Elevated paternal glucocorticoid exposure alters the small noncoding RNA profile in sperm and modifies anxiety and depressive phenotypes in the offspring

Abstract

Recent studies have suggested that physiological and behavioral traits may be transgenerationally inherited through the paternal lineage, possibly via non-genomic signals derived from the sperm. To investigate how paternal stress might influence offspring behavioral phenotypes, a model of hypothalamic–pituitary–adrenal (HPA) axis dysregulation was used. Male breeders were administered water supplemented with corticosterone (CORT) for 4 weeks before mating with untreated female mice. Female, but not male, F1 offspring of CORT-treated fathers displayed altered fear extinction at 2 weeks of age. Only male F1 offspring exhibited altered patterns of ultrasonic vocalization at postnatal day 3 and, as adults, showed decreased time in open on the elevated-plus maze and time in light on the light–dark apparatus, suggesting a hyperanxiety-like behavioral phenotype due to paternal CORT treatment. Interestingly, expression of the paternally imprinted gene Igf2 was increased in the hippocampus of F1 male offspring but downregulated in female offspring. Male and female F2 offspring displayed increased time spent in the open arm of the elevated-plus maze, suggesting lower levels of anxiety compared with control animals. Only male F2 offspring showed increased immobility time on the forced-swim test and increased latency to feed on the novelty-supressed feeding test, suggesting a depression-like phenotype in these animals. Collectively, these data provide evidence that paternal CORT treatment alters anxiety and depression-related behaviors across multiple generations. Analysis of the small RNA profile in sperm from CORT-treated males revealed marked effects on the expression of small noncoding RNAs. Sperm from CORT-treated males contained elevated levels of three microRNAs, miR-98, miR-144 and miR-190b, which are predicted to interact with multiple growth factors, including Igf2 and Bdnf. Sustained elevation of glucocorticoids is therefore involved in the transmission of paternal stress-induced traits across generations in a process involving small noncoding RNA signals transmitted by the male germline.

Adolescence and the next generation

“…The paternal preconception environment modulates the RNA content of the developing sperm, with possible effects on post-fertilization development and offspring phenotypes 53 . In animal studies, paternal exposures to high-fat and high-sugar diets produce metabolic disturbances in offspring 54 , and both stress and exercise affect stress responses of the offspring [55][56][57] . Animal and some human studies have found effects of preconceptional tobacco, alcohol and illicit drug use on gamete epigenomes, with diverse effects on offspring development 58,59 .…”

Paternal environmental enrichment transgenerationally alters affective behavioral and neuroendocrine phenotypes

“…Moreover, in rodents, transgenerational inheritance of stress can modify the F2 phenotype without alterations in the F1 phenotype. We previously showed that paternal exposure to CORT had an effect on F2 depression-like behavior but not in F1, an effect that was transmitted through the male lineage (Short et al, 2016). Other studies have also indicated that phenotypes in the F2 or F3 generations differ from those seen in the F1 animals (Bygren et al, 2001;Franklin et al, 2010), although these phenotypes could be affected by the changes in the F1 generation.…”

“…Observations took place every 5 minutes for 60 minutes in every session and were manually scored as previously described (Chourbaji et al, 2011;Short et al, 2016). …”

“…As we recently showed that paternally-mediated effects on offspring anxiety could manifest across two subsequent generations (Short et al, 2016), we broadened our investigation to examination of the F2 generation.…”

Percussions of Epigenetics on Mood Disorders; is it really A Charm or Just A Propaganda

“…On the other hand, epigenetic inheritance of depression associated phenotypes has been shown in an animal study in which paternal stress induced traits were transmitted across generations with involvement of small noncoding RNA signals which were passed through the male germline [18].…”