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TERATOGENIC RESPONSES ARE MODULATED IN MICE LACKING EXPRESSION OF EPIDERMAL GROWTH FACTOR (EGF) AND TRANSFORMING GROWTH FACTOR-ALPHA (TGF)
Citation:
Abbott, B D., D S. Best, AND M G. Narotsky. TERATOGENIC RESPONSES ARE MODULATED IN MICE LACKING EXPRESSION OF EPIDERMAL GROWTH FACTOR (EGF) AND TRANSFORMING GROWTH FACTOR-ALPHA (TGF). Presented at Society of Toxicology, Baltimore, MD, March 21-25, 2004.
Description:
TITLE:
TERATOGENIC RESPONSES ARE MODULATED IN MICE LACKING EXPRESSION OF EPIDERMAL GROWTH FACTOR (EGF) AND TRANSFORMING GROWTH FACTOR-ALPHA (TGF). AUTHORS (ALL): Abbott, Barbara D.1; Best, Deborah S.1; Narotsky, Michael G.1. SPONSOR NAME: None INSTITUTIONS (ALL): 1. Repro Tox Div, US EPA, RTP, NC, USA.
ABSTRACT BODY:
EGF and TGF regulate proliferation and differentiation in the embryo. EGF appears to mediate teratogenic responses, as the incidence of cleft palate (CP) is reduced and the severity and incidence of hydronephrosis are increased in EGF knockout (KO) mice after exposure to TCDD on gestation day (GD)12. Similarly, EGF KO mice have a lower incidence of CP after GD-12 exposure to retinioc acid (RA), whereas TGF KO mice show an increased incidence of CP after GD10 exposure. In the present study, pregnant C57BL/6J and TGF KO mice were exposed to a single oral dose of RA (100 mg/kg, 10 ml/kg) or vehicle on GD10, and wild type (WT) and EGF KO mice were exposed on GD12. GD18 fetuses were examined for external and visceral alterations. TGF KO mice and EGF KO mice had increased incidences of dilation of the renal pelvis compared to mice of background genotype; however, treatment of KO mice with RA significantly reduced the incidences of this defect compared to vehicle-treated KO mice. RA exposure produced effects on limb and heart development, however the incidence of specific limb defects was influenced by the developmental stage as well as the expression of EGF or TGF. After GD10 RA exposure, the incidence of forelimb digital and long-bone defects was significantly higher in TGF KO compared to C57BL/6J fetuses. Also, micrognathia, hindlimb digital deficits, and oligodactyly (fore and hind limbs) were only observed in the RA-treated TGF KO. RA exposure on GD12 of WT and EGF KO produced forelimb brachy-/oligodactyly and long-bone reduction of fore and hind limbs. However, the EGF KO was significantly more susceptible to digital deficits of the hind limb. In summary, in the developing limbs, the teratogenic effects of RA were influenced by developmental stage and responses were exacerbated in the absence of EGF and TGF expression. This study provides further evidence that the EGF pathway mediates responses to teratogens and that the influence depends on developmental stage and the target tissue. This abstract does not necessarily reflect EPA policy.