Developmental Patterns of Hepatic Peroxisome Proliferator-Activated Receptor (PPAR) Expression in Xenopus laevis and Response to Pharmaceutical Agonists During Metamorphic Climax.

Peroxisome proliferator-activated receptors (PPAR) are master transcriptional regulators that maintain metabolic homeostasis in vertebrates. Amphibians are often exposed to endocrine disrupting compounds (EDCs) that could dysregulate lipid metabolism. Larvae of the African clawed frog (Xenopus laevis) are routinely used as a model to study aquatic EDC exposures, but PPAR expression has not been characterized across larval development or metamorphosis in this species. We conducted two experiments to elucidate (a) the expression in late metamorphosis for xPPARα/β/γ subtypes, and (b) the effect of pharmaceutical PPAR agonists (pirinixic acid, bezafibrate, and ciprofibrate) on the expression of xPPARα/β/γ target genes. Additionally, we considered apical endpoints (body mass, body condition [scaled mass index, SMI], and relative liver mass). We hypothesized pharmaceuticals would agonize hepatic xPPARα/β/γ, upregulating expression of downstream target genes and reducing apical endpoints with variation reflective of developmental patterns of nuclear receptor expression. We observed upregulation of xPPARα during late premetamorphosis (NF 51), prometamorphosis (NF 56-57), and metamorphic climax (NF 58-66), which also held for xPPARγ with exception for peak of metamorphic climax (NF 62). For xPPARβ, we only observed upregulation at conclusion of metamorphic climax (NF 66). Agonists did not cause changes in gene expression for xPPARα/β/γ targets, but pirinixic acid exposure decreased female body condition. The dynamic hepatic expression of xPPARα/β/γ during late metamorphosis is presumably necessary to coordinate energy flux and highlights a potential period of susceptibility to PPAR agonism. However, pharmaceuticals identified to interact with xPPARα/β/γ did not elicit a response concordant with PPAR agonism at high doses. These results suggest that X. laevis may not be a sensitive model for studies testing PPAR-mediated effects of xenobiotics.