Exposure to a low dose of
2,3,7,8-tetrachlorodibenzo-p-dioxin (
TCDD) results in a variety of toxic manifestations, including
fetal death. In order to evaluate the effects of low dose
TCDD on placental function, pregnant Holtzman rats were given a single oral dose of 1600 ng
TCDD/kg body wt or an equivalent volume of vehicle (control) on gestation day 15 (GD15), and changes in the gene expression in the placenta on GD20 were analyzed by two comprehensive methods, representational difference analysis (RDA) and
DNA microarray technology. Candidates of
TCDD-inducible and -suppressive genes were selected. Quantitative real-time PCR analysis was then performed to verify the induction or suppression levels of the candidate genes. Finally, we identified 81
TCDD-inducible and 21
TCDD-suppressive genes from the placenta of
TCDD-treated Holtzman rats on GD20. One of the remarkable profiles of the gene expression was that
glucose transporters were strongly up-regulated by the
TCDD treatment. Furthermore, many
interferon-inducible genes were also up-regulated by the treatment. They included several
cytokines such as IP-10 known as a potent
angiogenesis inhibitor. In addition,
interferon molecules are known to suppress angiogenesis. The above observations suggest that activation of the
interferon signaling pathway and the induction of anti-angiogenic factors by
TCDD might have a role in causing the inhibition of neovascularization, resulting in the hypoxic state of placenta and increased incidence of
fetal death.