In addition to the often described action of NP as estrogen like substances it was possible to demonstrate that some NP have the potential to induce tail-malformation in fish embryos. The observed tail malformation seen in our experiments may be due to miss-migration of precursor cells of the mesoderm in early development. The correct migration is a prerequisite of normal development 34 The various spinal malformations induced by NP isomers underline the different effects and possible modes of action known for NP isomers. p353-NP showed a unique morphological alteration: A broadened tail tip. This deformity might be related to the tbx6 expression as discussed below.

To investigate gene expression pattern of the tbx6/16 family in zebrafish embryos it is necessary to study the role of the housekeeping genes which might be regulated depending on developmental stage and/or treatment of the organism 35. Data showed found that the often used expression of housekeeping gene B-actin gene is not suitable in experiments using NP. 36 previously demonstrated that the B-actin gene is upregulated by estrogens, interestingly a down regulation was found in the two antiestrogenic NP isomers (p22-NP and p262-NP)(Figure 2a). The partial estrogenic isomers show quantitative down regulation. This gene expression pattern, in line with the known mode of action for the isomers, indicates that at the selected time point gene expression react already to NP exposure. It was decided to use the average expression of two genes, i.e. efla gene and rp}13a gene, to normalize our data. An effect of NP on two other housekeeping genes (ef1a, rp}13a) used in our study was not observed, although chemical regulation of ef1a gene was reported when incubation was prolonged over 96 hr 37. The short incubation time of 1 hr in our study is probably the reason for our different observations.

Although the variation of the measure expression within the groups is not small, the correlation between the measured values for spt gene and nt} gene is remarkable high. This indicates that the observed variation is not due to experimental conditions but to different stages in development of the used embryos. However, the effects of different isomers of NP on the expression of transcription factors of the T-Box family in zebrafish embryos presented here shows that the increased expression of tbx6 gene was associated with the malformation of the tail produced by p353-NP 23. A numerical increase in tbx6 gene expression was also observable by using t-NP. This rise is only 1/10 of the increase observed with p353-NP (Fig 3c). The main components of t-NP are two diasteromeric forms of p353-NP with combined concentrations between 12.2 and 20% ’ ” . Given that still several of the components of t-NP are not identified so far, and that some isomers of NP act estrogenically while other act antiestrogenically 19 the expression of tbx6 gene as reaction of incubation the zebrafish embryos with t-NP is probably due to the p353-NP present in t-NP. The other genes belonging to the T-box6/16 subfamily (spt, ntl) are not fundamentally regulated by p353-NP within the incubation time of 1hr (Figure 3a,b). However, it needs to be emphasized that these observations are not a proof for a cause effect relationship, which further experiments may provide.

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