Kleeman Elizabeth A, Reisinger Sonali N, Adithya Pranav, Houston Brendan, Stathatos Gemma, Garnham Alexandra L, McLaughlin Shae, O'Bryan Moira K, Gubert Carolina, Hannan Anthony J
Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia.
Bio21 Institute, University of Melbourne, Parkville, Victoria, Australia; School of BioSciences, University of Melbourne, Parkville, Victoria, Australia.
Brain Behav Immun. 2024 Jan;115:258-279. doi: 10.1016/j.bbi.2023.10.005. Epub 2023 Oct 10.
Paternal pre-conceptual environmental experiences, such as stress and diet, can affect offspring brain and behavioral phenotypes via epigenetic modifications in sperm. Furthermore, maternal immune activation due to infection during gestation can reprogram offspring behavior and brain functioning in adulthood. However, the effects of paternal pre-conceptual exposure to immune activation on the behavior and physiology of offspring (F1) and grand-offspring (F2) are not currently known. We explored effects of paternal pre-conceptual exposure to viral-like immune activation on F1 and F2 behavioral and physiological phenotypes using a C57BL/6J mouse model. Males were treated with a single injection (intraperitoneal) of the viral mimetic polyinosinic:polycytidylic acid (Poly I:C: 12 mg/kg) then bred with naïve female mice four weeks after the Poly I:C (or 0.9% saline control) injection. The F1 offspring of Poly I:C treated fathers displayed increased depression-like behavior in the Porsolt swim test, an altered stress response in the novelty-suppressed feeding test, and significant transcriptomic changes in their hippocampus. Additionally, the F1 male offspring of Poly I:C treated F0 males showed significantly increased immune responsivity after a Poly I:C immune challenge (12 mg/kg). Furthermore, the F2 male grand-offspring took longer to enter and travelled significantly shorter distances in the light zone of the light/dark box. An analysis of the small noncoding RNA profiles in sperm from Poly I:C treated males and their male offspring revealed significant effects of Poly I:C on the sperm microRNA content at the time of conception and on the sperm PIWI-interacting RNA content of the male offspring. Notably, eight miRNAs with an FDR < 0.05 (miR-141-3p, miR-126b-5p, miR-669o-5p, miR-10b-3p, miR-471-5p, miR-463-5p, miR-148b-3p, and miR-181c-5p) were found to be significantly downregulated in the sperm of Poly I:C treated males. Collectively, we demonstrate that paternal pre-conceptual exposure to a viral immune challenge results in both intergenerational and transgenerational effects on brain and behavior that may be mediated by alterations in the sperm small noncoding RNA content.
父方孕前的环境经历，如压力和饮食，可通过精子中的表观遗传修饰影响子代的大脑和行为表型。此外，孕期感染引起的母体免疫激活可使子代成年后的行为和大脑功能发生重编程。然而，目前尚不清楚父方孕前暴露于免疫激活对其子代（F1）和孙代（F2）的行为和生理有何影响。我们使用C57BL/6J小鼠模型，探讨了父方孕前暴露于病毒样免疫激活对F1和F2行为及生理表型的影响。雄性小鼠单次腹腔注射病毒模拟物聚肌苷酸:聚胞苷酸（Poly I:C：12 mg/kg），然后在注射Poly I:C（或0.9%生理盐水对照）四周后与未接触过该物质的雌性小鼠交配。经Poly I:C处理的父代的F1子代在强迫游泳试验中表现出类似抑郁的行为增加，在新奇抑制摄食试验中应激反应改变，并且其海马体有显著的转录组变化。此外，经Poly I:C处理的F0雄性小鼠的F1雄性子代在接受Poly I:C免疫攻击（12 mg/kg）后免疫反应性显著增加。此外，F2雄性孙代进入明暗箱亮区的时间更长，在亮区的移动距离显著更短。对经Poly I:C处理的雄性小鼠及其雄性子代精子中的小非编码RNA谱进行分析发现，Poly I:C对受孕时精子中的微小RNA含量以及雄性子代精子中与PIWI相互作用的RNA含量有显著影响。值得注意的是，发现8种错误发现率（FDR）<0.05的微小RNA（miR-141-3p、miR-126b-5p、miR-669o-5p、miR-10b-3p、miR-471-5p、miR-463-5p、miR-148b-3p和miR-181c-5p）在经Poly I:C处理的雄性小鼠精子中显著下调。总的来说，我们证明父方孕前暴露于病毒免疫攻击会对大脑和行为产生代际和跨代影响，这可能是由精子中小非编码RNA含量的改变介导的。
