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Protein biomarkers for in vitro testing of embryotoxicity.

Abstract：

:There are new challenges for hazard and risk assessment in the chemical industry with regard to REACH legislation in Europe and related activities in the U.S. and Japan, which require the development of novel in vitro models for the molecular characterization of drug- or chemical-related effects replacing conventional animal testing. In the frame of a European FP6 project on reproductive toxicology ( www.reprotect.eu ), we prepared protein samples from mouse embryonic stem cells differentiated into contracting cardiomyocytes according to the validated embryonic stem cell test (EST) protocol, which had been exposed to toxic substances selected by an expert committee from different in vivo categories of embryotoxicity. Lysates were used to carry out the following investigations: (i) identify optimal dose range conditions in the EST that are suitable for (ii) performing a differential quantitative proteomic study of underlying molecular pathways, (iii) define classes of substances with similar proteomic response patterns, (iv) relate these classes to the traditional in vivo categories of embryotoxicity with (v) the final goal to identify novel surrogate protein biomarker candidates for embryo toxicity. We found two distinct classes of toxic substances (Dinoseb, Ochratoxin-A, and Nitrofen vs β-aminoproprionitril, Metoclopramide, Doxylamine succinate, and d-penicillamine) with clear pathway-related differences in their proteomic patterns. Most notably, different responses to cluster 1 and cluster 2 substances were observed for Heat shock protein β-1, Ras-GTPase-activating protein SH3-domain binding protein, Ran binding protein 5, and Calreticulin, Dihydropyrimidinase-like 2 (Ulip2 protein). On the other hand, Heat shock protein 8 and Fscn1 protein were down-regulated by all compounds from both clusters.

journal_name

J Proteome Res

journal_title

Journal of proteome research

authors

Groebe K,Hayess K,Klemm-Manns M,Schwall G,Wozny W,Steemans M,Peters AK,Sastri C,Jaeckel P,Stegmann W,Zengerling H,Schopf R,Poznanovic S,Stummann TC,Seiler A,Spielmann H,Schrattenholz A

doi

10.1021/pr100514e

subject

Has Abstract

pub_date

2010-11-05 00:00:00

pages

5727-38

issue

eissn

1535-3893

issn

1535-3907

journal_volume

pub_type

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Protein biomarkers for in vitro testing of embryotoxicity.