Workshop Report 30

Question 1: Epigenetic Design Studies: Relevance to Regulatory Applications?

Moderator:    Miriam Jacobs
Rapporteur:    Jessica LaRocca

The underlying question is: can epigenetics elucidate if/where early life exposures could potentially lead to the onset of disease later in life? Many participants with an experimental in vivo background emphasised that there is a great need to have reliable, reproducible in vivo experimental model substances. The following were suggested as appropriate models where the adverse phenotypic effect of exposure was well documented and the relevant tissues to analyse were well known:
Dexamethasone – known phenotypic effects on both the male and female germ line on fertility and cardiovascular disease.
Phthalates – known male reproductive effects.
Oestrogen exposure – known female only effects on pubertal onset later in life and reproductive effects.
Dioxin – male infertility.
Valproate as a control compound for its known epigenetic modifications: histone deacetylase inhibitor and neural tube defects.
All breakout groups agreed that analysing the methylome will be important to assess persistent changes that could potentially lead to adversity. However, discussion on the benefits of analysing the transcriptome as opposed to focusing on DNA methylation was left without agreement – and a suggestion for further discussion.
Other suggestions included:
Start with a thorough literature analysis to guide study design.
In addition to specified tissues, take blood samples because this is the tissue that epidemiologists are most likely to have access to.
Assess whether there is an epigenetic component that is driving a memory effect.
Include temperature when undertaking comparative analysis between fish species.
Exposure route: oral exposure was considered the primary route.
It was suggested that in parallel to in vivo models, in vitro assays (e.g. cell-type specific) are necessary to add value by elucidating and validating mechanistic information (cf. Jun Kanno’s and Joelle Ruegg’s presentations). These would also provide insight into secondary mechanisms that have been found in different tissues (for example lung, liver) that were not present in e.g. brain tissue. Teasing these out by using a co-culture format may help extrapolate those different mechanisms.