Department of Public Health, Division of Environmental Health Science, School of Health Sciences and Practice, New York Medical College, Valhalla, New York.
Institute of Experimental Endocrinology, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia.
Dev Neurobiol. 2018 Apr;78(4):403-416. doi: 10.1002/dneu.22582. Epub 2018 Feb 14.
Tetramethylenedisulfotetramine (TMDT) is a synthetic neurotoxic rodenticide considered a chemical threat agent. Symptoms of intoxication include seizures leading to status epilepticus and death. While children and women have been often the victims, no studies exist investigating the neurotoxic effects of TMDT in developing individuals or females. Thus, we performed such an investigation in developing Sprague-Dawley rats of both sexes in order to identify potential age- or sex-dependent vulnerability to TMDT exposure. Subcutaneous injection was chosen as the preferred route of TMDT exposure. EEG recordings confirmed the seizure activity observed in both postnatal day 15 (P15) and adult rats. Additionally, P15 rats displayed greater sensitivity to TMDT than postnanatal day 25 or adult animals. Seizures were generally more severe in females compared to males. Barrel rotations accompanied convulsions in P25 and adult, but sparsely in P15 rats. Adults developed barrel rolling less frequently than P25 population. Neuronal cell death was not present in 24-h TMDT survivors at any age or sex tested. A seizure rechallenge with flurothyl 7 days following TMDT exposure demonstrated longer latencies to the first clonic seizure but a faster progression into the tonic-clonic seizure in P15 and adult survivors as compared to their vehicle-injected counterparts. In conclusion, the youngest age group represents the most vulnerable population to the TMDT-induced toxidrome. Females appear to be more vulnerable than males. TMDT exposure promotes seizure spread and progression in survivors. These findings will help to establish sex- and age-specific treatment strategies for TMDT-exposed individuals. © 2018 Wiley Periodicals, Inc. Develop Neurobiol 78: 403-416, 2018.
四亚甲基二砜四胺（TMDT）是一种合成的神经毒性杀鼠剂，被认为是一种化学威胁剂。中毒症状包括导致癫痫持续状态和死亡的癫痫发作。虽然儿童和妇女经常成为受害者，但没有研究调查 TMDT 在发育中的个体或女性中的神经毒性作用。因此，我们在发育中的雄性和雌性 Sprague-Dawley 大鼠中进行了这样的调查，以确定对 TMDT 暴露的潜在年龄或性别依赖性易感性。皮下注射被选为 TMDT 暴露的首选途径。脑电图记录证实了在出生后第 15 天（P15）和成年大鼠中观察到的癫痫发作活动。此外，P15 大鼠对 TMDT 的敏感性高于出生后第 25 天或成年动物。与雄性相比，雌性的癫痫发作通常更严重。在 P25 和成年大鼠中，桶旋转伴随着抽搐，但在 P15 大鼠中则很少见。成年大鼠的桶旋转发作频率低于 P25 群体。在任何年龄或性别测试中，24 小时 TMDT 幸存者均未出现神经元细胞死亡。在 TMDT 暴露后 7 天用氟烷进行癫痫再挑战时，与对照组相比，P15 和成年幸存者的首次强直-阵挛性癫痫发作潜伏期延长，但进入强直-阵挛性癫痫发作的速度更快。总之，最年轻的年龄组代表最易受 TMDT 诱导的毒蕈碱样综合征影响的人群。女性比男性更容易受到影响。TMDT 暴露会促进幸存者的癫痫发作扩散和进展。这些发现将有助于为 TMDT 暴露个体建立特定于性别和年龄的治疗策略。©2018 威利期刊公司，发展神经生物学 78：403-416，2018 年。
