Department of Urology, Oregon Health & Science University; Portland, Oregon; Division of Reproductive and Developmental Sciences, Oregon National Primate Research Center; Department of Obstetrics and Gynecology, Oregon Health & Science University, Portland, Oregon.
Division of Reproductive and Developmental Sciences, Oregon National Primate Research Center.
Fertil Steril. 2023 Jul;120(1):163-174. doi: 10.1016/j.fertnstert.2023.02.034. Epub 2023 Mar 27.
To determine whether discontinuation of delta-9-tetrahydrocannabinol (THC) use mitigates THC-associated changes in male reproductive health using a rhesus macaque model of daily THC edible consumption.
Research animal study.
Research institute environment.
PATIENT(S): Adult male rhesus macaques (age, 8-10 years; n = 6).
INTERVENTION(S): Chronic daily THC edible administration at medically and recreationally relevant contemporary doses followed by cessation of THC use.
MAIN OUTCOME MEASURE(S): Testicular volume, serum male hormones, semen parameters, sperm deoxyribonucleic acid (DNA) fragmentation, seminal fluid proteomics, and whole genome bisulfite sequencing of sperm DNA.
RESULT(S): Chronic THC use resulted in significant testicular atrophy, increased gonadotropin levels, decreased serum sex steroid levels, changes in seminal fluid proteome, and increased DNA fragmentation with partial recovery after discontinuation of THC use. For every increase of 1 mg/7 kg/day in THC dosing, there was a significant decrease in the total testicular volume bilaterally by 12.6 cm (95% confidence interval [CI], 10.6-14.5), resulting in a 59% decrease in volume. With THC abstinence, the total testicular volume increased to 73% of its original volume. Similarly, with THC exposure, there were significant decreases in the mean total testosterone and estradiol levels and a significant increase in the follicle-stimulating hormone level. With increasing THC dose, there was a significant decrease in the liquid semen ejaculate volume and weight of coagulum; however, no other significant changes in the other semen parameters were noted. After discontinuing THC use, there was a significant increase in the total serum testosterone level by 1.3 ng/mL (95% CI, 0.1-2.4) and estradiol level by 2.9 pg/mL (95% CI, 0.4-5.4), and the follicle-stimulating hormone level significantly decreased by 0.06 ng/mL (95% CI, 0.01-0.11). Seminal fluid proteome analysis revealed differential expression of proteins enriched for processes related to cellular secretion, immune response, and fibrinolysis. Whole genome bisulfite sequencing identified 23,558 CpGs differentially methylated in heavy-THC vs. pre-THC sperm, with partial restoration of methylation after discontinuation of THC use. Genes associated with altered differentially methylated regions were enriched for those involved in the development and function of the nervous system.
CONCLUSION(S): This is the first study demonstrating that discontinuation of chronic THC use in rhesus macaques partially restores adverse impacts to male reproductive health, THC-associated sperm differentially methylated regions in genes important for development, and expression of proteins important for male fertility.
通过使用恒河猴每日食用大麻素模型，确定是否停止使用 δ-9-四氢大麻酚（THC）可以减轻与 THC 相关的男性生殖健康变化。
研究动物研究。
研究所环境。
成年雄性恒河猴（年龄 8-10 岁；n=6）。
以医学和娱乐相关的当代剂量持续每日摄入 THC 可食用物，然后停止使用 THC。
睾丸体积、血清男性激素、精液参数、精子脱氧核糖核酸（DNA）碎片化、精液蛋白质组学和精子 DNA 的全基因组亚硫酸氢盐测序。
慢性 THC 使用导致明显的睾丸萎缩、促性腺激素水平升高、血清性激素水平下降、精液蛋白质组变化以及 DNA 碎片化增加，停止 THC 使用后部分恢复。THC 剂量每增加 1mg/7kg/天，双侧睾丸总容积就会显著减少 12.6cm（95%置信区间[CI]，10.6-14.5），体积减少 59%。停止 THC 摄入后，睾丸总容积增加到原始体积的 73%。同样，暴露于 THC 时，总睾酮和雌二醇水平显著下降，促卵泡激素水平显著升高。随着 THC 剂量的增加，精液射出量和凝块重量显著减少，但其他精液参数无明显变化。停止使用 THC 后，总血清睾酮水平显著升高 1.3ng/ml（95%CI，0.1-2.4），雌二醇水平升高 2.9pg/ml（95%CI，0.4-5.4），促卵泡激素水平显著下降 0.06ng/ml（95%CI，0.01-0.11）。精液蛋白质组分析显示，与细胞分泌、免疫反应和纤维蛋白溶解相关的蛋白质表达丰富。全基因组亚硫酸氢盐测序确定了 23558 个在重 THC 与 THC 前精子中差异甲基化的 CpG，停止 THC 后部分恢复甲基化。与改变的差异甲基化区域相关的基因富集了与神经系统发育和功能相关的基因。
这是第一项研究表明，在恒河猴中停止慢性 THC 使用可部分恢复对男性生殖健康的不利影响、与 THC 相关的精子中对发育重要的基因的差异甲基化区域以及对男性生育能力重要的蛋白质的表达。
