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Phenytoin teratogenicity: hypoxia marker and effects on embryonic heart rhythm suggest an hERG-related mechanism.
Birth Defects Res A Clin Mol Teratol. 2005 Mar; 73(3):146-53.BD

Abstract

BACKGROUND

The antiepileptic drug phenytoin (PHT) is a human and animal teratogen. The teratogenicity has been linked to PHT-induced embryonic cardiac arrhythmia and hypoxic damage during a period when regulation of embryonic heart rhythm is highly dependent on a specific K(+) ion current (I(Kr)). PHT has been shown to inhibit I(Kr). The aims of this study were to investigate whether teratogenic doses cause embryonic hypoxia during and after the I(Kr) susceptible period and to further characterize PHT effects on embryonic heart rhythm.

METHODS

Pregnant C57BL mice were administered the hypoxia marker pimonidazole followed by PHT or saline (controls) on GD 10 or GD 15. The embryos were fixed and sectioned, and the immunostained sections were analyzed with a computer assisted image analysis. Effects of PHT (0-250 microM) on heart rhythm in GD 10 embryos cultured in vitro were videotaped and then analyzed by using a digitalization technique.

RESULTS

PHT dose-dependently increased the hypoxia staining (6- and 11-fold after maternal dosing of 100 and 150 mg/kg, respectively) during the period I(Kr) is expressed and functional (GD 10). In contrast, there were no differences between the PHT doses in hypoxia staining, and much less pronounced hypoxia after this period (GD 15). With increasing PHT concentrations, increased length of the interval (bradycardia) and large variations in length between individual heartbeats (arrhythmia) were recorded.

CONCLUSIONS

PHT induced bradycardia/arrhythmia and severe embryonic hypoxia during the I(Kr) susceptible period, supporting the idea of an I(Kr)-arrhythmia-hypoxia-related teratogenic mechanism.

Authors+Show Affiliations

Department of Pharmaceutical Biosciences, Division of Toxicology, Uppsala University, S-751 24 Uppsala, Sweden. Bengt.Danielsson@mpa.seNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

15744730

Citation

Danielsson, Bengt R., et al. "Phenytoin Teratogenicity: Hypoxia Marker and Effects On Embryonic Heart Rhythm Suggest an hERG-related Mechanism." Birth Defects Research. Part A, Clinical and Molecular Teratology, vol. 73, no. 3, 2005, pp. 146-53.
Danielsson BR, Johansson A, Danielsson C, et al. Phenytoin teratogenicity: hypoxia marker and effects on embryonic heart rhythm suggest an hERG-related mechanism. Birth Defects Res Part A Clin Mol Teratol. 2005;73(3):146-53.
Danielsson, B. R., Johansson, A., Danielsson, C., Azarbayjani, F., Blomgren, B., & Sköld, A. C. (2005). Phenytoin teratogenicity: hypoxia marker and effects on embryonic heart rhythm suggest an hERG-related mechanism. Birth Defects Research. Part A, Clinical and Molecular Teratology, 73(3), 146-53.
Danielsson BR, et al. Phenytoin Teratogenicity: Hypoxia Marker and Effects On Embryonic Heart Rhythm Suggest an hERG-related Mechanism. Birth Defects Res Part A Clin Mol Teratol. 2005;73(3):146-53. PubMed PMID: 15744730.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Phenytoin teratogenicity: hypoxia marker and effects on embryonic heart rhythm suggest an hERG-related mechanism. AU - Danielsson,Bengt R, AU - Johansson,Alf, AU - Danielsson,Christian, AU - Azarbayjani,Faranak, AU - Blomgren,Bo, AU - Sköld,Anna-Carin, PY - 2005/3/4/pubmed PY - 2005/8/24/medline PY - 2005/3/4/entrez SP - 146 EP - 53 JF - Birth defects research. Part A, Clinical and molecular teratology JO - Birth Defects Res. Part A Clin. Mol. Teratol. VL - 73 IS - 3 N2 - BACKGROUND: The antiepileptic drug phenytoin (PHT) is a human and animal teratogen. The teratogenicity has been linked to PHT-induced embryonic cardiac arrhythmia and hypoxic damage during a period when regulation of embryonic heart rhythm is highly dependent on a specific K(+) ion current (I(Kr)). PHT has been shown to inhibit I(Kr). The aims of this study were to investigate whether teratogenic doses cause embryonic hypoxia during and after the I(Kr) susceptible period and to further characterize PHT effects on embryonic heart rhythm. METHODS: Pregnant C57BL mice were administered the hypoxia marker pimonidazole followed by PHT or saline (controls) on GD 10 or GD 15. The embryos were fixed and sectioned, and the immunostained sections were analyzed with a computer assisted image analysis. Effects of PHT (0-250 microM) on heart rhythm in GD 10 embryos cultured in vitro were videotaped and then analyzed by using a digitalization technique. RESULTS: PHT dose-dependently increased the hypoxia staining (6- and 11-fold after maternal dosing of 100 and 150 mg/kg, respectively) during the period I(Kr) is expressed and functional (GD 10). In contrast, there were no differences between the PHT doses in hypoxia staining, and much less pronounced hypoxia after this period (GD 15). With increasing PHT concentrations, increased length of the interval (bradycardia) and large variations in length between individual heartbeats (arrhythmia) were recorded. CONCLUSIONS: PHT induced bradycardia/arrhythmia and severe embryonic hypoxia during the I(Kr) susceptible period, supporting the idea of an I(Kr)-arrhythmia-hypoxia-related teratogenic mechanism. SN - 1542-0752 UR - https://www.unboundmedicine.com/medline/citation/15744730/Phenytoin_teratogenicity:_hypoxia_marker_and_effects_on_embryonic_heart_rhythm_suggest_an_hERG_related_mechanism_ L2 - https://doi.org/10.1002/bdra.20124 DB - PRIME DP - Unbound Medicine ER -