Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, USA.
Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, USA.
Neurotoxicol Teratol. 2019 Jul-Aug;74:106806. doi: 10.1016/j.ntt.2019.04.003. Epub 2019 Apr 24.
Developmental neurotoxicity of a wide variety of toxicants mediated via maternal exposure during gestation is very well established. In contrast, the impacts of paternal toxicant exposure on offspring neurobehavioral function are much less well studied. A vector for paternal toxicant exposure on development of his offspring has been identified. Sperm DNA can be imprinted by chemical exposures of the father. Most but not all of the epigenetic marks in sperm are reprogrammed after fertilization. The persisting epigenetic marks can lead to abnormal genetic expression in the offspring. We have found that paternal delta-9-tetrohydrocannabinol (THC) exposure in rats causes changes in methylation of sperm (Murphy et al., 2018). This is similar to cannabis-associated changes in sperm DNA methylation we found in human males who smoke cannabis (Murphy et al., 2018). In the current study we investigated the intergeneration effects of THC exposure of young adult male rats (0 or 2 mg/kg/day orally for 12 days) to the neurobehavioral development of their offspring. This paternal THC exposure was not found to significantly impact the clinical health of the offspring, including litter size, sex ratio, pup birth weight, survival and growth. However, it did cause a long-lasting significant impairment in attentional performance in the offspring relative to controls when they were tested in adulthood. There was also a significant increase in habituation of locomotor activity in the adult offspring of the males exposed to THC prior to mating. This study shows that premating paternal THC exposure even at a modest dose for a brief period can cause deleterious long-term behavioral effects in the offspring, notably significant impairment in an operant attention task. Further research should be conducted to determine the degree to which this type of risk is seen in humans and to investigate the mechanisms underlying these effects and possible treatments to ameliorate these long-term adverse behavioral consequences of paternal THC exposure.
各种母体在妊娠期暴露于毒物所介导的发育神经毒性已得到充分证实。相比之下，父体毒物暴露对子代神经行为功能的影响研究得较少。现已确定了父体毒物暴露对子代发育的影响途径。精子 DNA 可被父体的化学暴露所印记。受精后，大多数（但不是全部）精子中的表观遗传标记被重新编程。持续存在的表观遗传标记可导致子代中异常的基因表达。我们发现，大鼠中父体 δ-9-四氢大麻酚（THC）暴露可导致精子甲基化发生变化（Murphy 等人，2018 年）。这与我们在吸食大麻的男性精子中发现的大麻相关的 DNA 甲基化变化相似（Murphy 等人，2018 年）。在目前的研究中，我们研究了年轻成年雄性大鼠（0 或 2mg/kg/天经口连续 12 天）的 THC 暴露对子代神经行为发育的代际影响。这种父体 THC 暴露并未显著影响子代的临床健康，包括窝仔数、性别比例、幼仔出生体重、存活率和生长。然而，与对照组相比，当它们在成年时进行测试时，它确实导致了子代注意力表现的持久而显著的损害。在交配前暴露于 THC 的雄性成年子代的运动活动习惯化也显著增加。这项研究表明，即使在短暂的时间内以适度剂量进行交配前父体 THC 暴露，也会导致子代产生有害的长期行为影响，特别是在操作性注意任务中出现显著损害。应进一步开展研究，以确定在人类中看到这种风险的程度，并研究这些影响的潜在机制以及可能的治疗方法，以减轻父体 THC 暴露的这些长期不良行为后果。
