propylthiouracil and Heart-Defects--Congenital

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.

Topics: Animals; Antithyroid Agents; Body Patterning; Cilia; Digestive System Abnormalities; Female; Gene Expression Regulation, Developmental; Graves Disease; Heart Defects, Congenital; Humans; Methimazole; Models, Animal; Pregnancy; Pregnancy Complications; Propylthiouracil; Teratogens; Time Factors; Triiodothyronine; Xenopus

Tropomyosin is an essential component of the sarcomeric thin filament in striated muscle that participates in the regulation of muscle contraction through Ca(2+)-mediated activation. The two predominant tropomyosin isoforms expressed in striated muscle are alpha- and beta-tropomyosin, which exhibit an 86% amino acid identity between themselves. Previous studies by our laboratory utilized a transgenic mouse system to overexpress beta-tropomyosin in the heart to address the functional differences between these two tropomyosin isoforms. Interestingly, when a high percentage of beta-tropomyosin replaces alpha-tropomyosin in the hearts of transgenic mice, the mice die due to severe cardiac abnormalities. In this study, we have rescued these high expression beta-tropomyosin mice by turning off the alpha-myosin heavy chain promoter, which is driving the beta-tropomyosin transgene. This down-regulation of the alpha-myosin heavy chain promoter was accomplished by the administration of 5-propyl-2-thiouracil, which disrupts thyroid hormone synthesis and inhibits promoter activity through thyroid regulatory elements located in the 5'-flanking region of the promoter. Results show that as beta-tropomyosin expression is down-regulated, alpha-tropomyosin expression is increased. Also, alpha- and beta-myosin heavy chain expression is modified in response to the changes in thyroid hormone expression. Morphological analysis of these rescued mice show a moderate pathological phenotype, characterized by atrial myocytolysis; echocardiographic analyses demonstrate altered ventricular functions, such as peak filling rates and left ventricular fractional shortening. This is the first report demonstrating that transcriptional regulatory elements located within the alpha-myosin heavy chain promoter can be manipulated to rescue potentially lethal phenotypes, such as high expression beta-tropomyosin transgenic mice.

Topics: Animals; Down-Regulation; Gene Expression Regulation; Heart Atria; Heart Defects, Congenital; Heart Function Tests; Mice; Mice, Transgenic; Myosin Heavy Chains; Myosins; Organ Size; Phenotype; Promoter Regions, Genetic; Propylthiouracil; RNA, Messenger; Tropomyosin