title: Embryonic exposure to propylthiouracil disrupts left-right patterning in Xenopus embryos.
abstract: Antithyroid medications are the preferred therapy for the treatment of Graves' disease during pregnancy. Propylthiouracil (PTU) is favored over methimazole (MMI) due to potential teratogenic concerns with MMI. This study was to determine the teratogenic potential of MMI and PTU using a validated Xenopus tropicalis embryo model. Embryos were exposed to 1 mM PTU (EC(50)=0.88 mM), 1 mM MMI, or vehicle control (water) from stages 2 to 45. Treated embryos were examined for gross morphological defects, ciliary function, and gene expression by in situ hybridization. Exposure to PTU, but not MMI, led to cardiac and gut looping defects and shortening along the anterior-posterior axis. PTU exposure during gastrulation (stage 8-12.5) was identified as the critical period of exposure leading to left-right (LR) patterning defects. Abnormal cilia polarization, abnormal cilia-driven leftward flow at the gastrocoel roof plate (GRP), and aberrant expression of both Coco and Pitx2c were associated with abnormal LR symmetry observed following PTU exposure. PTU is teratogenic during late blastula, gastrulation, and neurulation; whereas MMI is not. PTU alters ciliary-driven flow and disrupts the normal genetic program involved in LR axis determination. These studies have important implications for women taking PTU during early pregnancy.
authors.affiliation: Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Nicole R
authors.initials: NR
authors.lastname: van Veenendaal
authors.forename: Bärbel
authors.initials: B
authors.lastname: Ulmer
authors.forename: Marko T
authors.initials: MT
authors.lastname: Boskovski
authors.forename: Xiefan
authors.initials: X
authors.lastname: Fang
authors.forename: Mustafa K
authors.initials: MK
authors.lastname: Khokha
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Wendler
authors.forename: Martin
authors.initials: M
authors.lastname: Blum
authors.forename: Scott A
authors.initials: SA
authors.lastname: Rivkees
mesh_terms: D000818:Animals; D013956:Antithyroid Agents / Q000008:administration & dosage / Q000633:toxicity*; D019521:Body Patterning / Q000187:drug effects* / Q000235:genetics; D002923:Cilia / Q000187:drug effects; D004065:Digestive System Abnormalities / Q000139:chemically induced / Q000196:embryology; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D006111:Graves Disease / Q000150:complications / Q000188:drug therapy; D006330:Heart Defects, Congenital / Q000139:chemically induced / Q000196:embryology; D006801:Humans; D008713:Methimazole / Q000008:administration & dosage / Q000633:toxicity; D023421:Models, Animal; D011247:Pregnancy; D011248:Pregnancy Complications / Q000188:drug therapy; D011441:Propylthiouracil / Q000008:administration & dosage / Q000633:toxicity*; D013723:Teratogens / Q000633:toxicity*; D013997:Time Factors; D014284:Triiodothyronine / Q000494:pharmacology; D014981:Xenopus / Q000196:embryology* / Q000235:genetics
chemical_list: D013956:Antithyroid Agents; D013723:Teratogens; D014284:Triiodothyronine; D008713:Methimazole; D011441:Propylthiouracil