Heritable epigenetic mechanisms of paternal THC exposure

项目摘要 越来越多的人认识到，父亲的孕前压力、饮食或吸毒会直接影响孩子的健康。 通过生殖细胞中的表观遗传机制来发展他的孩子。因此，我们最近的研究结果 实验室发现，父母（母亲和父亲）接触到1，9-四氢大麻酚（THC）增加了药物， 寻找雄性后代的行为我发现四氢大麻酚对父亲的影响很大 改变精子中已知在遗传性神经行为表型中起因果作用的表观遗传机制。 鉴于娱乐性大麻使用的逐步合法化， 生殖健康和代际健康风险得到更好的界定。因此，我将检查遗传的 父亲THC暴露对精子、发育中的胚胎和胎儿大脑的表观遗传影响。 在目标1中，我将检查THC对精子小非编码RNA的影响，在三个方面- 相关剂量。随后，在目标2a中，我将描述父亲THC暴露对基因的影响。 在早期胚胎中的表达。此外，目标2b将对初步实验采取后续行动，这些实验表明， 剂量THC暴露通过检查microRNA-34 c抑制的影响减少精子携带的microRNA-34 c 早期胚胎基因表达编程最后，在目标3中，我将确定可遗传的表观遗传 通过检测全基因组染色质研究父亲THC暴露对产前神经发育的影响 胚胎纹状体神经元的可及性。 这个项目代表了我们对THC代际影响的理解的重要进展 暴露，旨在通过男性生殖系确定表观遗传遗传的新机制。的 调查结果将有助于确定与准父亲使用大麻有关的潜在健康风险。

PROJECT SUMMARY There is a growing appreciation that a father’s preconception stress, diet, or drug use can directly affect the development of his children via epigenetic mechanisms in the germline. Accordingly, recent findings from our lab revealed that parental (mother and father) exposure to 9-tetrahydrocannabinol (THC) increased drug- seeking behavior in male offspring. Suggesting a significant role for the father, I found that THC significantly alters an epigenetic mechanism in sperm known to play a causal role in heritable neurobehavioral phenotypes. Given the progressive legalization of recreational cannabis use, it is imperative that the associated reproductive and intergenerational health risks become better defined. Therefore, I will examine the heritable epigenetic effects of paternal THC exposure on the sperm, developing embryo, and fetal brain. In Aim 1, I will examine the effects of THC on sperm small noncoding RNAs across three translationally- relevant doses. Subsequently, in Aim 2a, I will characterize the effects of paternal THC exposure on gene expression in the early embryo. Moreover, Aim 2b will follow-up on preliminary experiments showing that a low dose THC exposure reduces sperm-borne microRNA-34c by examining the effects of microRNA-34c inhibition on early embryonic gene expression programming. Finally, in Aim 3, I will determine the heritable epigenetic effects of paternal THC exposure on prenatal neurodevelopment by examining genome-wide chromatin accessibility in embryonic striatal neurons. This project represents an important advancement in our understanding of the intergenerational effects of THC exposure, aiming to identify novel mechanisms of epigenetic inheritance through the male germline. The findings will help determine potential health risks associated with the cannabis use of fathers-to-be.