State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, Fujian 361102, People's Republic of China; Department of Occupational and Environmental Health, Guilin Medical University, Guilin, Guangxi 541004, People's Republic of China; Guangxi Colleges and University Key Laboratory of Preventive Medicine, Guilin Medical University, Guilin, Guangxi 541004, People's Republic of China.
Department of Nutrition and Food Hygiene, Guilin Medical University, Guilin, Guangxi 541004, People's Republic of China; Guangxi Colleges and University Key Laboratory of Preventive Medicine, Guilin Medical University, Guilin, Guangxi 541004, People's Republic of China.
Ecotoxicol Environ Saf. 2021 Jul 1;217:112198. doi: 10.1016/j.ecoenv.2021.112198. Epub 2021 Apr 13.
The mechanism of neurodevelopmental toxicity of decabromodiphenyl ether (BDE209) remains unclear. Recent evidence suggests that neurosteroids disorders play a vital role in BDE209 induced-neurodevelopmental toxicity. To explore the mechanism of it, pregnant ICR mice were orally gavaged with 0, 225, and 900 mg kg BDE209 for about 42 days. Spatial learning and memory abilities of offspring were tested on postnatal day (PND) 21. Offspring were euthanized at PND26, the neuronal structure, neurosteroids level, and related proteins including neurosteroids synthase, ionotropic receptors and cAMP-response element binding protein (CREB) pathway were evaluated, as well as Ca concentration and the mitochondrial membrane potential (Mmp). Our results showed that BDE209 impaired learning and memory abilities and disrupted neuronal structure. Meanwhile, BDE209 decreased the pregnenolone (PREG), dehydroepiandrosterone (DHEA), progesterone (PROG) and allopregnanolone (ALLO) levels in the serum and brain, as well as the mRNA and protein levels of cholesterol-side-chain cleavage enzyme (P450scc), steroid 17α-hy-droxylase (P450C17), 3β-hydroxysteroid dehydrogenase (3β-HSD) and steroid 5α-reductase of type I (5α-R) in the hippocampi. Also, BDE209 suppressed mRNA and protein levels of NR1, NR2A and NR2B subunits of the N-methyl-D-aspartic acid receptor (NMDAR) and α1 subunit of the Gamma-amino butyric acid A receptor (GABAAR), but increased the levels of β2 and γ2 subunits of the GABAAR in the hippocampi. Moreover, BDE209 increased the Ca concentration and phosphorylation extracellular regulated protein kinases (P-ERK) 1/2 level, but decreased the P-CREB and Mmp level in the hippocampi. These results indicate that BDE209 exposure during pregnancy and lactation is possible to affect learning and memory formation of offspring by the neurosteroid-mediated ionotropic receptors dysfunction.
十溴联苯醚（BDE209）的神经发育毒性机制尚不清楚。最近的证据表明，神经甾体紊乱在 BDE209 诱导的神经发育毒性中起着至关重要的作用。为了探讨其机制，将怀孕的 ICR 小鼠用 0、225 和 900mg/kg BDE209 灌胃约 42 天。在产后第 21 天（PND21）测试后代的空间学习和记忆能力。在 PND26 处死后代，评估神经元结构、神经甾体水平以及包括神经甾体合成酶、离子型受体和 cAMP 反应元件结合蛋白（CREB）通路在内的相关蛋白，以及 Ca 浓度和线粒体膜电位（Mmp）。结果显示，BDE209 损害了学习和记忆能力，破坏了神经元结构。同时，BDE209 降低了血清和脑中的 pregnenolone（PREG）、dehydroepiandrosterone（DHEA）、progesterone（PROG）和 allo-pregnanolone（ALLO）水平，以及海马中的胆固醇侧链裂解酶（P450scc）、类固醇 17α-羟化酶（P450C17）、3β-羟甾脱氢酶（3β-HSD）和 I 型类固醇 5α-还原酶（5α-R）的 mRNA 和蛋白水平。此外，BDE209 抑制了 N-甲基-D-天冬氨酸受体（NMDAR）NR1、NR2A 和 NR2B 亚单位以及γ-氨基丁酸 A 受体（GABAAR）α1 亚单位的 mRNA 和蛋白水平，但增加了海马中 GABAAR 的β2 和γ2 亚单位水平。此外，BDE209 增加了 Ca 浓度和磷酸化细胞外调节蛋白激酶（P-ERK）1/2 水平，但降低了海马中的 P-CREB 和 Mmp 水平。这些结果表明，孕期和哺乳期暴露于 BDE209 可能通过神经甾体介导的离子型受体功能障碍影响后代的学习和记忆形成。
