PMID- 25446330
OWN - NLM
STAT- MEDLINE
DCOM- 20150209
LR  - 20151119
IS  - 1879-3185 (Electronic)
IS  - 0300-483X (Linking)
VI  - 326
DP  - 2014 Dec 4
TI  - Maternal rat serum concentrations of dimethadione do not explain intra-litter 
      differences in the incidence of dimethadione-induced birth defects, including 
      novel findings in foetal lung.
PG  - 142-52
LID - S0300-483X(14)00210-8 [pii]
LID - 10.1016/j.tox.2014.10.014 [doi]
AB  - To investigate mechanisms of chemical-induced congenital heart defects (CHD) we 
      have developed a rat model using dimethadione (DMO), the N-demethylated 
      metabolite of the anticonvulsant, trimethadione (TMD). Dosing pregnant rats with 
      300mg/kg DMO every 12h from the evening of gestational day (GD) 8 until the 
      morning of GD 11 (six total doses) produces a mean 74% incidence of CHD with 
      inter litter variability ranging from 40 to 100%. The goal of this study was to 
      determine if the variability in maternal serum concentrations of DMO on GD 14, a 
      surrogate marker for total exposure, was related to the inter-litter differences 
      in teratogenic outcomes. To test this hypothesis, pregnant rats were dosed as 
      described above and serum levels of DMO assessed on GD 14. On GD 21, foetuses 
      were collected by caesarean section, assessed for a number endpoints and the 
      outcomes were correlated with the GD 14 serum concentrations of DMO. DMO exposure 
      was associated with decreased foetal body weight, increased incidence of sternal 
      defects and CHD, but these endpoints were not meaningfully correlated with 
      maternal concentrations of DMO. Novel findings were decreased viability as 
      measured one-hour following caesarean section, and delayed alveolar maturation. 
      The major conclusions from these studies were first, that serum DMO 
      concentrations on GD 14 did not predict teratogenicity, and second, delayed lung 
      development may contribute to the decreased survival of foetuses at the time of 
      caesarean section.
CI  - Copyright (c) 2014 Elsevier Ireland Ltd. All rights reserved.
FAU - Rodger, Ian
AU  - Rodger I
AD  - Faculty of Medicine and Dentistry, University of Alberta, Edmonton AB T6G 2R7, 
      Canada. Electronic address: irodger@ualberta.ca.
FAU - Lam, Isabel
AU  - Lam I
AD  - Department of Biomedical and Molecular Sciences, Queen's University, Kingston ON 
      K7L 3N6, Canada. Electronic address: isabel.lam@queensu.ca.
FAU - Purssell, Elizabeth
AU  - Purssell E
AD  - Faculty of Medicine, The University of British Columbia, Vancouver BC V6 T 1Z3, 
      Canada. Electronic address: elizabeth.purssell@gmail.com.
FAU - Thompson, Mesha
AU  - Thompson M
AD  - Analytical Services Unit, Queen's University, Kingston ON K7L 3N6, Canada. 
      Electronic address: thompson.mesha@queensu.ca.
FAU - Rutter, Allison
AU  - Rutter A
AD  - Analytical Services Unit, Queen's University, Kingston ON K7L 3N6, Canada. 
      Electronic address: ruttera@queensu.ca.
FAU - Ozolins, Terence Rs
AU  - Ozolins TR
AD  - Department of Biomedical and Molecular Sciences, Queen's University, Kingston ON 
      K7L 3N6, Canada. Electronic address: ozolinst@queensu.ca.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20141101
PL  - Ireland
TA  - Toxicology
JT  - Toxicology
JID - 0361055
RN  - 0 (Anticonvulsants)
RN  - 0 (Biomarkers)
RN  - ALU9NPM703 (Dimethadione)
SB  - IM
MH  - Abnormalities, Drug-Induced/blood/*etiology
MH  - Animals
MH  - Anticonvulsants/blood/*toxicity
MH  - Biomarkers/blood
MH  - Dimethadione/blood/*toxicity
MH  - Female
MH  - Fetal Weight/drug effects
MH  - Gestational Age
MH  - Heart Defects, Congenital/blood/*chemically induced
MH  - Maternal Exposure/*adverse effects
MH  - Pregnancy
MH  - Pulmonary Alveoli/*drug effects/embryology/physiopathology
MH  - Rats, Sprague-Dawley
MH  - Sternum/abnormalities/drug effects
OTO - NOTNLM
OT  - Alveolar development
OT  - Anticonvulsant
OT  - Congenital heart defect
OT  - Dimethadione
OT  - Lung
EDAT- 2014/12/03 06:00
MHDA- 2015/02/11 06:00
CRDT- 2014/12/03 06:00
PHST- 2014/08/14 00:00 [received]
PHST- 2014/10/25 00:00 [revised]
PHST- 2014/10/28 00:00 [accepted]
PHST- 2014/12/03 06:00 [entrez]
PHST- 2014/12/03 06:00 [pubmed]
PHST- 2015/02/11 06:00 [medline]
AID - S0300-483X(14)00210-8 [pii]
AID - 10.1016/j.tox.2014.10.014 [doi]
PST - ppublish
SO  - Toxicology. 2014 Dec 4;326:142-52. doi: 10.1016/j.tox.2014.10.014. Epub 2014 Nov 
      1.