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J Exp Zool A Ecol Integr Physiol
2025 Dec 03;34310:1191-1204. doi: 10.1002/jez.70031.
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Developmental Patterns of Hepatic Peroxisome Proliferator-Activated Receptor (PPAR) Expression in Xenopus laevis and Response to Pharmaceutical Agonists During Metamorphic Climax.
Bushong A
,
Hoskins TD
,
Scherer M
,
Sepúlveda MS
.
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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.
Figure 1. Summary of xPPARα/β/γ target genes selected for RT‐qPCR analysis and the function of the encoded protein. HDL = High Density Lipoprotein, FA = Fatty Acid, TAFs = Transcription factors.
Figure 2. Marginal mean ± 95% CI of mass (A), Scaled Mass Index (B), Snout‐Vent‐Length (C), liver mass (D), Scaled Liver Index, SLI (E), Hepatic Somatic Index, HSI (F), fat body mass (G), Scaled Fat Body Index, SFI (H), and Fat Body somatic Index, FSI (I) of X. laevis across NF Stages for the characterization study. Colors represent NF Stages. Triangles denote for which plots compact letter display represents Tukey post‐hoc test at 5% threshold of significance. No letter indicates NF Stage was excluded from parametric analysis due to severe heteroskedasticity. Circles denote for which plots compact letter display represents Games‐Howells post‐hoc test at 5% threshold of significance. Marginal means not sharing any letters are statistically different. n = 12–19 per NF Stage.
Figure 3. Marginal mean ± 95% CI of liver xPPARα, xPPARβ, and xPPARγ relative mRNA (i.e., fold change) for X. laevis (NF 51‐66) relative to whole animal NF 48 expression represented by a dash line at 1. Dots represent treatment marginal mean ± 95% C.I. Asterisks (*) indicate the marginal mean was significantly different from NF 48 (p < 0.05) from a Dunnett post‐hoc test. n = 5–8 per NF stage.
Figure 4. Marginal mean ± 95% CI of concentrations of pirinixic acid PA (A), bezafibrate BZ (B), and ciprofibrate CP (C) using LC/MS/MS. Panels A–C represent concentrations in exposure solution from pooled water samples collected at the initiation of each temporal block (n = 9) taken immediately after addition of the tadpole. Dashed line represents nominal concentration for exposure solution (A–C).
Figure 5. Marginal mean ± 95% CI of mass (A), SMI (B), SVL (C), liver mass (D), and HSI (E) for X. laevis exposed to a DMSO vehicle control or a xPPAR agonist (pirinixic acid, bezafibrate, ciprofibrate). n = 11–12 per treatment.
Figure 6. Interaction plot between genotypic sex and treatment means ± 95% CI for Scaled Mass Index, SMI (A) or Hepatic Somatic Index, HSI (B) for X. laevis exposed to either a DMSO vehicle control or an agonist (bezafibrate [BZ], ciprofibrate [CP], pirinixic acid [PA]) with raw data displayed in the background. Dots represent treatment mean ± 95% CI “*” indicates a significant (p < 0.05) and “^” indicates a weak (p < 0.1) treatment effect from a Dunnett post‐hoc test. n = 12 per treatment (nfemale = 4–6/treatment, nmale = 6–8/treatment).
Figure 7. Marginal mean ± 95% CI of xPPAR target genes (acox1, apoa5, fabp1, pck1) expression in livers of X. laevis exposed to a xPPAR agonist (pirinixic acid, PA; bezafibrate, BZ; ciprofibrate, CP). Values relative to DMSO vehicle controls represented by the dashed line at 1.0. Raw data displayed in the background. n = 11–12 per treatment.
