Paternal Cannabis Exposure Prior to Mating, but Not Δ9-Tetrahydrocannabinol, Elicits Deficits in Dopaminergic Synaptic Activity in the Offspring.
Paternal Cannabis Exposure Prior to Mating, but Not Δ9-Tetrahydrocannabinol, Elicits Deficits in Dopaminergic Synaptic Activity in the Offspring.
复制标题
父本在交配前接触大麻，但不是α9-四氢大麻酚，会导致后代多巴胺能突触活动缺陷。
DOI：
10.1093/toxsci/kfab117
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发表时间：
2021
期刊：
影响因子：
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通讯作者：
Seidler,FredericJ
中科院分区：
文献类型：
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作者：
Slotkin,TheodoreA;Levin,EdwardD;Seidler,FredericJ
大麻产品的合法化和供应量的增加引起了人们对使用者后代影响的关注，而父亲使用大麻的潜在贡献几乎没有出现。我们在交配前给雄性大鼠施用大麻提取物，两种不同的28天暴露，一种是暴露结束和交配之间有56天的间隔（“早期大麻”），另一种是在交配前（“晚期大麻”）;提取物提供了4 mg/kg/天的主要精神活性成分Δ9-四氢大麻酚。然后，我们评估了从青春期开始（出生后第30天）到中年（出生后第150天）对后代多巴胺（DA）系统的影响，测量了DA及其主要代谢产物3，4-二羟基苯乙酸（DOPAC）在不同脑区的水平。父亲的大麻与方案引起了深刻的和持久的赤字DA利用（DOPAC/DA比）的后代，表明低于正常的突触前活动。然而，这两种方案的潜在机制不同，早期大麻减少DOPAC，而晚期大麻增加DA，并引起DOPAC的较小减少。影响仅限于雄性后代。大麻的影响并没有通过等同地暴露于其Δ9-四氢大麻酚来重现，我们也没有看到围产期暴露于烟草烟雾或其一些胎儿毒性贡献者（苯并[a]芘，不含或含尼古丁）的影响。我们的研究提供了一些第一批证据，证明父亲大麻给药对后代神经发育的不良影响，并加强了父亲在孕前使用药物的重要后果。
The legalization and increasing availability of cannabis products raises concerns about the impact on offspring of users, and little has appeared on the potential contribution of paternal use. We administered cannabis extract to male rats prior to mating, with two different 28-day exposures, one where there was a 56-day interval between the end of exposure and mating (“Early Cannabis”), and one just prior to mating (“Late Cannabis”); the extract delivered 4 mg/kg/day of the main psychoactive component, Δ9-tetrahydrocannabinol. We then assessed the impact on dopamine (DA) systems in the offspring from the onset of adolescence (postnatal day 30) through middle age (postnatal day 150), measuring the levels of DA and its primary metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC) in various brain regions. Paternal cannabis with either regimen elicited a profound and persistent deficit in DA utilization (DOPAC/DA ratio) in the offspring, indicative of subnormal presynaptic activity. However, the two regimens differed in the underlying mechanism, with Early Cannabis reducing DOPAC whereas Late Cannabis increased DA and elicited a smaller reduction in DOPAC. Effects were restricted to male offspring. The effects of cannabis were not reproduced by equivalent exposure to its Δ9-tetrahydrocannabinol, nor did we see the effects with perinatal exposure to tobacco smoke or some of its fetotoxic contributors (benzo[a]pyrene without or with nicotine). Our studies provide some of the first evidence for adverse effects of paternal cannabis administration on neurodevelopment in the offspring, and reinforce the important consequences of paternal drug use in the preconception period.