Imaoka S et al. (2007), Bisphenol A causes malformation of the head reg...

XB-ART-35278

Biol Pharm Bull 2007 Feb 01;302:371-4. doi: 10.1248/bpb.30.371.

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Bisphenol A causes malformation of the head region in embryos of Xenopus laevis and decreases the expression of the ESR-1 gene mediated by Notch signaling.

Imaoka S , Mori T , Kinoshita T .

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Bisphenol A (BpA) is widely used in industry and dentistry. Its effects on the embryonic development of Xenopus laevis were investigated. Xenopus embryos at stage 10.5 were treated with BpA. Developmental abnormalities were observed at stage 35; malformation of the head region including eyes and scoliosis. The expression of several markers of embryonic development was investigated by reverse transcription-polymerase chain reaction (RT-PCR). The pan-neural marker SOX-2, the neural stem cell marker nrp-1, the mesodermal marker MyoD, and the endodermal marker sox17alpha, were used. Although the expression of marker genes was not changed by treatment with BpA, that of Pax-6, a key regulator of the morphogenesis of the eyes, was decreased by BpA. Pax-6 is a downstream factor of Notch signaling. So, the expression of a typical Notch-dependent factor, ESR-1, was investigated in the presence of BpA. The expression of ESR-1 was efficiently suppressed by BpA. In whole mount in situ hybridization (WISH), Pax-6 was expressed in the central nervous system and eyes. The expression was lost completely on treatment with BpA. The expression of ESR-1 in the central nervous system and eyes also disappeared with BpA treatment. Injection of the intracellular domain of Notch efficiently recovered ESR-1 expression in the presence of BpA although injection of a ligand for notch, Delta, did not. These results suggest that BpA decreased the expression of ESR-1 by disrupting the Notch signal.

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Species referenced: Xenopus laevis
Genes referenced: hes5 pax6 sox2

Phenotypes: Xla wt + Bisphenol A [100uM] (Fig. 3 ) [+]

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	Fig. 1. Embryos exposed to BpA, at Stage 35. Embryos at stage 10.5 were treated with 25 or 50 uM BpA.
	Fig. 2. Expression of Marker Genes Treated with BpA Embryos at stage 10.5 were treated with 50 or 100uM BpA. Total RNA was isolated from whole embryos at stage 28. RT-PCR was done with total RNA. Relative expression levels were measured from the intensity of bands. Values were normalized by dividing by the intensity of the band for b-actin or histone H4. The values of control embryos were set at 100%. The columns indicate mean values and error bars indicate the standard deviation calculated from three different experiments. ∗ p􏰃0.01, significantly different from the control with Student’s t-test.
	Fig. 3. Expression of Pax-6 and ESR-1 in Embryos Treated with BpA. Embryos at stage 10.5 were treated with 50 or 100mM BpA. Total RNA was isolated from embryos at stage 28 and subjected to RT-PCR. The spatial expression of genes was also analyzed with embryos at stage 28 by whole mount in situ hybridization. Values were normalized by dividing by the intensity of the band for histone H4. The values of control embryos were set at 100%. The columns indicate mean values and error bars indicate standard deviation calculated from three different experiments. ∗ p􏰃0.01, significantly different from the control by Student’s t-test.
	Fig. 4. Effects of Delta and NICD on the Expression of ESR-1 in Embryos Delta or NICD mRNA (2 ng each) was injected into control embryos and embryos which were treated with 100mM BpA. The embryos were subjected to whole mount in situ hybridization. The expression of ESR-1 in the BpA-treated embryos was also detected by RT-PCR.