The potential application of microRNAs in regulatory reproductive toxicology
Public Health, England
Dr Marczylo began with a description of microRNAs (miRNAs) ― a family of endogenous short (18-22 nt), single-stranded, non-coding RNA species that regulate gene expression at the post-transcriptional level (predominantly via mRNA degradation or the inhibition of mRNA translation). They are important in fine tuning gene expression in a wide variety of cellular functions including proliferation, differentiation and development, and have been shown to be involved in both toxicity and disease. Recent evidence has also implicated miRNAs in the transmission of altered phenotypes across generations through the male germline. As such miRNAs can be classed as epigenetic mediators that play critical roles in developmental and reproductive toxicology.
Dr Marczylo then went on to introduce miRNAs as epigenetic regulators of the mammalian life cycle and potential environmentally-induced toxicity. She described ongoing work in Public Health England on human spermatozoa and primordial germ cell models investigating the roles of miRNAs in epigenetic toxicity, indicating applicability to regulatory assessment.
Finally, she discussed some of the issues and next steps, including initiatives currently in development within Public Health England, to help guide and drive the integration of epigenetics into regulatory toxicology. For example, next steps for moving forward with alternatives to in vivo models include: understanding / characterising variance in epigenetic responses to changes in the normal environment (what is normal?); assessment of stability and reproducibility; development of cost-effective assays with appropriate quality controls, possible potential for higher throughput and extrapolation to humans and human phenotypic endpoints. With regards to the bigger picture and the relevance of epigenetics to public health, Dr Marczylo explained the need to relate molecular initiating events (including epigenetic endpoints) to actual human disease outcomes and help identify knowledge gaps to guide epigenetic technical guideline development.