In a new collaborative study conducted at the University of Hawaiʻi at Mānoa (UHM) and Washington State University (WSU) at Pullman, researchers provided new data refining the mechanistic basis of paternal epigenetic inheritance.
The study was led by Professor Wei Yan from WSU and Monika Ward from the Department of Anatomy, Biochemistry & Physiology and the Yanagimachi Institute for Biogenesis Research (YIBR) at UHM. The team addressed a controversial claim that environmental exposures induce mitochondrial DNA (mtDNA)-dependent transcription in sperm during epididymal transit, leading to the production of small RNAs that, upon transmission to eggs, alter offspring phenotype.
In the new study, published on June 10th in PNAS, the team showed that mature mouse sperm were devoid of mtDNA, precluding the possibility of mtDNA-dependent transcription, and thus confirming the prevailing view that mitochondrial RNA would have to be acquired in the testes. Next, the team exposed male mice to a high-fat diet, performed intracytoplasmic sperm injection (ICSI) with testicular and cauda epididymal sperm, and examined the resulting ICSI offspring for metabolic phenotype. The researchers demonstrated that testicular sperm transmitted diet-induced epigenetic traits similarly, if not more strongly, than epididymal sperm.
“This work is a perfect example of how assisted reproduction technologies (ART) can be used to advance understanding of key processes in male reproduction. Here, using ICSI with testicular sperm, we provided an explicit proof that exposure to epididymal milieu is not necessary for transmission of epigenetic information by sperm,” said Dr. Ward.
“We also resolved a long-standing discrepancy in the field regarding sperm mtDNA number. To define mtDNA copy number dynamics during sperm formation and epididymal maturation, we quantified multiple mtDNA loci using highly sensitive quantitative PCR and digital PCR. Both methods revealed progressive depletion with mature cauda epididymal sperm being essentially devoid of mtDNA. We also demonstrated the presence of mtRNA in testicular germ cells, with its abundance declining in parallel with spermatogenesis progression, further supporting that sperm small RNA is largely established during spermatogenesis,” adds Dr. Yan.
“Ryuzo Yanagimachi (Yana), the founder of YIBR, was the first to inject human sperm into an egg, establishing what is now known as ICSI. His group later expanded on these initial sperm micromanipulation experiments to include injections of other male germ cells, such as round spermatids, leading to the development of (ROSI), and injections of somatic cells in nuclear transfer/cloning. The current study nicely exemplifies how Yana’s legacy and YIBR’s unique expertise in ART find their way to another scientific breakthrough,” said Dr. Ward.
The study represents a significant step forward in our understanding of paternal epigenetic inheritance. It supports a framework that environmentally responsive, heritable molecular information is programmed during spermatogenesis within the testis and subsequently delivered to the oocyte by mtDNA-depleted sperm.
The study details can be found in an article published in PNAS, a leading peer-reviewed journal.
For media inquiries, please contact:
University of Hawaiʻi at Mānoa
John A. Burns School of Medicine
Matthew Campbell, Director of Communications
Matthew.Campbell@hawaii.edu