Department of Anatomy, Showa University School of Medicine, Tokyo, Japan.
Laboratory of Safety Evaluation, Division of Safety, Hatano Research Institute, Food and Drug Safety Center, Hadano, Japan.
Neuropsychobiology. 2020;79(2):161-169. doi: 10.1159/000504552. Epub 2019 Dec 10.
Prenatal treatment of rats with 5-bromo-2'-deoxyuridine (BrdU) is a neurodevelopmental model showing hyperactivity and impaired sexual activity. Human neurodevelopmental disorders, such as autism, exhibit sex-related pathology, but sex-related neurodevelopment has not been fully investigated in this model. We conducted this study to facilitate the understanding of the pathophysiology of neurodevelopmental disorders.
Pregnant rats received 50 mg/kg BrdU on gestational days 9-15. The tissue content of dopamine (DA), serotonin (5-HT), and their metabolites dihydroxyphenylacetic acid, homovanillic acid, and 5-hydroxyindoleacetic acid were measured in male and female offspring at 3 weeks (juveniles) and 10 weeks (adults) of age.
Prenatally BrdU-treated rats had reduced DA metabolism or DA content in the hypothalamus from the juvenile through the adult period without sex differences, but sex-specific striatal DA abnormalities emerged after maturation. A reduction in 5-HT metabolism was measured in the hypothalamus without sex differences throughout development. Developmental alterations in the striatal 5-HT states were sex-dependent. Temporal changes in DA or 5-HT metabolism were found in the frontal cortex and midbrain.
The sex-specific influence of a genotoxic factor on the development of the DA and 5-HT systems was clarified in the hypothalamus and striatum. The results suggest that the observed sex dependence and region specificity are related to the pathology of social dysfunction in neurodevelopmental disorders.
用 5-溴-2'-脱氧尿苷（BrdU）对大鼠进行产前处理，可建立一种表现出过度活跃和性行为受损的神经发育模型。人类神经发育障碍，如自闭症，表现出与性别相关的病理，但在该模型中，尚未充分研究与性别相关的神经发育。我们进行这项研究，旨在促进对神经发育障碍病理生理学的理解。
在妊娠第 9-15 天，给孕鼠注射 50mg/kg BrdU。在雄性和雌性后代 3 周龄（幼年期）和 10 周龄（成年期）时，测量多巴胺（DA）、5-羟色胺（5-HT）及其代谢物二羟苯乙酸、高香草酸和 5-羟吲哚乙酸在组织中的含量。
从幼年期到成年期，经产前 BrdU 处理的大鼠下丘脑的 DA 代谢或 DA 含量减少，且无性别差异，但成熟后出现了特定于性别的纹状体 DA 异常。在整个发育过程中，下丘脑的 5-HT 代谢减少，且无性别差异。纹状体 5-HT 状态的发育变化具有性别依赖性。在额皮质和中脑发现了 DA 或 5-HT 代谢的时间变化。
在下丘脑和纹状体中，阐明了遗传毒性因素对 DA 和 5-HT 系统发育的特定性别影响。研究结果表明，观察到的性别依赖性和区域特异性与神经发育障碍中社交功能障碍的病理有关。
