Key Metabolic Pathway Changes in Human Embryonic Stem Cells Exposed to Methyl Parathion and Methyl Paraoxon

Toxic industrial chemicals (TICs) represent a threat to soldiers, first responders and other civilians. One class of toxic industrial chemicals, pesticides, is particularly accessible and used widely in crop, industrial, and home applications. For many pesticides, including methyl parathion (MP), there is incomplete and sometimes conflicting information regarding the basic molecular toxicological consequences of exposure in humans. Most documented effects reported are from epidemiological studies in adult humans and laboratory studies in adult animals. It is important to consider that many chemicals, including pesticides, have dramatically different toxic effects in developing embryos. Thus, any thorough chemical or drug toxicological evaluation must examine the compound’s effect on early development. Since not all cell types contain fully active metabolic enzymes required to carry out Phase I and II transformation reactions, it is important to examine the effects of both the parent compound and the active metabolite(s) normally transformed by the liver. In this work, we have compared the effects of MP and its active metabolite methyl paraoxon (MPO) on the secreted metabolic products (measured via LC-ESI-QTOF MS) found in the spent cell culture medium from MP-exposed, MPO-exposed, and control pluripotent WA09 human embryonic stem cells. Employing Stemina’s devTOX teratogenicity prediction model, MPO was predicted to be tetratogenic at all 3 concentrations tested (180 ?M, 130 ?M, 72 ?M) and MP was predicted to be tetratogenic at 500 ?M, the highest concentration tested. Several hundred statistically significant differences were observed between the treated and the untreated cells with 13 human metabolic pathways exhibiting statistically significant enrichment in the treated cells. These data suggest that MP and MPO exposure may significantly impact the metabolism of undifferentiated hES cells.

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