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      Propylthiouracil Is Teratogenic in Murine Embryos

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          Abstract

          Background

          Hyperthyroidism during pregnancy is treated with the antithyroid drugs (ATD) propylthiouracil (PTU) and methimazole (MMI). PTU currently is recommended as the drug of choice during early pregnancy. Yet, despite widespread ATD use in pregnancy, formal studies of ATD teratogenic effects have not been performed.

          Methods

          We examined the teratogenic effects of PTU and MMI during embryogenesis in mice. To span different periods of embryogenesis, dams were treated with compounds or vehicle daily from embryonic day (E) 7.5 to 9.5 or from E3.5 to E7.5. Embryos were examined for gross malformations at E10.5 or E18.5 followed by histological and micro-CT analysis. Influences of PTU on gene expression levels were examined by RNA microarray analysis.

          Results

          When dams were treated from E7.5 to E9.5 with PTU, neural tube and cardiac abnormalities were observed at E10.5. Cranial neural tube defects were significantly more common among the PTU-exposed embryos than those exposed to MMI or vehicle. Blood in the pericardial sac, which is a feature indicative of abnormal cardiac function and/or abnormal vasculature, was observed more frequently in PTU-treated than MMI-treated or vehicle-treated embryos. Following PTU treatment, a total of 134 differentially expressed genes were identified. Disrupted genetic pathways were those associated with cytoskeleton remodeling and keratin filaments. At E 18.5, no gross malformations were evident in either ATD group, but the number of viable PTU embryos per dam at E18.5 was significantly lower from those at E10.5, indicating loss of malformed embryos. These data show that PTU exposure during embryogenesis is associated with delayed neural tube closure and cardiac abnormalities. In contrast, we did not observe structural or cardiac defects associated with MMI exposure except at the higher dose. We find that PTU exposure during embryogenesis is associated with fetal loss. These observations suggest that PTU has teratogenic potential.

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          Most cited references53

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          Antithyroid drugs.

          David Cooper (2005)
          Article 0 comments Cited 216 times – based on 0 reviews     Review now
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            Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society Clinical Practice Guideline.

            Jack Mandel, J Boo, Daniel Glinoer … (2007)
            The objective is to provide clinical guidelines for the management of thyroid problems present during pregnancy and in the postpartum. The Chair was selected by the Clinical Guidelines Subcommittee (CGS) of The Endocrine Society. The Chair requested participation by the Latin American Thyroid Society, the Asia and Oceania Thyroid Society, the American Thyroid Association, the European Thyroid Association, and the American Association of Clinical Endocrinologists, and each organization appointed a member to the task force. Two members of The Endocrine Society were also asked to participate. The group worked on the guidelines for 2 yr and held two meetings. There was no corporate funding, and no members received remuneration. Applicable published and peer-reviewed literature of the last two decades was reviewed, with a concentration on original investigations. The grading of evidence was done using the United States Preventive Services Task Force system and, where possible, the GRADE system. Consensus was achieved through conference calls, two group meetings, and exchange of many drafts by E-mail. The manuscript was reviewed concurrently by the Society's CGS, Clinical Affairs Committee, members of The Endocrine Society, and members of each of the collaborating societies. Many valuable suggestions were received and incorporated into the final document. Each of the societies endorsed the guidelines. Management of thyroid diseases during pregnancy requires special considerations because pregnancy induces major changes in thyroid function, and maternal thyroid disease can have adverse effects on the pregnancy and the fetus. Care requires coordination among several healthcare professionals. Avoiding maternal (and fetal) hypothyroidism is of major importance because of potential damage to fetal neural development, an increased incidence of miscarriage, and preterm delivery. Maternal hyperthyroidism and its treatment may be accompanied by coincident problems in fetal thyroid function. Autoimmune thyroid disease is associated with both increased rates of miscarriage, for which the appropriate medical response is uncertain at this time, and postpartum thyroiditis. Fine-needle aspiration cytology should be performed for dominant thyroid nodules discovered in pregnancy. Radioactive isotopes must be avoided during pregnancy and lactation. Universal screening of pregnant women for thyroid disease is not yet supported by adequate studies, but case finding targeted to specific groups of patients who are at increased risk is strongly supported.
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              Hyperthyroidism.

              B. D. Cooper (2003)
              Hyperthyroidism is a pathological syndrome in which tissue is exposed to excessive amounts of circulating thyroid hormone. The most common cause of this syndrome is Graves' disease, followed by toxic multinodular goitre, and solitary hyperfunctioning nodules. Autoimmune postpartum and subacute thyroiditis, tumours that secrete thyrotropin, and drug-induced thyroid dysfunction, are also important causes. The diagnosis of hyperthyroidism is generally straightforward, with raised serum thyroid hormones and suppressed serum thyrotropin in almost all cases. Appropriate treatment of hyperthyroidism relies on identification of the underlying cause. Antithyroid drugs, radioactive iodine, and surgery are the traditional treatments for the three common forms of hyperthyroidism. Beta-adrenergic blocking agents are used in most patients for symptomatic relief, and might be the only treatment needed for thyroiditis, which is transient. The more unusual causes of hyperthyroidism, including struma ovarii, thyrotropin-secreting tumours, choriocarcinoma, and amiodarone-induced thyrotoxicosis are, more often than not, a challenge to diagnose and treat.
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                Author and article information

                Contributors
                : Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, USA )
                ISSN (Electronic): 1932-6203
                Publication date Collection: 2012
                Publication date (Electronic): 18 April 2012
                Volume: 7
                Issue: 4
                Electronic Location Identifier: e35213
                Affiliations
                [1 ]Section of Developmental Endocrinology and Biology, Yale Pediatric Thyroid Center, Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut, United States of America
                [2 ]Section of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut, United States of America
                [3 ]Department of Pediatrics, University of Florida, Gainesville, Florida, United States of America
                Fudan University, China
                Author notes

                Conceived and designed the experiments: VB MM CB CW SAR. Performed the experiments: VB MM CB CW SAR. Analyzed the data: VB MM CB CW SAR. Contributed reagents/materials/analysis tools: VB MM CB CW SAR. Wrote the paper: VB MM CB CW SAR.

                Article
                Publisher ID: PONE-D-11-23016
                DOI: 10.1371/journal.pone.0035213
                PMC ID: 3329451
                PubMed ID: 22529993
                SO-VID: a200f227-8f08-45db-bdfe-0808df075716
                Copyright © Benavides et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                Date received : 21 November 2011
                Date accepted : 12 March 2012
                Page count
                Pages: 8
                Categories
                Subject: Research Article
                Subject: Biology
                Subject: Developmental Biology
                Subject: Morphogenesis
                Subject: Birth Defects
                Subject: Embryology
                Subject: Model Organisms
                Subject: Animal Models
                Subject: Mouse
                Subject: Medicine
                Subject: Drugs and Devices
                Subject: Adverse Reactions
                Subject: Endocrinology
                Subject: Thyroid
                Subject: Graves' Disease
                Subject: Obstetrics and Gynecology
                Subject: Pregnancy

                ScienceOpen disciplines: Uncategorized
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                ScienceOpen disciplines: Uncategorized

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