Involvement of circulating factors in the transmission of paternal experiences through the germline

Using a mouse model of paternal exposure to traumatic stress, we identify circulating factors involving peroxisome proliferator-activated receptor (PPAR) pathways in the effects of exposure to the germline. Chronic injection of serum from trauma-exposed males into controls recapitulates metabolic phenotypes in the offspring. Pharmacological PPAR activation in vivo reproduces metabolic dysfunctions in the offspring and grand-offspring of injected males, and affects the sperm transcriptome in fathers and sons. In germ-like cells in vitro, both serum and PPAR agonist induce PPAR activation. Together, these results highlight the role of circulating factors as potential communication vectors between the periphery and the germline. Overall design: 3-month old mice were injected i.p. with either tesaglitazar solution at 10 µg per kg body weight or vehicle control twice per week for 4 weeks. Tesaglitazar (Sigma Aldrich) was solubilized in DMSO at 10 µg per µl and resuspended in sterile 0.9% saline. Vehicle consisted of equivalent DMSO in 0.9% sterile saline. Sperm was collected 24h and 46 days after the last injection. For MSUS, litters were exposed to unpredictable maternal separation combined with unpredictable maternal stress (MSUS) during the first 14 days after birth (Franklin et al., 2010), and serum was collected from 3 months old MSUS and CTRL mice.