| Summary: | The objective of this work was to explore the environmental modification of the expression
of neural tube defects (NTDs) in SELH/Bc mice. One approach was to examine the potential of
SELH/Bc mice as an animal model for the reduction in recurrence and occurrence rates of NTDs in
women given periconceptional folic acid supplementation. Neither folic acid nor methionine
supplementation produced a detectable reduction of the exencephaly frequency in SELH/Bc mice.
However, the frequency of exencephaly was consistently higher in SELH/Bc dams fed a
chemically-defined Harlan Teklad diet than in SELH/Bc dams fed the standard ration of Purina Lab
Chow. This observation was directly tested. The exencephaly frequency was 7-fold higher on
Harlan Teklad diet than on the Purina Lab Chow diet (21% versus 3%). This finding represents
the first demonstration of the nutritional modification of the expression of NTDs in SELH/Bc mice,
and it affords a unique opportunity to study the mechanism of prevention of exencephaly in the
SELH/Bc mouse model, something that is not possible to examine directly in human studies of
NTDs.
Another approach tested for the presence of a genotype-teratogen interaction of SELH/Bc
mice with valproic acid as an animal model of the effect of genetic liability to NTDs on the liability
to anticonvulsant induced birth defects. The SELH/Bc response to valproic acid treatment was
compared to the response of two inbred strains of mice that rarely have spontaneous exencephaly.
When the data were transformed according to the developmental threshold model with an
underlying normally distributed scale of liability, the response to valproic acid treatment was found
to be additive with the genetic liability. The genetic liability to exencephaly in SELHBc mice
greatly increased the absolute risk after valproic acid treatment. At the peak response time, the
frequency of exencephaly in SELH/Bc mice was 69% compared to 35% and 40% respectively in
SWV/Bc and ICR/Be mice. This observation may have clinical significance for women with a
positive family history of NTDs taking valproic acid during the first trimester of pregnancy.
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