Buchenauer Lisa, Haange Sven-Bastiaan, Bauer Mario, Rolle-Kampczyk Ulrike E, Wagner Marita, Stucke Johanna, Elter Elena, Fink Beate, Vass Maren, von Bergen Martin, Schulz Angela, Zenclussen Ana C, Junge Kristin M, Stangl Gabriele I, Polte Tobias
Helmholtz Centre for Environmental Research - UFZ, Department of Environmental Immunology, Leipzig, Germany; University of Leipzig, Leipzig University Medical Center, Department of Dermatology, Venerology and Allergology, Leipzig, Germany.
Helmholtz Centre for Environmental Research - UFZ, Department of Molecular Systems Biology, Leipzig, Germany.
Sci Total Environ. 2023 Dec 20;905:167034. doi: 10.1016/j.scitotenv.2023.167034. Epub 2023 Sep 12.
The past decade has been characterized by increased awareness and de-stigmatization of mental health issues, in particular the most common neuropsychiatric disorders depression and anxiety. Further, with growing understanding of neurodevelopmental disorders such as attention deficit and hyperactivity disorder and autism spectrum disorder, the number of diagnosed patients has increased. The pathogenesis of these behavioral disorders is multifactorial and early-life exposure to environmental chemicals has been proposed to be a relevant risk factor that might mediate these effects by disturbances on the gut-brain-axis. However, for glyphosate, the most widely used pesticide worldwide, there are only limited and inconsistent findings that link chronic low-dose exposure in particular during early life to neurobehavioral disorders. Here, we explored the impact of maternal oral glyphosate exposure (0.5 and 50 mg/kg body weight/day) during pregnancy and the lactational period on offspring's behavior, brain gene expression and gut microbiota using a cross-generational mouse model. Behavioral analyses revealed a depression- and anxiety-like behavior as well as social deficits most notably in adult female offspring of glyphosate-exposed dams. Furthermore, the expression of tryptophan hydroxylase 2, an enzyme discussed to be linked to behavioral problems, was reduced in the hippocampus of female offspring and correlated to a glyphosate-induced DNA hypermethylation of the gene. Moreover, maternal glyphosate exposure significantly altered the gut microbiota in the female offspring including a decreased abundance of Akkermansia and increased abundance of Alistipes and Blautia, bacteria involved in tryptophan metabolism and associated with depression- and anxiety-like disorders. Our results suggest that glyphosate might influence the gut-brain axis crosstalk following in-utero and lactational exposure. This study underlines the importance of understanding the impact of exposure to pesticides on the gut-brain axis and further emphasizes the need for microbiome analyses to be compulsorily included in health risk assessments of pesticides.
在过去十年中，人们对心理健康问题的认识有所提高，对其污名化程度也有所降低，尤其是最常见的神经精神疾病——抑郁症和焦虑症。此外，随着对注意力缺陷多动障碍和自闭症谱系障碍等神经发育障碍的了解不断增加，确诊患者的数量也有所上升。这些行为障碍的发病机制是多因素的，有观点认为，生命早期接触环境化学物质可能是一个相关风险因素，它可能通过扰乱肠脑轴来介导这些影响。然而，对于草甘膦这种全球使用最广泛的农药，仅有有限且不一致的研究结果表明，尤其是生命早期的慢性低剂量接触与神经行为障碍有关。在此，我们使用跨代小鼠模型，探究了孕期和哺乳期母体经口暴露于草甘膦（0.5和50毫克/千克体重/天）对后代行为、脑基因表达和肠道微生物群的影响。行为分析显示，暴露于草甘膦的母鼠所产成年雌性后代出现了类似抑郁和焦虑的行为以及社交缺陷。此外，色氨酸羟化酶2（一种被认为与行为问题有关的酶）在雌性后代海马体中的表达降低，且与草甘膦诱导的该基因DNA高甲基化相关。此外，母体草甘膦暴露显著改变了雌性后代的肠道微生物群，包括阿克曼氏菌丰度降低，以及参与色氨酸代谢且与类似抑郁和焦虑障碍相关的阿利斯杆菌属和布劳特氏菌属丰度增加。我们的结果表明，草甘膦可能在子宫内和哺乳期暴露后影响肠脑轴的相互作用。这项研究强调了了解农药暴露对肠脑轴影响的重要性，并进一步强调了在农药健康风险评估中必须纳入微生物组分析的必要性。
