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2007 Progress Report: Genetics of Phthalate and Bisphenol A Risk in Minority Populations (Individual Susceptibility)
EPA Grant Number: R831711C003Subproject: this is subproject number 003 , established and managed by the Center Director under grant R831711
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
Center: Mount Sinai Center for Children’s Health and the Environment
Center Director: Wolff, Mary S.
Title: Genetics of Phthalate and Bisphenol A Risk in Minority Populations (Individual Susceptibility)
Investigators: Wetmur, James G.
Institution: Mount Sinai School of Medicine
EPA Project Officer: Fields, Nigel
Project Period: November 1, 2003 through October 31, 2008
Project Period Covered by this Report: November 1, 2006 through October 31,2007
RFA: Centers for Children's Environmental Health and Disease Prevention Research (2003)
Research Category: Children's Health , Health Effects
Description:
Objective:Project 3 has been studying seven genetic polymorphisms in the enzymes that activate and detoxify organophosphates and other pesticides in the population of mothers and infants enrolled in Project 2. Genotypes and phenotypes have been assessed in 656 samples, including maternal and cord bloods. Genotype/haplotype-phenotype associations of PON1 vary by allele, are independent of race/ethnicity, and are stronger for infants than mothers. Results suggest that infants may be more susceptible to toxic effects of PON1 substrates, and that fetal development may be impaired if maternal PON1 or genotype are low-activity. We have developed a new robust single molecule-based haplotyping technology that was verified by showing haplotype-based variation in PON1 activity in mothers heterozygous at two loci, a result that could not have been determined by genotyping or by haplotype inference. We have established an assay for lingual lipase (conversion of phthalate diester to monoester) in collaboration with Dr. Calafat at the CDC. We have genotyped the common missense polymorphism in human UGT2B7 in our population and examined its association with urinary metabolites, also measured at the CDC. There is a significant association with exposure to several phenols, including BPA. We have designed and implemented a panel of 58 genetic variants related to obesity and growth, to be evaluated in Project 1.
Progress Summary:Specific Aims
No modification
Studies and Results/Significance
We have written a book chapter describing our emulsion haplotyping method in detail We sent in the galleys in July, and publication is slated for September.
Wetmur JG, Chen J. An emulsion PCR-based method for molecular haplotyping. In: Methods in Molecular Biology. Environmental Genomics, Martin, C, ed., Humana Press, Totowa, NJ, 2007 (in press).
We have collaborated with Project 2 on the following studies:
1. Wolff, M.S., Engel, S., Berkowitz, G., Teitelbaum, S., Siskind, J., Barr, D.B. & Wetmur, J.G. Prenatal pesticide and PCB exposures and birth outcomes. Pediatric Res. 61, 243-250 (2007).
Birth length was shorter for mothers with PON192RR slow genotype compared with PON192QQ (p=0.026), and head circumference was inversely associated with maternal PON1 activity (p=0.004). With slow-activity PON1 or PON192, DEP was associated with lower birthweight and DMP with shorter birth length.
2. Engel, S., Berkowitz, G., Barr, D.B., Teitelbaum, S.L., Siskind, J., Meisel, S.J., Wetmur, J.G. & Wolff, M.S. Prenatal exposure to organophosphates and organochlorines and performance on the Brazelton neonatal behavioral assessment scale in a multiethnic pregnancy cohort. Am. J. Epidemiol. 165, 1397-404 (2007).+
Higher levels of total diethylphosphates and total dialkylphosphates were associated with an increase in abnormal reflexes, as was total dimethylphosphates after paraoxonase expression was considered.
3. Voho, A., Chen, J., Calafat, A.M., Ye, X., Doucette, J., Engel, S.M., Wolff, M.S. & Wetmur, J.G. (2007) Urinary phenol metabolites among pregnant women in New York City. Submitted.
Background: Phenols and their metabolites are frequently detected in human biological fluids suggesting prevalent exposure to the parent environmental agents. Little information is available regarding these chemicals about factors responsible for variability in their concentrations.
Objectives: We characterized 9 phenols in urine and associations with the UDP-glucuronosyltransferase 2B7 (UGT2B7) His268Tyr polymorphism as well as population characteristics as predictors of their concentrations.
Methods: Total urinary concentrations of phenolic metabolites were measured in 367 pregnant women in a New York City cohort. Multivariate analyses were conducted to identify predictors of phenol urinary metabolite concentrations including polymorphism in the UGT2B7 gene, ethnicity, socioeconomic status and use of consumer products.
Results: Bisphenol A, 2-hydroxy-4-methoxybenzophenone, triclosan, 2,4- and 2,5-dichlorophenol (DCP) were detected in at least 78% of samples. Median concentration of 2,5-DCP was 52.9 µg/L, with an adjusted geometric mean of 165 µg/L for mothball users. Differences by race/ethnicity were seen in 2,4-DCP and 2,5-DCP concentrations in adjusted models. UGT2B7 Tyr268 allele carriers had lower bisphenol A and triclosan urinary concentrations than non-carriers (p<0.05).
Conclusions: This study represents the first systematic evaluation of phenolic metabolites in pregnant women. Five of the nine metabolites were detected in more than three quarters of women. Product use as well as individual metabolism may influence urinary concentrations of these chemicals.
As reported last year, we have continued our studies of phthalate activation by lingual lipase (conversion of diester to monoester) in collaboration with the Dr. Dana Barr at the CDC. Lipase enzymes hydrolyze phthalates to monoesters. Monoesters have been detected in human saliva, and saliva has been shown to be active in metabolizing diethylphthalate to monoethylphthalate. Saliva samples were collected from 85 women with informed consent and stored at –70ºC (the number is now >180 and will be reanalyzed). As the source of lipase enzyme in saliva is not known, we are also studying the expression of five candidate lipase genes in the major salivary glands and tongue. Real time RT-PCR was carried out using two primer sets per gene and normalization to two different housekeeping genes (ALAD and beta-actin). Expression of both gastric and pancreatic lipase mRNA was demonstrated in total mRNA from human tongue. Lipase activity and a-amylase were measured using specific colorimetric assays. Amylase was originally chosen for normalization for salivary protein. Mean lipase and amylase activities varied significantly between individuals. Mean lipase and amylase activities were 5.45 U/L (SD ±6.96) and 47.25U/ml (SD ±38.76), respectively. Correlation between lipase and amylase was low (R2=0.208), suggesting different glands of origin. Although lipase activity in saliva was low, as supported by the observed low level of expression of lipase genes, high inter-individual variation in the lipase activity suggests a regulatory role of environmental and possible genetic factors. These results were presented at: Voho A, Chen J, Kumar, A. Rao M, Wetmur JG. Lipase expression and activity in saliva in a healthy population, ISEE/ISEA International Meeting, Paris (2006).
Future Activities:Plans (in addition to analyses described above):
1. Continue to collaborate with Project 2 to examine PON1 genotype and phenotype effects on developmental outcomes.
2. Phthalate studies: We will determine significant gene variants and examine association with expression, exposures and outcomes.
3. Phenol studies: We will examine associations the common UGT2B7 gene variant with outcomes.
Journal Articles on this Report: 2 Displayed | Download in RIS Format
| Other subproject views: | All 153 publications | 91 publications in selected types | All 82 journal articles |
| Other center views: | All 168 publications | 96 publications in selected types | All 86 journal articles |
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Engel SM, Berkowitz GS, Barr DB, Teitelbaum SL, Siskind J, Meisel SJ, Wetmur JG, Wolff MS. Prenatal organophosphate metabolite and organochlorine levels and performance on the Brazelton Neonatal Behavioral Assessment Scale in a multiethnic pregnancy cohort. American Journal of Epidemiology 2007;165(12):1397-1404. |
R831711C002 (2007) R831711C003 (2007) |
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Wolff MS, Engel S, Berkowitz G, Teitelbaum S, Siskind J, Barr DB, Wetmur J. Prenatal pesticide and PCB exposures and birth outcomes. Pediatric Research 2007;61(2):243-250. |
R831711 (2005) R831711 (2006) R831711 (2007) R831711C001 (2006) R831711C002 (2006) R831711C002 (2007) R831711C003 (2006) R831711C003 (2007) |
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, POLLUTANTS/TOXICS, ENVIRONMENTAL MANAGEMENT, Scientific Discipline, Health, RFA, Endocrine Disruptors - Environmental Exposure & Risk, Risk Assessment, Health Risk Assessment, endocrine disruptors, Chemicals, Children's Health, Biochemistry, Environmental Chemistry, Endocrine Disruptors - Human Health, neurodevelopmental toxicity, endocrine disrupting chemicals, children's environmental health, childhood development, exposure pathways, pesticide exposure, genetic polymorphisms, environmental health, phthalates, phtalates, pesticides, children's vulnerablity, exposure studies
Progress and Final Reports:
2004 Progress Report
2005 Progress Report
2006 Progress Report
Original Abstract
Main Center Abstract and Reports:
R831711 Mount Sinai Center for Children’s Health and the Environment