Methanol exposure during gastrulation causes holoprosencephaly, facial dysgenesis, and cervical vertebral malformations in C57BL/6J mice.
BACKGROUND
Exposure of pregnant outbred CD-1 mice to methanol during the period of gastrulation results in exencephaly, cleft palate, and cervical vertebra malformations [Rogers and Mole, Teratology 55: 364, 1997], while inbred C57BL/6J mice are sensitive to the teratogenicity of ethanol. C57BL/6J fetuses exhibit the holoprosencephaly spectrum of malformations after maternal exposure to ethanol during gastrulation, but the sensitivity of C57BL/6J mice to methanol-induced teratogenesis has not been previously described.


METHODS
Pregnant C57BL/6J mice were administered two i.p. injections totaling 3.4 or 4.9 g/kg methanol or distilled water four hrs apart on gestation day 'GD' 7. On GD 17, litters were examined for numbers of live, dead and resorbed conceptuses, fetuses were weighed as a litter and examined externally, and all fetuses were double stained for skeletal analysis.


RESULTS
No maternal intoxication was apparent, but the high dosage level caused a transient deficit in maternal weight gain. The number of live fetuses per litter was reduced at both dosages of methanol, and fetal weight was lower in the high dosage group. Craniofacial defects were observed in 55.8% of fetuses in the low dosage group and 91.0% of fetuses in the high dosage group, including micro/anophthalmia, holoprosencephaly, facial clefts and gross facial angenesis. Skeletal malformations, particularly of the cervical vertebrae, were observed at both dosages of methanol, and were similar to those previously reported in the CD-1 mouse following methanol exposure.


CONCLUSIONS
The types of craniofacial malformations induced in the C57BL/6J mouse by methanol indicate that methanol and ethanol have common targets and may have common modes of action.
Rogers
John M
JM
Reproductive Toxicology Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, United States Environmental Protection Agency, Research Triangle Park, North Carolina 27711, USA. rogers.john@epa.gov
Brannen
Kimberly C
KC
Barbee
Brenda D
BD
Zucker
Robert M
RM
Degitz
Sigmund J
SJ
D000014:Abnormalities, Drug-Induced; D000015:Abnormalities, Multiple / Q000139:chemically induced*; D000818:Animals; D001846:Bone Development; D002574:Cervical Vertebrae / Q000187:drug effects*; D047108:Embryonic Development / Q000187:drug effects*; D000431:Ethanol / Q000633:toxicity; D005260:Female; D005775:Gastrula / Q000187:drug effects*; D016142:Holoprosencephaly / Q000139:chemically induced*; D018398:Homeodomain Proteins / Q000096:biosynthesis; D017403:In Situ Hybridization; D018811:Maternal Exposure; D008445:Maxillofacial Development / Q000187:drug effects*; D000432:Methanol / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D009056:Mouth Abnormalities / Q000139:chemically induced*; D011247:Pregnancy; D011270:Pregnancy, Animal; D013045:Species Specificity; D013723:Teratogens; D013997:Time Factors
C080330:En1 protein, mouse; C101121:HOXB1 homeodomain protein; D018398:Homeodomain Proteins; D013723:Teratogens; D000431:Ethanol; D000432:Methanol