Intoxication by dioxins such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) leads, among other damages, to early embryo loss, fetal malformations and cardiovascular toxicity. Apart from binding to the arylhydrocarbon receptor (AhR) the mechanism of TCDD-mediated embryo toxicity is still unclear. We investigated possible modes of a TCDD-mediated toxicity, particularly in glucose metabolism, in pluripotent P19 mouse embryonic carcinoma cells (ECC). Undifferentiated P19 cells were exposed to 1 to 100 nM TCDD and characterized for AhR signaling. For studying cell differentiation P19 cells were exposed to 10 nM TCDD at stage of embryoid body (EB) formation and analyzed on glucose metabolism and cardiac differentiation during the next 3 weeks.

TCDD treatment activated the AhR-signaling cascade within 1 hour, confirmed by AhR translocation, induction of CYP1A1 expression and activation of the xenobiotic response element. Although cell viability and transcription of the cardiac marker protein alpha-MHC were affected, TCDD did not inhibit the differentiation of P19 cells to pulsating cardiomyocytes. TCDD significantly downregulated the expression levels of the glucose transporter isoforms (GLUT) 1 and 3. After 24 hours of TCDD treatment GLUT1 was no longer localized in the plasma membrane of P19 cells. The impaired GLUT expression correlated with a lower glucose uptake in 5 day-old EBs. The TCDD effects were mediated by AhR as shown by pre-culture with the AhR antagonist -naphthoflavone. Our data demonstrate that an AhR-mediated disturbance in GLUT expression and insufficient glucose uptake may be major mechanisms in TCDD embryo toxicity.