Division of High Risk Pregnancy, Department of Obstetrics and Gynecology, MacKay Memorial Hospital, Taipei, Taiwan.
Department of Medical Research, MacKay Memorial Hospital, Taipei, Taiwan.
Cell Mol Biol Lett. 2023 Aug 17;28(1):67. doi: 10.1186/s11658-023-00480-7.
Prenatal infection has been implicated in the development of neuropsychiatric disorders in children. We hypothesised that exposure to lipopolysaccharide during prenatal development could induce anxiety-like behaviour and sensorineural hearing loss in offspring, as well as disrupt neural differentiation during embryonic neural development.
We simulated prenatal infection in FVB mice and mouse embryonic stem cell (ESC) lines, specifically 46C and E14Tg2a, through lipopolysaccharide treatment. Gene expression profiling analyses and behavioural tests were utilized to study the effects of lipopolysaccharide on the offspring and alterations in toll-like receptor (TLR) 2-positive and TLR4-positive cells during neural differentiation in the ESCs.
Exposure to lipopolysaccharide (25 µg/kg) on gestation day 9 resulted in anxiety-like behaviour specifically in male offspring, while no effects were detected in female offspring. We also found significant increases in the expression of GFAP and CNPase, as well as higher numbers of GFAP + astrocytes and O4+ oligodendrocytes in the prefrontal cortex of male offspring. Furthermore, increased scores for genes related to oligodendrocyte and lipid metabolism, particularly ApoE, were observed in the prefrontal cortex regions. Upon exposure to lipopolysaccharide during the ESC-to-neural stem cell (NSC) transition, Tuj1, Map2, Gfap, O4, and Oligo2 mRNA levels increased in the differentiated neural cells on day 14. In vitro experiments demonstrated that lipopolysaccharide exposure induced inflammatory responses, as evidenced by increased expression of IL1b and ApoB mRNA.
Our findings suggest that prenatal infection at different stages of neural differentiation may result in distinct disturbances in neural differentiation during ESC-NSC transitions. Furthermore, early prenatal challenges with lipopolysaccharide selectively induce anxiety-like behaviour in male offspring. This behaviour may be attributed to the abnormal differentiation of astrocytes and oligodendrocytes in the brain, potentially mediated by ApoB/E signalling pathways in response to inflammatory stimuli.
产前感染被认为与儿童神经精神疾病的发生有关。我们假设，在胚胎发育过程中暴露于脂多糖可能会导致后代出现类似焦虑的行为和感觉神经性听力损失，并破坏胚胎神经发育过程中的神经分化。
我们通过脂多糖处理模拟了 FVB 小鼠和小鼠胚胎干细胞（ESC）系 46C 和 E14Tg2a 的产前感染。利用基因表达谱分析和行为测试研究了脂多糖对后代的影响，以及脂多糖对 ESC 中神经分化过程中 TLR2 阳性和 TLR4 阳性细胞的影响。
在妊娠第 9 天给予脂多糖（25μg/kg）暴露，仅雄性后代出现类似焦虑的行为，而雌性后代未出现这种影响。我们还发现雄性后代前额叶皮层中 GFAP 和 CNPase 的表达显著增加，GFAP+星形胶质细胞和 O4+少突胶质细胞数量也增加。此外，还观察到与少突胶质细胞和脂质代谢相关的基因，特别是 ApoE，在额前皮质区域的表达增加。在 ESC 向神经干细胞（NSC）过渡期间暴露于脂多糖，在分化的神经细胞中，Tuj1、Map2、Gfap、O4 和 Oligo2 的 mRNA 水平在第 14 天增加。体外实验表明，脂多糖暴露诱导了炎症反应，表现为 IL1b 和 ApoB mRNA 的表达增加。
我们的研究结果表明，神经分化的不同阶段的产前感染可能导致 ESC-NSC 过渡期间神经分化的不同程度的紊乱。此外，早期产前脂多糖暴露选择性地诱导雄性后代出现类似焦虑的行为。这种行为可能归因于大脑中星形胶质细胞和少突胶质细胞的异常分化，可能是对炎症刺激的 ApoB/E 信号通路的反应。
