Toxicological Sciences, Vol 47, 62-75, Copyright © 1999 by Society of Toxicology
BD Abbott, GA Held, CR Wood, AR Buckalew, JG Brown and J Schmid
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is developmentally toxic in many
species and induces cleft palate in the C57BL/6N mouse embryo.
Palatogenesis in mouse and human embryos involves homologous processes at
the morphological, cellular, and molecular levels. In organ culture, mouse
and human palates respond similarly to TCDD. The present study quantitates
the expression of AhR, ARNT, and CYP1A1 mRNA in human embryonic palates in
organ culture. Palatal tissues were exposed to 1 x 10(-10), 1 x 10(-9), or
1 x 10(-8) M TCDD or control medium and sampled at 0, 2, 4, and 6 hours for
quantitative RT-PCR using a synthetic RNA internal standard. Similar
measurements of CYP1A1 gene expression were collected for mouse palates
cultured in this model. In human palates, AhR expression correlated with
ARNT and CYP1A1 mRNA expression. TCDD induction of CYP1A1 was time- and
concentration-dependent. The expression of these genes presented a uniform
and continuous distribution across the group of embryos, with no subset of
either high or low expressors/responders. The ratio of AhR to ARNT was
approximately 4:1. AhR mRNA increased during the culture period in both
treated and control subjects; however, ARNT expression was relatively
constant. TCDD did not alter either AhR or ARNT expression in a consistent
dose- or time-related manner. Comparison of human and mouse data showed a
high correlation across species for the induction of CYP1A1. Human embryos
expressed approximately 350 times less AhR mRNA than the mouse, and in
earlier studies it was shown that human palates required 200 times more
TCDD to produce the same effects. When the morphological, cellular, and
molecular responses to TCDD between mouse and human are compared, it seems
highly unlikely that human embryos could be exposed to sufficient TCDD to
achieve changes in palatal differentiation that would lead to cleft palate.
ARTICLES
AhR, ARNT, and CYP1A1 mRNA quantitation in cultured human embryonic palates exposed to TCDD and comparison with mouse palate in vivo and in culture
Reproductive Toxicology Division, National Health Effects and Environmental Research Laboratory, Environmental Protection Agency, Research Triangle Park, North Carolina 27711, USA.
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