;86(2):354-364.

Judd NL, Griffith WC, Ylitalo GM, et al. Alternative strategies for PCB risk reduction from contaminated seafood: Options for children as susceptible populations. Bull Environ Contam and Toxicol, 2002. 69:847-854.

Kelada SN, Checkoway H, Kardia SL, Carlson CS, Costa-Mallen P, Eaton DL, Firestone J, Powers KM, Swanson PD, Franklin GM, Longstreth WT Jr, Weller TS, Afsharinejad Z, Costa LG. 5' and 3' region variability in the dopamine transporter gene (SLC6A3), pesticide exposure and Parkinson's Disease risk: A hypothesis generating study. Hum Mol Genet. 2006 Sep 8; [Epub ahead of print] print citation?

Kelada SN, Costa-Mallen P, Checkoway H, Carlson CS, Weller TS, Swanson PD, Franklin GM, Longstreth WT Jr, Afsharinejad Z, Costa LG. Dopamine transporter (SLC6A3) 5' region haplotypes significantly affect transcriptional activity in vitro but are not associated with Parkinson's disease. Pharmacogenet Genomics. 2005 Sep;15(9):659-668.

Knoll N, Ruhe C, Veeriah S, Sauer J, Glei M, Gallagher EP, Pool-Zobel BL. Genotoxicity of 4-hydroxy-2-nonenal in human colon tumor cells is associated with cellular levels of glutathione and the modulation of glutathione S-transferase A4 expression by butyrate. Toxicol Sci. 2005 Jul;86(1):27-35.

Kramer CB, Cullen AC, Faustman EM. Policy implications of genetic information on regulation under the Clean Air Act: The case of particulate matter and asthmatics. Environmental Health Perspective 2006; 114 (3): 313-319.

Li WF, Costa LG, Richter RJ, et al. Catalytic efficiency determines the in-vivo efficacy of PON1 for detoxifying organophosphorus compounds. Pharmacogenetics, 2000. 10(9):767-79.

Maraganore DM, de Andrade M, Elbaz A, Farrer MJ, Ioannidis JP, Kruger R, Rocca WA, Schneider NK, Lesnick TG, Lincoln SJ, Hulihan MM, Aasly JO, Ashizawa T, Chartier-Harlin MC, Checkoway H, Ferrarese C, Hadjigeorgiou G, Hattori N, Kawakami H, Lambert JC, Lynch T, Mellick GD, Papapetropoulos S, Parsian A, Quattrone A, Riess O, Tan EK, Van Broeckhoven C; Genetic Epidemiology of Parkinson's Disease (GEO-PD) Consortium. Collaborative analysis of alpha-synuclein gene promoter variability and Parkinson disease. JAMA. 2006 Aug 9;296(6):661-670.

McKone EF, Shao J, Frangolias DD, Keener CL, Shephard CA, Farin FM, Tonelli MR, Pare PD, Sandford AJ, Aitken ML, Kavanagh TJ. Variants in the glutamate-cysteine-ligase gene are associated with cystic fibrosis lung disease. Am J Respir Crit Care Med. 2006 Aug 15;174(4):415-419.

Moneypenny CG, Shao J, Song Y, Gallagher EP. MLL rearrangements are induced by low doses of etoposide in human fetal hematopoietic stem cells. Carcinogenesis. 2006 Apr;27(4):874-881.

Peterson S, Lampe JW, Bammler TK, Gross-Steinmeyer K, Eaton DL. Apiaceous vegetable constituents inhibit human cytochrome P-450 1A2 (hCYP1A2) activity and hCYP1A2-mediated mutagenicity of aflatoxin B1. Food Chem Toxicol. 2006 Sep;44(9):1474-1484.

Polifka J, Faustman E. Developmental toxicity: web resources for evaluating risk in humans. Toxicology, 2002. 173:35-65.

Sieh W, Edwards KL, Fitzpatrick AL, Srinouanprachanh SL, Farin FM, Monks SA, Kronmal RA, Eaton DL. Genetic Susceptibility to Prostate Cancer: Prostate-specific Antigen and its Interaction with the Androgen Receptor (United States). Cancer Causes Control. 2006 Mar;17(2):187-197.

Woods JS, Echeverria D, Heyer NJ, Simmonds PL, Wilkerson J, Farin FM. The association between genetic polymorphisms of coproporphyrinogen oxidase and an atypical porphyrinogenic response to mercury exposure in humans. Toxicol Appl Pharmacol. 2005 Aug 7;206(2):113-120.

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Conference Presentations

Bekris L, Janer M, Kavanagh T, Lernmark A. The glutamate cysteine ligase catalytic subunit -129 C/T single nucleotide polymorphism is associated with the level of GAD65 auto-antibodies in Type 1 diabetes patients with a delayed age-at-onset, Society of Toxicology, March 6-10, 2005, New Orleans

Botta D, McGrath MB, Neff-LaFord HD, Kavanagh TJ. Upregulation of GCLM expression restores glutathione and protects against APAP-induced liver injury in GCLM null mice, Society of Toxicology, Charlotte, NC, March 25-29, 2007

Botta D, McConnachie LA, Fernandez C, Vliet PA, White CC, Kavanagh TJ. A model system to assess the role of modulated glutamate-cysteine ligase in toxicant induced oxidative stress, Society of Toxicology, March 5–9, 2006, San Diego

Carlsten C, De Roos AJ, Kaufman J, Checkoway H, Seixas N. Cell markers and cytokines in cement masons: Associations between silica dust exposure, inflammation and immunity, American Thoracic Society, May 20–25, 2005, San Diego

Cole TB, Pettan-Brewer C, Forbes A, Proll S, Furlong J, Costa LG, Furlong CE. Modulation of low-level organophosphate toxicity by human PON1, as assessed by microarray analysis, Society of Toxicology, March 5–9, 2006, San Diego

Cole T, Walter B, Shih D, Tward A, Lusis A, Costa L, Furlong C. Toxicity of chlorpyrifos and chlorpyrifos oxon in a transgenic mouse model of the human paraoxonase (PON1) Q192R polymorphism, Society of Toxicology, March 6-10, 2005, New Orleans

Eaton D. Functional genomics and public health decisions, National Toxicology Program, National Academy of Sciences, May 11, 2005, Washington, DC

Faustman E. Systems biology in public health decisions, National Toxicology Program, National Academy of Sciences, May 11, 2005, Washington, DC

Faustman EM, Yu X, Griffith B. The future of genomics in dose response modeling: Useful lessons from systems based approaches, Society of Toxicology, Charlotte, NC, March 25-29, 2007

Garry MR, Deeb SS, Kavanagh TJ, Yu X, Vredevoogd MA, Kim E, Faustman EM. Differential modulation of stress signaling pathways by cadmium in cultured mouse lung fibroblasts heterozygous for GPx4, Society of Toxicology, Charlotte, NC, March 25-29, 2007

Gilbert SG, Sette WF, Scarano L, Fortmann R, Mortensen SR. Scientific and ethical considerations in human exposure studies, Society of Toxicology, Charlotte, NC, March 25-29, 2007

Li T, Simmonds L, Woods JS. Cloning, expression and biochemical properties of CPOX4, a genetic variant of coproporphyrinogen oxidase that modifies the effect of mercury exposure on porphyrin excretion in humans, Society of Toxicology, Charlotte, NC, March 25-29, 2007

McConnachie L, Fernandez C, Mohar I, Pierce R, Kavanagh T. Acetaminophen induced hepatoxicity in a GCLM- null mouse model, Society of Toxicology, March 6-10, 2005, New Orleans

McConnachie L, Mohar I, Kavanagh TJ. Gender differences in acetaminophen-induced hepatoxicity in wild-type and GCLM-null mice, Society of Toxicology, March 5–9, 2006, San Diego

Mohar I, McConnachie L, Fernandez C, Kavanagh T. Effect of acetaminophen on cytosolic and mitochondrial glutathione in the livers of wild-type, GCLM-heterozygous, and GCLM-null mice, Society of Toxicology, March 6-10, 2005, New Orleans

Peck EC, McConnachie LA, Beyer RP, Bammler TK, Baker C, Ceballos D, Vliet PA, Stewart JA, Luchtel DL, Kaufman JD, Kavanagh TJ. Differential gene expression in GCLM-null and wild-type mice exposed to diesel exhaust, Society of Toxicology, March 5–9, 2006, San Diego

Pettan-Brewer C, Cole T, Fisher J, Walter B, Forbes A, Yee N, Costa L, Furlong C. PON1 modulates OP toxicity during development, Society of Toxicology, March 6-10, 2005, New Orleans

Robinson JF, Yu X, Hong S, Kim E, Griffith WC, Faustman EM. Examination of metal induced toxicogenomic response during neurulation in resistant mouse strains, Society of Toxicology, Charlotte, NC, March 25-29, 2007

Sullivan JH, Peretz A, Carlsten C, Moody MM, Trenga CA, Jansen KA, Kaufman JD, Stewart JA, Bammler TK, Hallstrand TS. Genomic analysis of the effects of diesel exhaust particles on asthmatic airways, American Thoracic Society, May 19–24, 2006, San Diego

Sumner A, Thornquist M, Checkoway H, Balmes J, Takaro TK. Glutathione S-Transferase Mu 1 polymorphism and asbestos-related lung disease, American Thoracic Society, May 20–25, 2005, San Diego

Vredevoogd M, Yu X, Griffith B, Faustman EM. Quantification of genomic data: Value-added assessment and applicability to toxicologically significant endpoints, Society of Toxicology, Charlotte, NC, March 25-29, 2007

White CC, Dabrowski CM, Fernandez C, Botta D, Beyer R, Bammler TC, Kavanagh TJ. Differential gene expression in hepatocyte subpopulations sorted from acetaminophen-treated mice, Society of Toxicology, March 5–9, 2006, San Diego

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