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ToxSci Advance Access published online on November 4, 2003
Toxicological Sciences, doi:10.1093/toxsci/kfg241
Toxicological Sciences © Society of Toxicology 2003; all rights reserved
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Received July 7, 2003; accepted September 8, 2003
© 2003 Society of Toxicology

Neurotoxicology

Neuro-Developmental Defects in Zebrafish (Danio rerio) at Environmentally Relevant Dioxin (TCDD) Concentrations

Adrian Hill 1*, C. Vyvyan Howard 2, Uwe Strahle 3, and Andrew Cossins 1

1 Laboratory for Environmental Gene Regulation, School of Biological Sciences, Biosciences Building, University of Liverpool, Crown Street, Liverpool, Merseyside L69 7ZB, UK
2 Toxico-Pathology Research Group, Department of Human Anatomy and Cell Biology, Ashton Street Building, University of Liverpool L69 3PX, UK
3 IGBMC BP10142, 1 rue Laurent Fries 67404 Illkirch France

* To whom correspondence should be addressed. E-mail: ajhill{at}pharmacy.wisc.edu.


  Abstract

Persistent ecotoxicants such as dioxin and PCBs are thought to pose one of the greatest threats to public and ecological health in the industrial world. These compounds cause a range of macroscopic malformations particularly to the craniofacial apparatus and cardiovascular system during vertebrate development. However, little is known about microscopic effects especially on the sensitive early life stages, or on the molecular basis of developmental neurotoxicity. Using zebrafish (Danio rerio) we have explored neurological deficits caused by early life exposure to environmentally-relevant concentrations of dioxin. We show using a quantitative stereological technique that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) substantially reduces the capacity for embryonic brain development, causing a 30% reduction in total neuronal number in the 168 h larval brain. Using transgenic GFP-expressing zebrafish lines we link this to decreased expression of key developmentally regulated genes, namely neurogenin and sonic hedgehog. This disruption of neuronal development provides the basis for understanding the neurotoxic effects of these compounds.

Key Words: neurotoxicity, TCDD, zebrafish, embryo, sonic hedgehog, neurogenin .


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