gw-7647 and perfluorooctanoic-acid

Untargeted metabolic profiling of body fluids in experimental animals and humans exposed to chemicals may reveal early signs of toxicity and indicate toxicity pathways. Avian embryos develop separately from their mothers, which gives unique possibilities to study effects of chemicals during embryo development with minimal confounding factors from the mother. In this study we explored blood plasma and allantoic fluid from chicken embryos as matrices for revealing metabolic changes caused by exposure to chemicals during embryonic development. Embryos were exposed via egg injection on day 7 to the environmental pollutant perfluorooctanoic acid (PFOA), and effects on the metabolic profile on day 12 were compared with those caused by GW7647 and rosiglitazone, which are selective agonists to peroxisome-proliferator activated receptor α (PPARα) and PPARγ, respectively. Analysis of the metabolite concentrations from allantoic fluid by Orthogonal Partial Least Squares Discriminant Analysis (OPLS-DA) showed clear separation between the embryos exposed to GW7647, rosiglitazone, and vehicle control, respectively. In blood plasma only GW7647 caused a significant effect on the metabolic profile. PFOA induced embryo mortality and increased relative liver weight at the highest dose. Sublethal doses of PFOA did not significantly affect the metabolic profile in either matrix, although single metabolites appeared to be altered. Neonatal mortality by PFOA in the mouse has been suggested to be mediated via activation of PPARα. However, we found no similarity in the metabolite profile of chicken embryos exposed to PFOA with those of embryos exposed to PPAR agonists. This indicates that PFOA does not activate PPAR pathways in our model at concentrations in eggs and embryos well above those found in wild birds. The present study suggests that allantoic fluid and plasma from chicken embryos are useful and complementary matrices for exploring effects on the metabolic profile resulting from chemical exposure during embryonic development.

Topics: Animals; Blood Chemical Analysis; Butyrates; Caprylates; Chick Embryo; Embryonic Development; Fluorocarbons; Liver; Metabolomics; Phenylurea Compounds; PPAR alpha; PPAR gamma; Rosiglitazone; Thiazolidinediones

Perfluoroalkyl acids (PFAAs) such as perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) are developmental toxicants in various animal classes, including birds. Both compounds interact with peroxisome proliferator-activated receptors (PPARs), but it is not known whether activation of PPARs is involved in their embryo toxicity in birds. We exposed chicken embryos via egg injection at a late developmental stage to GW7647, a potent PPARα agonist in mammals, and to PFOS or PFOA. Mortality was induced by PFOS and PFOA but not by GW7647. Transcripts of a number of genes activated by PPARα agonists in mammals were analyzed in liver and kidney of 18-day-old embryos. Several of the genes were induced in both liver and kidney following exposure to GW7647. Treatment with PFOA resulted in induction of acyl-coenzyme A oxidase mRNA in liver, whereas none of the genes were significantly induced by PFOS treatment. No up-regulation of gene transcription was found in kidney following treatment with PFOS or PFOA. Principal component analysis showed that PFOA caused an mRNA expression pattern in liver more similar to the pattern induced by GW7647 than PFOS did. Our findings do not support that the embryo mortality by PFOS and PFOA in chicken embryos involves PPARα activation.

Topics: Acyl-CoA Oxidase; Alkanesulfonic Acids; Animals; Butyrates; Caprylates; Chick Embryo; Chickens; Fluorocarbons; Kidney; Lipid Metabolism; Liver; Phenylurea Compounds; PPAR alpha; RNA, Messenger; Transcription, Genetic; Transcriptional Activation; Up-Regulation; Zygote