PMID- 26375719
OWN - NLM
STAT- MEDLINE
DCOM- 20160208
LR  - 20151031
IS  - 1096-0333 (Electronic)
IS  - 0041-008X (Linking)
VI  - 289
IP  - 1
DP  - 2015 Nov 15
TI  - Dimethadione embryotoxicity in the rat is neither correlated with maternal 
      systemic drug concentrations nor embryonic tissue levels.
PG  - 89-97
LID - S0041-008X(15)30079-X [pii]
LID - 10.1016/j.taap.2015.09.005 [doi]
AB  - Pregnant rats treated with dimethadione (DMO), the N-demethylated metabolite of 
      the anticonvulsant trimethadione, produce offspring having a 74% incidence of 
      congenital heart defects (CHD); however, the incidence of CHD has high 
      inter-litter variability (40-100%) that presents a challenge when studying the 
      initiating events prior to the presentation of an abnormal phenotype. We 
      hypothesized that the variability in CHD incidence was the result of differences 
      in maternal systemic concentrations or embryonic tissue concentrations of DMO. To 
      test this hypothesis, dams were administered 300 mg/kg DMO every 12h from the 
      evening of gestational day (GD) 8 until the morning of GD 11 (six total doses). 
      Maternal serum levels of DMO were assessed on GD 11, 12, 13, 14, 15, 18 and 21. 
      Embryonic tissue concentrations of DMO were assessed on GD 11, 12, 13 and 14. In 
      a separate cohort of GD 12 embryos, DMO concentrations and parameters of growth 
      and development were assessed to determine if tissue levels of DMO were 
      correlated with these endpoints. Embryos were exposed directly to different 
      concentrations of DMO with whole embryo culture (WEC) and their growth and 
      development assessed. Key findings were that neither maternal systemic 
      concentrations nor tissue concentrations of DMO identified embryos that were 
      sensitive or resistant to DMO in vivo. Direct exposure of embryos to DMO via WEC 
      also failed to show correlations between embryonic concentrations of DMO with 
      developmental outcomes in vitro. We conclude that neither maternal serum nor 
      embryonic tissue concentrations of DMO predict embryonic outcome.
CI  - Copyright (c) 2015 Elsevier Inc. All rights reserved.
FAU - Ozolins, Terence R S
AU  - Ozolins TR
AD  - Department of Biomedical and Molecular Sciences, Program in Pharmacology and 
      Toxicology, Queen's University, Botterell Hall, Kingston, ON K7L 3N6, Canada. 
      Electronic address: ozolinst@queensu.ca.
FAU - Weston, Andrea D
AU  - Weston AD
AD  - Currently at Applied Biotechnology/Lead Discovery, Bristol-Myers Squibb, 5 
      Research Pkwy Wallingford, CT 06492-1996, USA.
FAU - Perretta, Anthony
AU  - Perretta A
AD  - Currently at Pfizer Research and Development, Eastern Point Road, Groton, CT 
      06340, USA.
FAU - Thomson, Jason J
AU  - Thomson JJ
AD  - Currently at Yale Stem Cell Center, Yale School of Medicine, PO Box 208073, New 
      Haven, CT 06520-8073, USA.
FAU - Brown, Nigel A
AU  - Brown NA
AD  - Division of Basic Medical Sciences, St. George's University of London, UK SW17 
      0RE.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150913
PL  - United States
TA  - Toxicol Appl Pharmacol
JT  - Toxicology and applied pharmacology
JID - 0416575
RN  - 0 (Anticonvulsants)
RN  - ALU9NPM703 (Dimethadione)
RN  - R7GV3H6FQ4 (Trimethadione)
SB  - IM
MH  - Animals
MH  - Anticonvulsants/toxicity
MH  - Dimethadione/blood/*toxicity
MH  - Dose-Response Relationship, Drug
MH  - Embryo Culture Techniques
MH  - Embryo, Mammalian/*drug effects
MH  - Embryonic Development/*drug effects
MH  - Female
MH  - Gestational Age
MH  - Pregnancy
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Trimethadione/toxicity
OTO - NOTNLM
OT  - Cardiac defects
OT  - Dimethadione
OT  - Pharmacokinetics
OT  - Teratogens
OT  - Ventricular septation defect
OT  - Whole embryo culture
EDAT- 2015/09/17 06:00
MHDA- 2016/02/09 06:00
CRDT- 2015/09/17 06:00
PHST- 2015/06/01 00:00 [received]
PHST- 2015/08/09 00:00 [revised]
PHST- 2015/09/07 00:00 [accepted]
PHST- 2015/09/17 06:00 [entrez]
PHST- 2015/09/17 06:00 [pubmed]
PHST- 2016/02/09 06:00 [medline]
AID - S0041-008X(15)30079-X [pii]
AID - 10.1016/j.taap.2015.09.005 [doi]
PST - ppublish
SO  - Toxicol Appl Pharmacol. 2015 Nov 15;289(1):89-97. doi: 
      10.1016/j.taap.2015.09.005. Epub 2015 Sep 13.