The Sperm Epigenome: ART and effects of environmental exposures

 Sperm RNAs

ART & Environment

Next Gen Analytics

4D Genome

We examined the epigenetic signatures of offspring from couples seeking the use of Assisted Reproductive Technologies (ARTs) to begin a family.  Comparison of this signature to that from the unassisted normal live birth offspring enabled us to address two questions: is the epigenetic signature altered, and if altered, could it revert to a “normal” state?  As couples seek ART to help begin a family, our data shows that frozen embryo transfer can reset the epigenetic methylation signature back to what appears as a normal state (1).  It was interesting that this reflects a reset of environmentally responsive metastable epialleles.  While the ability to reset this epigenetic methylation signature is encouraging, this may not always be the case and, if so, indicative of the father’s contribution. For example, after some continuous exposures like those from phthalates, there may be a point in time of no return when a reset to ‘normal’ is not possible (2). Understanding how exposures impact the interpretation of the information transferred from the father to the next generation is critical.

ART highlights the gap in our understanding of the long-term effects of side-stepping some of the barriers to conception.  Using male obesity as a model in couples seeking to have a child, we have shown that a global response like inflammation is mediated by a series of Chromatin regulators, Erasers and Writers (CrEWs), which place and remove epigenetic marks (3).  Acting together and above transcription, they affect many and sometimes discordant pathways in a coordinated manner.  Spermatozoa deliver CrEWs to the oocyte at fertilization, reflecting a father’s health.  We continue to assess whether the effects of these male derived CrEWs are evident during this early stage of development.

1. Estill, M.S., Bolnick, J.M., Waterland, R.A., Bolnick, A.D., Diamond, M.P., Krawetz, S.A. (2016) Assisted reproductive technologies alter DNA methylation profiles in bloodspots of newborn infants. Fertility and Sterility. 106:629-639. PMID: 27288894
2. Estill, M., Hauser, R., Moss, A.E., Nassan F. and Krawetz, S.A. (2019) The effects of di-butyl phthalate exposure from medications on human sperm RNA among men. Nature Scientific Reports (pdf).  9:12397 PMID: 31455814.
3. Swanson, G., Estill, M., Diamond, M.P., Legro, R.S., Coutifaris, C., Barnhart, M.D., Huang, H., Hansen, K.R., Trussell, M.D., Coward, R.M. Zhang, H., Goodrich, R. and Krawetz, S.A. (2020) Human Chromatin remodeler cofactor, RNA interactor, Eraser and Writer Sperm RNAs responding to Obesity (pdf)15:32-46. PMID: 31354029.