The increasing use of illegal drugs by pregnant women causes a public health concern because it is associated with health risks for mothers and their developing children. One of such drugs is MDMA (3,4-methylenedioxymethamphetamine) or ecstasy due to its high consumption in relevant age and sex groups and its adverse effects on human and rodent developing brains. To thoroughly review the current knowledge on the developmentally neurotoxic potential of MDMA we systematically collected and summarized articles investigating developmental neurotoxicity (DNT) of MDMA in humans and animals in vivo and in vitro. In addition, we summarized the findings in a putative adverse outcome pathway (AOP). From an initial 299 articles retrieved from the bibliographic databases Web of Science, PubMed and DART, we selected 39 articles according to inclusion/exclusion criteria for data collection after title/abstract and full text screening. Of these 3 where epidemiological studies, 34 where in vivo studies in mice and rats and 2 were in vitro studies. The three epidemiological studies reported from the same longitudinal study and suggested that MDMA exposure during pregnancy impairs neuromotor function in infants. In rat, postnatal exposure towards MDMA also caused locomotor deficits as well as impaired spatial learning that might be associated with decreased serotonin levels in the hippocampus. In vitro MDMA caused cytotoxicity at high concentrations and effects on the serotonergic and neuritogenic alterations at lower concentrations which are in line with some of the in vivo alterations observed. Considering the adverse outcomes of developmental MDMA described in humans and in rodents we summarized the first putative AOP on developmental compound exposure leading to impaired neuromotor function in children. For generation of this AOP, MDMA exposure was taken as a model compound. In addition, we hypothesized a second AOP involving developmental disturbance of the dopaminergic system. However, further in vitro mechanistic studies are needed to understand the molecular initiating event(s) (MIE) triggering the downstream cascades and obtain consistent evidences causally linking the adverse outcome to effects at the cellular, organ and organism level.

中文翻译：

---

MDMA的发育性神经毒性。系统的文献综述总结了一个假定的不良结局途径。

孕妇越来越多地使用非法药物引起了公共卫生方面的关注，因为这与母亲及其成年子女的健康风险有关。这类药物之一是MDMA（3,4-亚甲二氧基甲基苯丙胺）或摇头丸，因为它在相关年龄和性别人群中消耗量很大，并且对人和啮齿动物的大脑产生不利影响。为了彻底回顾有关MDMA的发展性神经毒性潜力的当前知识，我们系统地收集和总结了研究MDMA在体内和体外对人和动物的发育性神经毒性（DNT）的文章。此外，我们在推定的不良结局途径（AOP）中总结了这些发现。从书目数据库Web of Science，PubMed和DART检索到的最初299条文章中，我们根据纳入/排除标准选择了39篇文章，用于标题/摘要和全文筛选后的数据收集。在这3项流行病学研究中，有34项在小鼠和大鼠中进行了体内研究，有2项是在体外进行了研究。同一纵向研究报告的三项流行病学研究表明，怀孕期间的MDMA暴露会损害婴儿的神经运动功能。在大鼠中，产后暴露于MDMA也会导致运动功能障碍以及空间学习受损，这可能与海马体中5-羟色胺水平降低有关。体外MDMA在高浓度下会引起细胞毒性，在较低浓度下会对血清素能和神经原性改变产生影响，这与观察到的某些体内改变一致。考虑到在人类和啮齿动物中描述的发育性MDMA的不良后果，我们总结了关于发育性化合物暴露导致儿童神经运动功能受损的第一个推定的AOP。为了产生该AOP，将MDMA暴露作为模型化合物。此外，我们假设第二个AOP涉及多巴胺能系统的发育障碍。但是，需要进一步的体外机制研究来了解触发下游级联反应的分子引发事件（MIE），并获得一致的证据，将不良后果与细胞，器官和生物体水平的影响联系起来。将MDMA暴露作为模型化合物。此外，我们假设第二个AOP涉及多巴胺能系统的发育障碍。但是，需要进一步的体外机制研究来了解触发下游级联反应的分子引发事件（MIE），并获得一致的证据，将不良后果与细胞，器官和生物体水平的影响联系起来。将MDMA暴露作为模型化合物。此外，我们假设第二个AOP涉及多巴胺能系统的发育障碍。但是，需要进一步的体外机制研究来了解触发下游级联反应的分子引发事件（MIE），并获得一致的证据，将不良后果与细胞，器官和生物体水平的影响联系起来。