Biology subjects

Pilsner, J. R.

Publications and source records attributed to Pilsner, J. R..

3 recordsLinked to original sources

bioRxiv2025

Mechanistic target of rapamycin/blood-testes 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 present study, we use our newly developed epigenetic clock model to investigate whether the mTOR/BTB mechanism is involved in the epigenetic reprogramming of sperm in mice exposed to heat stress (HS) and cadmium (Cd). Our findings show that both mTOR-dependent BTB disruption caused by HS and mTOR-independent BTB disruption due to Cd exposure accelerate sperm epigenetic aging, resulting in similar changes to sperm DNA methylation patterns. These results suggest that the mTOR/BTB mechanism is a novel molecular pathway through which environmental stressors influence sperm epigenetic aging, and this pathway may be relevant to a broad range of factors, including environmental, lifestyle, dietary, and health influences.

molecular biology↗

bioRxiv2024

Molecular Basis of Sperm Methylome Response to Aging and Stress

Changes in the sperm epigenome induced by age and/or stressors often follow common unexplained patterns affecting genes responsible for embryonic development and neurodevelopment. The stochastic epigenetic variation (SEV) hypothesis proposes that in response to stressors naturally variable methylation regions (VMRs) associated with morphogenic genes increase in methylation variation to diversify phenotypes and improve chances of survival of the genetic lineage. Here, we test predictions from the SEV hypothesis using mouse and rat sperm DNA methylation and other -omics data. We demonstrate that the context of DNA regions determines the response of sperm methylome to various factors rather than the stressors and/or timing of these factors. We propose a model explaining age/stress-dependent shifts in methylation in VMRs by an asymmetric increase in methylation variation of these regions. Because methylation variation in VMRs increases with age, sperm methylome response to stressors may be characterized as an acceleration of epigenetic aging.

systems biology↗

bioRxiv2023

Mechanistic target of rapamycin (mTOR) pathway in Sertoli cells regulates age-dependent changes in sperm DNA methylation

Over the past several decades, a trend toward delayed childbirth has led to increases in parental age at the time of conception. Sperm epigenome undergoes age-dependent changes increasing risks of adverse conditions in offspring conceived by fathers of advanced age. The mechanism(s) linking paternal age with epigenetic changes in sperm remain unknown. The sperm epigenome is shaped in a compartment protected by the blood-testes barrier (BTB) known to deteriorate with age. Permeability of the BTB is regulated by the balance of two mTOR complexes in Sertoli cells where mTOR complex 1 (mTORC1) promotes the opening of the BTB and mTOR complex 2 (mTORC2) promotes its integrity. We hypothesized that this balance is also responsible for age-dependent changes in the sperm epigenome. To test this hypothesis, we analyzed reproductive outcomes, including sperm DNA methylation in transgenic mice with Sertoli cell-specific suppression of mTORC1 (Raptor KO) or mTORC2 (Rictor KO). mTORC2 suppression accelerated aging of the sperm DNA methylome and resulted in a reproductive phenotype concordant with older age, including decreased testes weight and sperm counts, and increased percent of morphologically abnormal spermatozoa and mitochondrial DNA copy number. Suppression of mTORC1 resulted in the shift of DNA methylome in sperm opposite to the shift associated with physiological aging - sperm DNA methylome rejuvenation, and mild changes in sperm parameters. These results demonstrate for the first time that the balance of mTOR complexes in Sertoli cells regulates the rate of sperm epigenetic aging. Thus, mTOR pathway in Sertoli cells may be used as a novel target of therapeutic interventions to rejuvenate the sperm epigenome in advanced-age fathers. Ethics statementAll procedures followed the guidelines of the National Institutes of Health Guide for the Care and Use of Laboratory Animals and the approval for this study was received from the Institutional Animal Care and Use Committee at University of Massachusetts, Amherst.

developmental biology↗