Date of Graduation
Master of Science in Biology
Verapamil, Amlodipine, 2, 3-Butanedione monoxime, Teratogen, Zebrafish
Congenital, Hereditary, and Neonatal Diseases and Abnormalities | Developmental Biology
Birth defects are abnormalities in a developing organism that lead to a malformation in structure or function. Over half of birth defects have no determined cause; however, known causes occur by genetic anomalies, exposure to environmental agents (a.k.a. teratogens), or multifactorial reasons. To explain the unknown causes of birth defects, an area of focus in this study is to identify potential teratogens. Identifying these teratogens, is key to preventing future birth defects. An obvious source of teratogens in pregnant women would be that of pharmaceuticals. Thus, a main goal of this study is to identify drugs that cause birth defects. To ensure their cardiovascular health, some pregnant women need to take cardiac drugs for a variety of reasons. However, few studies have evaluated whether these drugs negatively affect developing embryos. This study uses the zebrafish model to assess the teratogenic effects of multiple cardiac inhibitors including verapamil, amlodipine, and 2,3-butanedione monoxime (BDM). The results of this study show that use of all three cardiac inhibitors impaired heart function at their lethal dose 50 (LD50). The severity and types of defects observed in non-cardiac tissues varied for each drug treatment. For example, verapamil exposed larvae exhibited yolk sac edema, a unique dorsal tail curvature, and altered jaw development. BDM-exposed larvae also exhibited yolk sac edema but had a different tail curvature and jaw defect distinguishable from verapamil treatment. Whereas, larvae exposed to amlodipine, which is in a similar class of drugs to verapamil, only exhibited a mild yolk sac edema and no defects in non-cardiac tissues. This study revealed that all the drugs tested impaired embryonic heart contraction, and led to cardiovascular defects, at their LD50. However, verapamil showed unique defects in non-cardiac tissues likely caused by the direct action of verapamil on these tissues, and not due to impaired blood flow. Based on similar defects observed in pkd2 (polycystin2) mutants, I hypothesized that verapamil may inhibit Pkd2 (a non-selective cation channel) in the kidney, skeletal muscle/notochord, and pharyngeal cartilage, and thus providing a plausible explanation for the defects of yolk sac edema, dorsal tail curvature, and jaw formation. Results from this study identified concentrations and developmental defects that could negatively affect human embryos. More studies are needed to validate these findings in a mammalian model.
© Blake Stephan Justis
Justis, Blake Stephan, "Elucidating the Developmental Defects in Zebrafish Associated With the Cardiac Drug Verapamil" (2020). MSU Graduate Theses. 3492.
Available for download on Sunday, May 01, 2022