Mechanistic target of rapamycin/blood test barrier mechanism mediates acceleration of sperm epigenetic aging by environmental factors.

Our previous research suggested that mechanistic target of rapamycin (mTOR)/blood-testis barrier (BTB) mechanism is involved in the regulation of the rates of epigenetic aging of sperm, where increased activity of mTORC1 opens BTB and accelerates epigenetic aging and increased activity of mTORC2 produces opposite results – increases BTB integrity and rejuvenates sperm epigenome. In the current study using newly developed epigenetic clock model we tested if this mechanism is involved in epigenetic reprograming of sperm in mice by heat stress (HS) and Cd exposure.

We demonstrate that mTOR-dependent BTB disruption by HS and mTOR-independent BTB disruption by Cd accelerate epigenetic aging of sperm and produce similar effects on sperm DNA methylation. Thus, we identified the novel molecular mechanism that mediates effects of environmental stressors on sperm epigenetic aging and may be common to a broad range of environmental, lifestyle, dietary, health and other factors.