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Sperm carry much more than DNA. During spermatogenesis and epididymal maturation they acquire a diverse repertoire of RNAs and other molecules, many of which are essential for sperm development and function. Increasing evidence suggests that some of these molecules may also influence fertilization and early embryo development.

Environmental factors such as diet and metabolic health can remodel the molecular composition of sperm. However, it remains largely unknown which molecular changes simply reflect sperm physiology and which carry biologically meaningful information capable of influencing the next generation.

Our research aims to identify these functional molecular signals and understand how they are shaped by the environment. Decoding this molecular language is a critical step towards understanding how sperm influence fertility, embryo development and lifelong health.

Our approach

We combine human intervention studies with mechanistic experimental models to identify how environmental information is encoded in sperm and to determine which molecular signals influence embryo development.

Human studies allow us to investigate how lifestyle factors rapidly remodel the molecular composition of sperm under physiologically relevant conditions. Experimental models, particularly Drosophila melanogaster, enable us to test the function of candidate RNAs in a genetically tractable system and establish causal links between sperm RNA, fertilization and early embryonic development.

Together, these complementary approaches bridge human reproductive medicine with fundamental molecular biology, allowing us to move from clinical observations to molecular mechanisms.

Current studies

• ÌýA randomized dietary intervention study investigating how short-term dietary changes remodel the human sperm small RNA profile in men undergoing IVF.
• Diet-responsive sperm RNA in Drosophila – Functional studies identifying RNAs that regulate early embryonic development.
  
  

Key publications

Ost et al., Cell (2014)
First demonstration in Drosophila that paternal diet before conception alters offspring metabolism through changes in sperm-mediated molecular information.

Natt et al., PLOS Biology (2019)
Showed that the small RNA profile of human sperm can be remodeled within days by dietary intervention, demonstrating that sperm rapidly respond to environmental change.

Ramesh et al., Antioxidants & Redox Signaling (2023)
Identified mitochondrial small RNAs as diet-sensitive components of sperm, linking metabolic state to mitochondrial RNA biology.

Outlook

Can we develop evidence-based lifestyle recommendations for prospective fathers?

Despite growing evidence that paternal lifestyle influences sperm biology, there are currently no evidence-based dietary recommendations for men planning fatherhood. Answering this question requires us to identify which molecular changes in sperm are biologically meaningful and how they influence reproduction and early development.

Fertilization marks the beginning of a new individual. At this defining moment, the sperm delivers not only the paternal genome but also a rich repertoire of RNAs and other molecules to the oocyte. While DNA provides the genetic blueprint, increasing evidence suggests that some of these additional molecules influence the earliest stages of embryonic development.

How the embryo interprets these paternal molecular signals remains one of the fundamental questions in reproductive biology. Identifying which sperm RNAs regulate early developmental events, and understanding how they influence embryo quality and developmental potential, is essential for understanding male fertility and the origins of lifelong health.

Our research aims to identify which sperm-derived molecules act as functional signals during fertilization and early embryonic development, and to uncover the molecular mechanisms through which they influence developmental potential.

Our approach

We combine human IVF studies with functional experiments in Drosophila to determine how sperm-derived RNAs influence early embryonic development.

Human studies enable us to identify sperm RNA signatures associated with embryo quality and reproductive outcome. Experimental models allow us to manipulate candidate RNAs and directly test their function during fertilization and embryogenesis.

Current studies

• Sperm RNA and embryo quality in human IVF
  Identifying sperm-derived small RNAs associated with embryo quality and developmental potential in couples undergoing IVF.
• Functional analysis of sperm RNAs in Drosophila
  Using genetic models to determine how candidate sperm RNAs regulate the earliest stages of embryonic development and establish causal links between paternal RNA and developmental outcomes.
• Human embryo and blastoid models
  Investigating how sperm-derived RNAs influence early developmental programs, with a particular focus on trophectoderm specification and placental development.

Key publications

Isacson et al., Nature Communications (2025)
Identified sperm small RNAs associated with embryo quality in human IVF, providing evidence that paternal RNAs contribute to early human embryonic development.

Örkenby et al., Molecular Systems Biology (2023)
Demonstrated that small RNAs regulate some of the earliest developmental events in the Drosophila embryo, linking transient RNA changes to long-term developmental programming.

Ost et al., Cell (2014)
Provided the first evidence that paternal environmental exposures before conception can influence offspring development through sperm-mediated molecular information.

Outlook

Can sperm RNA become a new dimension of reproductive medicine?

Current assessment of male fertility relies largely on sperm count, motility and morphology. By understanding how sperm-derived RNAs influence embryo development, we hope to identify new molecular markers of sperm quality and, ultimately, improve the diagnosis and treatment of male infertility.

The RNA landscape of sperm is far more complex than previously appreciated. Advances in sequencing technologies continue to reveal new classes of RNAs and RNA modifications, many of which remain functionally unexplored. Understanding which of these molecules carry biologically meaningful information represents one of the next frontiers in reproductive biology.

Our research aims to discover novel RNA species and RNA modifications, determine how they respond to environmental change, and uncover their roles in fertilization and embryonic development.

Our approach

Discovering new biology requires new tools. We develop and apply innovative RNA sequencing strategies together with computational analyses and functional experimental models to uncover previously unexplored classes of sperm RNAs and RNA modifications.

Candidate molecules are subsequently investigated in experimental systems to determine how they contribute to sperm function, fertilization and embryonic development. By combining technology development with mechanistic biology, we aim to reveal the molecular signals that form the hidden RNA landscape of sperm.

Current study

• Discovery of novel sperm RNAs
  Conventional RNA sequencing captures only part of the molecular complexity of sperm. Using our sequencing strategy, 5XP-seq, together with the computational framework Seqpac, we are uncovering previously hidden populations of sperm RNAs that escape detection by standard approaches. Our current work focuses on determining how these newly identified RNAs are molecularly processed after fertilization and whether they contribute to the regulation of early embryonic development.

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Key publications

Kugelberg et al., (under review) - Non-canonical sperm-borne miRNAs regulate maternal mRNA in the Drosophila embryo
Identifies a previously hidden population of sperm miRNAs and demonstrates that paternal miRNAs regulate maternal mRNA dynamics during early embryonic development.

Kugelberg et al., RNA Biology (2021)
Developed 5XP-seq, a sequencing strategy that identifies small RNAs with and without 5′ phosphorylation.

Skog et al., Bioinformatics (2023)
Developed Seqpac, a sequence-based framework for reproducible small RNA-seq analysis.

Outlook

What else have we been missing?

Advances in RNA biology continue to reveal previously unrecognized classes of regulatory molecules. As new technologies expand our ability to detect and interpret these signals, we expect to uncover entirely new layers of molecular communication between sperm and the next generation.

Our research has been driven by a long-term goal: to understand how information beyond DNA is transmitted through sperm and influences the next generation. Over the past decade, we have gradually moved from demonstrating that paternal diet can influence offspring metabolism to uncovering the molecular mechanisms through which sperm communicate with the embryo.