Oummadi Asma, Menuet Arnaud, Méresse Sarah, Laugeray Anthony, Guillemin Gilles, Mortaud Stéphane
Experimental and Molecular Immunology and Neurogenetics, UMR7355 CNRS, Orléans, France.
Faculty of Medicine and Human Health Sciences, Center for MND Research, Macquarie University, Sydney, NSW, Australia.
Front Neurosci. 2023 Jun 9;17:1172693. doi: 10.3389/fnins.2023.1172693. eCollection 2023.
Prenatal maternal immune activation (MIA) and/or perinatal exposure to various xenobiotics have been identified as risk factors for neurological disorders, including neurodegenerative diseases. Epidemiological data suggest an association between early multi-exposures to various insults and neuropathologies. The "multiple-hit hypothesis" assumes that prenatal inflammation makes the brain more susceptible to subsequent exposure to several kinds of neurotoxins. To explore this hypothesis and its pathological consequences, a behavioral longitudinal procedure was performed after prenatal sensitization and postnatal exposure to low doses of pollutants.
Maternal exposure to an acute immune challenge (first hit) was induced by an asymptomatic lipopolysaccharide (LPS) dose (0.008 mg/kg) in mice. This sensitization was followed by exposing the offspring to environmental chemicals (second hit) postnatally, by the oral route. The chemicals used were low doses of the cyanotoxin β-N-methylamino-l-alanine (BMAA; 50 mg/kg), the herbicide glufosinate ammonium (GLA; 0.2 mg/kg) or the pesticide glyphosate (GLY; 5 mg/kg). After assessing maternal parameters, a longitudinal behavioral assessment was carried out on the offspring in order to evaluate motor and emotional abilities in adolescence and adulthood.
We showed that the low LPS immune challenge was an asymptomatic MIA. Even though a significant increase in systemic pro-inflammatory cytokines was detected in the dams, no maternal behavioral defects were observed. In addition, as shown by rotarod assays and open field tests, this prenatal LPS administration alone did not show any behavioral disruption in offspring. Interestingly, our data showed that offspring subjected to both MIA and post-natal BMAA or GLA exposure displayed motor and anxiety behavioral impairments during adolescence and adulthood. However, this synergistic effect was not observed in the GLY-exposed offspring.
These data demonstrated that prenatal and asymptomatic immune sensitization represents a priming effect to subsequent exposure to low doses of pollutants. These double hits act in synergy to induce motor neuron disease-related phenotypes in offspring. Thus, our data strongly emphasize that multiple exposures for developmental neurotoxicity regulatory assessment must be considered. This work paves the way for future studies aiming at deciphering cellular pathways involved in these sensitization processes.
产前母体免疫激活（MIA）和/或围产期接触各种外源性物质已被确定为包括神经退行性疾病在内的神经系统疾病的风险因素。流行病学数据表明，早期多次接触各种损伤因素与神经病理学之间存在关联。“多重打击假说”认为，产前炎症会使大脑更容易受到随后接触几种神经毒素的影响。为了探索这一假说及其病理后果，在产前致敏和产后接触低剂量污染物后进行了一项行为纵向研究。
通过给小鼠注射无症状剂量的脂多糖（LPS，0.008mg/kg）诱导母体暴露于急性免疫挑战（首次打击）。在这种致敏之后，通过口服途径使后代在出生后接触环境化学物质（第二次打击）。所使用的化学物质为低剂量的氰毒素β-N-甲基氨基-L-丙氨酸（BMAA，50mg/kg）、除草剂草铵膦（GLA，0.2mg/kg）或杀虫剂草甘膦（GLY，5mg/kg）。在评估母体参数后，对后代进行纵向行为评估，以评估其在青春期和成年期的运动和情绪能力。
我们表明，低剂量LPS免疫挑战是一种无症状的MIA。尽管在母鼠中检测到全身促炎细胞因子显著增加，但未观察到母体行为缺陷。此外，如转棒试验和旷场试验所示，单独给予这种产前LPS并未在后代中显示出任何行为干扰。有趣的是，我们的数据表明，同时经历MIA和产后BMAA或GLA暴露的后代在青春期和成年期表现出运动和焦虑行为障碍。然而，在接触GLY的后代中未观察到这种协同效应。
这些数据表明，产前无症状免疫致敏对随后接触低剂量污染物具有启动作用。这两次打击协同作用，在后代中诱导出与运动神经元疾病相关的表型。因此，我们的数据强烈强调，在发育神经毒性监管评估中必须考虑多次暴露。这项工作为未来旨在破译这些致敏过程中涉及的细胞途径的研究铺平了道路。
