Blocking key gene in fish may reduce smoke toxicity effect

Blocking the production of a key receptor may reduce the effects of particulate matter from cigarette smoke in zebrafish embryos, a study has found.

The effects of this toxicity which include malformed blood vessels and brain hemorrhages may affect early development in zebrafish embryos and increases the risk of neurological disorders and physical deformities.

Zebrafish are a widely used as model species for studying human genetics and disease.

The researchers injected early-stage zebrafish embryos with a molecule to block a specific gene's activity and prevented the production of the aryl hydrocarbon receptor 2 (AHR2). This disrupted the metabolic pathway thought to play an important role in cigarette smoke toxicity.

"The knockdown resulted in a significant reduction in the incidence of deformities in the modified embryos. Deformities still occurred, but far less frequently than in embryos without the modification," said Andrey Massarsky, Researcher at the Duke's Nicholas School of the Environment in Durham, US.

Initially, Massarsky and his colleagues hypothesised that their knockdown of the AHR2 receptor worked because it concurrently blocked the expression of the two main enzymes - cytochrome P450 1A (CYP1A) and cytochrome P450 1B1 (CYP1B1) - involved with PAH metabolism.

But subsequent experiments, in which these enzymes were each knocked down, suggested that there was more to it.

"We found that deformities were actually exacerbated when CYP1A and CYP1B1 were blocked. This shows that, if anything, these enzymes play a protective role. To some extent, they help prevent the deformities from occurring," Massarsky added in the study published in the journal Toxicology and Applied Pharmacology.

These seemingly contradictory findings could be because the CYP1A and CYP1B1 knockdowns may decrease the toxicity of some of the PAHs found in cigarette smoke's total particulate matter, while increasing the toxicity of others.

But it is also possible that turning up the AHR2 pathway interferes with other biochemical signalling pathways. For example, recent studies show that activation of the AHR2 pathway may in fact inhibit the proper operation of pathways that pass signals into a cell through cell surface receptors.

These pathways are critical to early embryonic development, particularly the formation of bone, heart and muscle tissues.