Effect of prenatal peroxisome proliferator-activated receptor α (PPARα) agonism on postnatal development

Abstract

Recent work indicates that PPARalpha is required for perfluorooctanoic acid (PFOA)-induced postnatal lethality resulting from prenatal exposure. The present study tested the hypothesis that relatively modest activation of PPARalpha during prenatal development will cause postnatal lethality, similar to that observed with PFOA, a relatively low affinity PPARalpha agonist. Female wild-type and Pparalpha-null mice were mated overnight with males of the same genotype. The presence of a copulatory plug on the morning after mating was indicative of pregnancy and considered gestation day (GD) 0. Plugged female mice were fed either a control diet or one containing clofibrate (0.5%) or Wy-14,643 (0.005%) until GD18 or until parturition. Mice were examined on GD18 or on postnatal day (PND) 20 following the prenatal exposure period. Dietary administration of clofibrate or Wy-14,643 did not affect maternal weight or weight gain, the average number of implantations, the percentage of litter loss, the average number of live/dead fetuses, average crown-rump length, or the average fetal weight on GD18 in either genotype. An increase in relative maternal liver weight and elevated expression of PPARalpha target genes in maternal and fetal livers on GD18 were observed, indicative of PPARalpha-dependent changes in both the maternal and fetal compartments. However, no defects in postnatal development were observed by either clofibrate or Wy-14,643 in either genotype by PND20. These results demonstrate that relatively low level activation of PPARalpha by clofibrate or Wy-14,643 during prenatal development does not cause postnatal lethality.

Metabolic Profiling of Chicken Embryos Exposed to Perfluorooctanoic Acid (PFOA) and Agonists to Peroxisome Proliferator-Activated Receptors

“…Studies with knock-out mice showed that postnatal mortality in mouse could be mediated via mouse PPARα but not via a humanized form of the receptor, suggesting species differences in response to receptor binding [ 38 , 39 ]. However, modest activation of PPARα during prenatal development using the agonists clofibrate and Wy14,643 caused no postnatal mortality in mouse [ 40 ]. In chicken, cardiac effects induced by embryonic PFOA exposure could partly be reproduced by the PPARα agonist Wy 14,643 [ 41 ].…”

A putative adverse outcome network for neonatal mortality and lower birth weight in rodents: Applicability to per‐ and polyfluoroalkyl substances and relevance to human health

“…Exposure of pregnant mice to etofylline clofibrate or fenofibrate from GD7 to 16 at high dosages resulted in FGR (etofylline clofibrate) and higher postimplantation loss (fenofibrate) (Ujhazy et al, 1989). Palkar et al (2010) saw no increase in neonatal mortality in offspring of mice fed diets containing clofibrate or WY-14643 during pregnancy, in contrast to their subsequent findings with PFOA (Albrecht et al, 2013). The authors suggested that the lack of neonatal mortality from clofibrate or WY-14643 was due to lower activation of PPARα compared with treatments with PFOA that did cause neonatal mortality.…”

A influência de agonistas PPARgama ou PPARalpha na programação metabólica decorrente de restrição calórica durante a gestação e a lactação

“…Já no 21° DL, a redução da massa corporal foi de 19,8% nas mães RC e de 22,7% nas mães RC+GEM (vs. CTL; p<0,01 e p<0,0001).Até o momento, não foram encontrados na literatura trabalhos que correlacionam a exposição da GEM e o peso das ratas prenhas e/ou lactantes. Porém, o estudo de Palkar e colaboradores demonstrou que a administração do clofibrato durante a gestação não afetou o peso ou o ganho de peso das ratas(102). Dessa maneira, observando nossos resultados, a GEM também não foi capaz de alterar o peso das mães que foram expostas à RC.…”