Reproductive tract extracellular vesicles are sufficient to transmit intergenerational stress and program neurodevelopment

Abstract

Extracellular vesicles (EVs) are a unique mode of intercellular communication capable of incredible specificity in transmitting signals involved in cellular function, including germ cell maturation. Spermatogenesis occurs in the testes, behind a protective barrier to ensure safeguarding of germline DNA from environmental insults. Following DNA compaction, further sperm maturation occurs in the epididymis. Here, we report reproductive tract EVs transmit information regarding stress in the paternal environment to sperm, potentially altering fetal development. Using intracytoplasmic sperm injection, we found that sperm incubated with EVs collected from stress-treated epididymal epithelial cells produced offspring with altered neurodevelopment and adult stress reactivity. Proteomic and transcriptomic assessment of these EVs showed dramatic changes in protein and miRNA content long after stress treatment had ended, supporting a lasting programmatic change in response to chronic stress. Thus, EVs as a normal process in sperm maturation, can also perform roles in intergenerational transmission of paternal environmental experience.

Limitations to intergenerational inheritance: subchronic paternal stress preconception does not influence offspring anxiety

“…Future studies could incorporate a post-treatment recovery period aligned to the mouse spermatogenic cycle (~ 42 days) before mating for the F1 generation. A www.nature.com/scientificreports/ very recent study reported that effects of 28 days of paternal chronic stress had intergenerational effects after 12 weeks of post-stress recovery but not after 1 week 30 . That extended period exceeds several spermatogenic cycles, and when allowing for the elimination of mature epididymal sperm, it suggests that a life-long imprint of that history of paternal stress is likely to originate from testicular germ cells through more stable epigenetic modifications, such as DNA methylation or other alterations in various somatic cells that maintain differences in non-coding RNAs in germ cells.…”

Functional Aspects of Seminal Plasma in Bird Reproduction

“…In mammals, different exosomes, such as epididymosomes, are important actors in sperm maturation through their constant exchanges with epididymal sperm [82]. They also have an action on the transfer to the progeny of epigenetic traits [82,83]. In birds, many protein components expected to make part of seminal exosomes were reported to be present in the seminal plasma of the domestic chicken [14,19,23] and of one of the chicken ancestors, the red jungle fowl [14].…”

La herencia de la pandemia por COVID-19

“…También se han encontrado cambios en el grado de metilación de las histonas H3 y H4 asociado con restricción calórica y trastornos de aprendizaje [1][2][3] ; y en el contenido de miARN en oocitos y espermatozoides. Estos miRNA regulan la modificaciones post-traduccionales de las histonas y afectan el neurodesarrollo fetal 5,6 . Al respecto, recientemente Chan y cols.…”

“…En este estudio, los miARNs encontrados en los exosomas de las células epiteliales epididimales de animales estresados afectaron genes relacionados con señales sinápticas y transporte de neurotransmisores en el sistema nervioso central del feto. Estudios complementarios realizados in vitro en el mismo trabajo permitieron determinar que corticosterona 1,4 μM pudo replicar el efecto del estrés en el perfil de miARN de las células epiteliales epididimales, y que los espermatozoides aislados de sujetos estresados (6 meses de puntuación alta en examen de percepción de estrés) presentaron un perfil de miARN diferente al de los sujetos normales, revelando que los miARN constituyen otro factor epigenético posiblemente responsable de la herencia transgeneracional masculina en caso de estrés 5 .…”