The proposed studies aim to develop high throughput protocols for assessing OP exposures by characterizing specific biomarker proteins in blood, and to make use of these more accurate measures of exposure to investigate gene/environment interactions related to genetic variability in the paraoxonase (PONI) gene, particularly with respect to OP exposures that occur during early development.
Specific Aim 1 is to validate high throughput immunomagnetic bead (1MB) based isolation protocols for rapid purification and analysis of the active site peptides of two proteins, red cell acyl peptide hydrolase (APH) and plasma butyrylcholinesterase (BChE), as biomarkers of exposure to OP compounds. A targeted proteomics strategy based on microcapillary liquid chromatography-selected reaction monitoring-mass spectrometry (?mu?LC-SRM-MS) will be validated and used to quantify the percentage modification of BChE and APH in archived samples from the Community Based Participatory Research Project. Data from the biomarker experiments will be correlated with other data available on urinary metabolite levels, inhibition of APH and/or BChE, and PONI status.
Specific Aims 2 and 3 use knockout and humanized mouse models to determine the importance of PONI status for OP exposures that occur during critical periods of early development.
Specific Aim 2 is to determine the extent to which APH and BChE are covalently modified following test exposure of pregnant mice to chlorpyrifos (CP) or CPO.
Specific Aim 3 is to determine the extent to which BChE and APH are covalently modified following exposure of neonatal mice to CP or CPO.
These aims will evaluate interactions among biomarkers of sensitivity, exposure and response in an in vivo system, allowing us to determine full dose responses of the OP compounds and generate quantitative biomarker data.
These experiments will integrate the the interactions among biomarkers of susceptibility, exposure, and response to OP compounds during critical periods of development. Using MS analysis of modified APH and BChE to examine the role of genetic variability of P0N1 in modulating gene environment interactions will provide a more detailed understanding of the role of P0N1 in modulating environmental exposures to OPs.
|Kim, Hee Yeon; Wegner, Susanna H; Van Ness, Kirk P et al. (2016) Differential epigenetic effects of chlorpyrifos and arsenic in proliferating and differentiating human neural progenitor cells. Reprod Toxicol 65:212-223|
|Smith, Marissa N; Grice, Joshua; Cullen, Alison et al. (2016) A Toxicological Framework for the Prioritization of Children's Safe Product Act Data. Int J Environ Res Public Health 13:431|
|Marsillach, Judit; Costa, Lucio G; Furlong, Clement E (2016) Paraoxonase-1 and Early-Life Environmental Exposures. Ann Glob Health 82:100-10|
|Holme, Francesca; Thompson, Beti; Holte, Sarah et al. (2016) The role of diet in children's exposure to organophosphate pesticides. Environ Res 147:133-40|
|Furlong, Clement E; Marsillach, Judit; Jarvik, Gail P et al. (2016) Paraoxonases-1, -2 and -3: What are their functions? Chem Biol Interact :|
|Peter, Beate; Wijsman, Ellen M; Nato Jr, Alejandro Q et al. (2016) Genetic Candidate Variants in Two Multigenerational Families with Childhood Apraxia of Speech. PLoS One 11:e0153864|
|Weldon, Brittany A; Shubin, Sara Pacheco; Smith, Marissa N et al. (2016) Urinary microRNAs as potential biomarkers of pesticide exposure. Toxicol Appl Pharmacol 312:19-25|
|Smith, Marissa N; Wilder, Carly S; Griffith, William C et al. (2015) Seasonal variation in cortisol biomarkers in Hispanic mothers living in an agricultural region. Biomarkers 20:299-305|
|Harris, Sean; Hermsen, Sanne A B; Yu, Xiaozhong et al. (2015) Comparison of toxicogenomic responses to phthalate ester exposure in an organotypic testis co-culture model and responses observed in vivo. Reprod Toxicol 58:149-59|
|Wegner, Susanna H; Yu, Xiaozhong; Pacheco Shubin, Sara et al. (2015) Stage-specific signaling pathways during murine testis development and spermatogenesis: A pathway-based analysis to quantify developmental dynamics. Reprod Toxicol 51:31-9|
Showing the most recent 10 out of 94 publications