US EPA

2198931 

Journal Article 

Abstract 

The utility of large-scale insertional mutagenesis screens to identify and disrupt novel PCB-induced genes in mouse embryonic stem (ES) cells 

Brzezicki, JM; Legare, ME; Hanneman, WH 

2004 

1 

NeuroToxicology
ISSN: 0161-813X
EISSN: 1872-9711 

25 

4 

696-696 

English 

http://www.sciencedirect.com/science/article/pii/S0161813X04000385
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is part of a larger document 2161630 NTX XXI Conference Abstracts: Infant and child neurotoxicity studies: Subtle and long-term effects. Focusing on methylmercury, PCBs, heptachlor and other persistent pollutants

Polychlorinated biphenyls (PCBs) are industrial chemicals which have been identified in fish, wildlife and humans. Recently, PCBs have been the focus of extensive toxicological studies and serious public debate with much attention focusing on the potential for adverse effects on the developing Central Nervous System (CNS). In light of this attention, numerous behavioral studies have been conducted in primates and in rodents exposed in utero to PCBs all of which indicate that developmental exposure can cause persistent cognitive deficits. While these studies report the neurobehavioral effects in offspring exposed in utero, no overt pathology or persistent neurochemical changes have ever been detected. Thus, the current dogma is that PCB-induced cognitive deficits reflect subtle neuronal organizational defects in the developing brain. However, to date, no common mechanisms or molecular pathways have been elucidated that can explain these potential organizational defects. Therefore, a mechanistic understanding of the effects of PCBs on the genes that control neurodevelopment is highly relevant to further our understanding of the observed neurobehavioral changes seen in humans and rodents. Towards this goal, the objectives of this study were to identify critical PCB regulated developmental genes in the rodent brain. We have developed an experimental strategy that simultaneously identifies PCB-inducible genes, mutates them, tags them with a reporter molecule, and enables the production of knockout animals carrying the induced mutations. This process has been termed "gene-trapping." The power of this technology is the ability to discover novel genes responsive to a particular chemical, rather than testing the responsiveness of a known gene. Within the scope of this research, we have conducted the molecular and functional characterization of several of these genes in cells and animals. 

21st International Neurotoxicology Conference 

Honolulu, HI 

February 10-14, 2004