Perfluorooctanoic acid induced-developmental cardiotoxicity: are peroxisome proliferator activated receptor α (PPARα) and bone morphorgenic protein 2 (BMP2) pathways involved?
Perfluorooctanoic acid (PFOA) is an environmental contaminant known to induce developmental toxicity in animal models through activation of the peroxisome proliferator-activated receptor α (PPARα). Previously, it was demonstrated that in ovo exposure to PFOA induced cardiotoxicity in chicken embryos and hatchlings. To investigate potential PPARα-mediated mechanisms, fertile chicken eggs were injected prior to incubation with WY 14,643, a PPARα agonist. Cardiac morphology and function were evaluated in late-stage embryos and hatchlings. Histologically, unlike PFOA, WY 14,643 did not induce thinning of the right ventricular wall. Via echocardiography, however, WY 14,643 induced effects similar to those of PFOA, including increased left ventricular wall thickness and mass, elevated heart rate, ejection fraction, fractional shortening, and decreased stroke volume. Additionally, to investigate mechanisms associated with early heart development, a separate group of fertile chicken eggs was injected prior to incubation with PFOA or WY 14,643 and in early-stage embryos, gene expression and protein concentration associated with the bone morphogenic protein (BMP2) pathway were determined. Although changes were not statistically consistent among doses, expression of BMP2, Nkx2.5, and GATA4 mRNA in early embryos was altered by PFOA exposure; however, protein concentrations of these targets were not markedly altered by either PFOA or WY 14,643. Protein levels of pSMAD1/5, a transcriptional regulator stimulated by BMPs, were altered by both PFOA and WY 14,643, but in different directions; PFOA reduced cytoplasmic pSMAD1/5, whereas WY 14,643 decreased nuclear pSMAD1/5. Taken together, these data suggest that developmental cardiotoxicity induced by PFOA likely involves both PPARα and BMP2 pathways.
Department of Pharmacology and Toxicology, Brody School of Medicine, East Carolina University, Greenville, North Carolina 27834, USA.
Qixiao
Q
Jiang
Robert M
RM
Lust
Jamie C
JC
DeWitt
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D055396:Bone Morphogenetic Protein 2 / Q000235:genetics / Q000378:metabolism; D002210:Caprylates / Q000633:toxicity*; D002642:Chick Embryo; D004195:Disease Models, Animal; D004625:Embryo, Nonmammalian / Q000187:drug effects* / Q000378:metabolism; D004785:Environmental Pollutants / Q000633:toxicity*; D005318:Fetal Heart / Q000002:abnormalities / Q000187:drug effects* / Q000378:metabolism; D005466:Fluorocarbons / Q000633:toxicity*; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D006330:Heart Defects, Congenital / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D006352:Heart Ventricles / Q000187:drug effects / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism; D047493:PPAR alpha / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D020025:Peroxisome Proliferators / Q000633:toxicity; D011743:Pyrimidines / Q000633:toxicity; D051785:Smad Proteins / Q000378:metabolism
D015415:Biomarkers; D055396:Bone Morphogenetic Protein 2; D002210:Caprylates; D004785:Environmental Pollutants; D005466:Fluorocarbons; D047493:PPAR alpha; D020025:Peroxisome Proliferators; D011743:Pyrimidines; D051785:Smad Proteins; C006253:pirinixic acid; C023036:perfluorooctanoic acid