Sumner, S., Snyder, R., Burgess, J., Myers, C., Tyl, R., Sloan, C., & Fennell, T. (2008). Metabolomics: Application to the study of phthalates in reproduction and development. Toxicologist, 63.
This study was conducted to evaluate the use of metabolomics for improving our ability to draw correlations between early life exposures and reproductive and/or developmental outcomes. Pregnant CD rats were exposed daily during gestation (gd 14-21) to vehicle or to butyl benzyl phthalate (BBP) at a level (750 mg/kg) known to induce effects in the offspring and at a level (25 mg/kg) not expected to induce effects. Urine was collected for 24 h (on dry ice using all glass metabolism chambers) from dams on gd 18 (during exposure) and pnd 21 (3 wk after exposure), and from pnd 24 pups (~ 4 wk after dams exposure to vehicle or BBP). Traditional phenotypic anchors (e.g., anogenital distance, retained nipples, hormones) were measured in pups (between pnd 0 and pnd 26). Metabolomics of urine collected from dams (gd 18 and pnd 21) exposed to vehicle or BBP exhibited different patterns for endogenous metabolites. Even three weeks after gestational exposure, metabolic profiles of endogenous compounds in urine could differentiate dams that received the vehicle, low dose, or high dose of BBP. Metabolomic profiles of pnd 25 urine from offspring of dams exposed to vehicle, low dose or high dose of BBP were also significantly different. Metabolic profiles could differentiate male
from female pups, pups born to dams receiving the vehicle, low or high BBP dose, and pups with measurable reproductive effects from pups with no observed effects. Metabolites significant to the separation of dose groups and the relationship with effects measured in the study were mapped to biochemical pathways for determining mechanistic relevance. The application of metabolomics to understand the mechanistic link between low levels of environmental exposure and disease/dysfunction holds a huge promise, because this technology is ideal for the analysis of biological fluids (e.g., urine, serum) in population studies, as well as the development
of mechanistic insights from dose-response studies conducted in animal models. Supported by RTI International.