Paternal sepsis induces alterations of the sperm methylome and dampens offspring immune responses—an animal study

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.Electronic supplementary materialThe online version of this article (10.1186/s13148-018-0522-z) contains supplementary material, which is available to authorized users.

The Effects of Biological Sex on Sepsis Treatments in Animal Models: A Systematic Review and a Narrative Elaboration on Sex- and Gender-Dependent Differences in Sepsis

“…Further, recurrent methylation of this promoter may contribute to “endotoxin tolerance” in the sepsis-associated immune suppression observed in later stages of the disease ( 96 ). Male (but not female) offspring of fathers subjected to CLP were shown to have a depressed response 24 hours after a subsequent endotoxin challenge, with lower plasma concentrations of IL-6, TNF-α, and IL-10 ( 97 ). Interestingly, these findings were attributed to alterations in sperm DNA methylation, providing evidence for intergenerational sex-dependent differences mediated via epigenetics.…”

Postoperative abdominal sepsis induces selective and persistent changes in CTCF binding within the MHC-II region of human monocytes

“…It is well known that epigenetic changes can endure [49], with even transgenerational effects such as alterations in DNA-methylation found in a murine model of sepsis survivors [50]. Although DNA-methylation especially at CpG sites of the genome represents another known determinant of CTCF occupancy [51], it is so far unknown whether CTCF binding itself is a PLOS ONE long-lasting or even heritable epigenetic mark in human disease [23].…”

The Systemic and Cellular Metabolic Phenotype of Infection and Immune Response to Listeria monocytogenes

“…Numerous studies have also examined the metabolic changes associated with polymicrobial sepsis using a cecal ligation and puncture model ( 9 ). These studies have observed similar outcomes as LPS administration including fever, weight loss, decrease activity, and decreased food and water consumption ( 9 – 12 ).…”