Embryonic exposure to propylthiouracil disrupts left‐right patterning inXenopusembryos

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.

Evaluation of Developmental Toxicity of Propylthiouracil and Methimazole

“…When Xenopus embryos were treated very early during embryogenesis with MMI, no adverse effects were observed (van Veenendaal et al, 2013). Yet, PTU-treated embryos manifested heterotaxy defects, and PTU was shown to directly adversely affect ciliary movement (van Veenendaal et al, 2013).…”

“…More recently, we observed that administration of PTU during organogenesis caused delayed neural tube closure in E10.5 murine embryos, but these defects were not seen at the end of gestation (Benavides et al., ). In frog embryos, very early exposure to PTU results in heterotaxy defects (van Veenendaal et al., ). Despite widespread ATD use in pregnancy, formal studies of teratogenicity, similar to those required by the U.S. Food and Drug Administration (ICH S5(R2)), have yet to be performed (Wise, ).…”

THERAPY OF ENDOCRINE DISEASE: Antithyroid drug use in early pregnancy and birth defects: time windows of relative safety and high risk?

“…Still, some studies have been negative (16,17), and until recently, the additional risk of birth defects after early pregnancy use of MMI/CMZ was considered to be very low (2,3). PTU was considered not to be teratogenic (2,3), even if some non-human studies were positive (18,19). However, two recent large controlled studies have shown that the risk is not negligible (10,11).…”

A changing signaling environment induces multiciliated cell trans-differentiation during developmental remodeling

“…acetyl]-L-al-anyl-2-phenyl]glycine-1,1-dimethylethyl ester; Sigma-Aldrich #05942) was dissolved in DMSO and used at 100-200M (Myers et al, 2014). PTU (Propylthiouracil; Sigma-Aldrich #1578000; 10mM stock stored at -80°C for long term and -20°C for short term) was dissolved in Ultrapure water (ThermoFisher #10977035) and used at 1mM (Veenendaal et al, 2013). Rapamycin (Sigma-Aldrich #37094) was dissolved in DMSO and used at 100nM.…”