Abstract
BackgroundSepsis represents the utmost severe consequence of infection, involving a dysregulated and self-damaging immune response of the host. While different environmental exposures like chronic stress or malnutrition have been well described to reprogram the germline and subsequently offspring attributes, the intergenerational impact of sepsis as a tremendous immunological stressor has not been examined yet.MethodsPolymicrobial sepsis in 12-week-old male C57BL/6 mice was induced by cecal ligation and puncture (CLP), followed by a mating of the male survivors (or appropriate sham control animals) 6 weeks later with healthy females. Alveolar macrophages of offspring animals were isolated and stimulated with either LPS or Zymosan, and supernatant levels of TNF-α were quantified by ELISA. Furthermore, systemic cytokine response to intraperitoneally injected LPS was assessed after 24 h. Also, morphology, motility, and global DNA methylation of the sepsis survivors’ sperm was examined.ResultsComparative reduced reduction bisulfite sequencing (RRBS) of sperm revealed changes of DNA methylation (n = 381), most pronounced in the intergenic genome as well as within introns of developmentally relevant genes. Offspring of sepsis fathers exhibited a slight decrease in body weight, with a more pronounced weight difference in male animals (CLP vs. sham). Male descendants of sepsis fathers, but not female descendants, exhibited lower plasma concentrations of IL-6, TNF-alpha, and IL-10 24 h after injection of LPS. In line, only alveolar macrophages of male descendants of sepsis fathers produced less TNF-alpha upon Zymosan stimulation compared to sham descendants, while LPS responses kept unchanged.ConclusionWe can prove that male—but surprisingly not female—descendants of post-sepsis fathers show a dampened systemic as well as pulmonary immune response. Based on this observation of an immune hypo-responsivity, we propose that male descendants of sepsis fathers are at risk to develop fungal and bacterial infections and might benefit from therapeutic immune modulation.
Highlights
Sepsis represents the utmost severe consequence of infection, involving a dysregulated and selfdamaging immune response of the host
Sepsis impairs sperm function and alters the Deoxyribonucleic acid (DNA) methylome After cecal ligation and puncture (CLP), nearly half of the paternal animals died within 5 days (9/20 animals), while no animal of the sham group died (Fig. 1b)
We found an increased number of sperm cells in animals after CLP (Fig. 2a), but these tended to be immobile (Fig. 2b) or to show a defect appearance (Fig. 2c)
Summary
Sepsis represents the utmost severe consequence of infection, involving a dysregulated and selfdamaging immune response of the host. Changes in progenitor cells like hematopoietic stem cells (HSC) of the bone marrow have been hypothesized to occur during inflammation [11], with recent proof of this concept during chronic inflammation in diabetes [12] as well as in the acute inflammatory condition of sepsis [13, 14]. While the negative impact of inflammation on the overall male fertility has been well characterized [16, 17], it is unclear if individual sperm cells or even their progenitors might be affected on a more subtle epigenetic level, enabling the carrying forward of information onto the generation
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