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<p>Autism spectrum disorders (ASD) affect approximately 1.0% of children worldwide with still increasing global prevalence. The fact that genetic factors contribute to less than 50% of ASD suggests some critical yet enigmatic roles of non-genetic factors in ASD etiology. Here, we reported that montelukast (MTK), a cysteinyl leukotriene receptor antagonist and one of the most commonly prescribed anti-asthma drugs, potently disrupted neuronal retinoic acid (RA) signaling and altered synaptic plasticity of the primary neurons from rat pre-frontal cortex (PFC). Prenatal or early postnatal exposure to MTK induced autistic-like behaviors in wild-type rats, which could be significantly alleviated by supplementing all-trans retinoic acid (atRA). MTK altered neuronal RA signaling and forebrain patterning in brain organoids derived from human embryonic stem cells through antagonizing RA in RA signaling. Meanwhile, molecular docking followed by biochemical validation strongly indicated that MTK could physically interact with RA receptors (RARs), e.g. RA receptor α (RARA). Furthermore, multi-center survey with a large Chinese ASD cohort suggested that MTK administration during early childhood might indeed increase the risk of ASD in children. Altogether, our findings have not only established MTK use as a yet unrecognized risk factor for human ASD, but highlighted the key importance of safer use of medicines to prevent ASD.</p>

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Anti-asthma drug montelukast induces autistic behaviors via disrupting neuronal retinoic acid signaling

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月2日

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  • Zi-Jian Hao,
  • Qiong-Hui Wu,
  • Ya-Li Li,
  • Zhen-Ming Guo,
  • Zheng-Wei Li,
  • Gui Wang,
  • Meng Meng,
  • Shi-Lin Yuan,
  • Yilimire Wufuer,
  • Meng-Huan Zhang,
  • Jie Chen,
  • Ting Yang,
  • Meng-Xia Chen,
  • Jiang Zhu,
  • Wang Qi-Hang,
  • Qiu Li,
  • Shi-Hu Yu,
  • Min Lu,
  • Hai-Yi Xiong,
  • Yu-Ru Feng,
  • Meng-Qi Dong,
  • Jun-Hao Xu,
  • Jia-Lin Xu,
  • Li Chen,
  • Han-Ting Yang,
  • Jing-Kun Miao,
  • Hong Zhu,
  • Bo Yang,
  • Hui-Ying Zhao,
  • Xiao-Ming Shi,
  • Shan Bian,
  • Ting-Yu Li,
  • Rong-Gui Hu

摘要

Autism spectrum disorders (ASD) affect approximately 1.0% of children worldwide with still increasing global prevalence. The fact that genetic factors contribute to less than 50% of ASD suggests some critical yet enigmatic roles of non-genetic factors in ASD etiology. Here, we reported that montelukast (MTK), a cysteinyl leukotriene receptor antagonist and one of the most commonly prescribed anti-asthma drugs, potently disrupted neuronal retinoic acid (RA) signaling and altered synaptic plasticity of the primary neurons from rat pre-frontal cortex (PFC). Prenatal or early postnatal exposure to MTK induced autistic-like behaviors in wild-type rats, which could be significantly alleviated by supplementing all-trans retinoic acid (atRA). MTK altered neuronal RA signaling and forebrain patterning in brain organoids derived from human embryonic stem cells through antagonizing RA in RA signaling. Meanwhile, molecular docking followed by biochemical validation strongly indicated that MTK could physically interact with RA receptors (RARs), e.g. RA receptor α (RARA). Furthermore, multi-center survey with a large Chinese ASD cohort suggested that MTK administration during early childhood might indeed increase the risk of ASD in children. Altogether, our findings have not only established MTK use as a yet unrecognized risk factor for human ASD, but highlighted the key importance of safer use of medicines to prevent ASD.