Sheibani Tezerji Sara, Jonaidi Hossein, Sheibani Vahid, Moslemizadeh Amirhossein, Azizi Shahrzad, Dalili Maryam, Bashiri Hamideh, Amiresmaili Sedigheh
Faculty of Veterinary Medicine, Shahid Bahonar University of Kerman, Kerman, Iran.
Department of Behavioral and Molecular Neurobiology, Regensburg Center for Neuroscience, University of Regensburg, Regensburg, Germany.
Int J Dev Neurosci. 2025 Feb;85(1):e70004. doi: 10.1002/jdn.70004.
Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by persistent social communication deficits and restricted, repetitive behaviours, with significant overlap in anxiety-related symptoms. Both genetic and environmental factors contribute to the development of ASD, with early-life stressors, such as maternal separation (MS), and exposure to neurotoxic agents, like valproic acid (VPA), being key environmental contributors. This study investigates the combined impact of maternal deprivation (MD) and postnatal VPA exposure on autism-like behaviours and neurodevelopmental outcomes in male and female rats. Rats exposed to MD from postnatal days 2 to 4 exhibited significant changes in social interaction and anxiety-like behaviours, with female rats being more sensitive to MD than males. Postnatal VPA exposure resulted in similar behavioural alterations, including increased anxiety and social impairment, aligning with previous findings of VPA-induced neurodevelopmental deficits. A combination of MD and VPA exposure exacerbated anxiety-like behaviours in females, indicating that early-life stress and environmental toxins can synergistically affect neurodevelopment. Our results further suggest that the impact of these exposures may differ between sexes, with females showing heightened sensitivity to both MD and VPA-induced stress. These findings provide valuable insights into the complex interactions between genetic, environmental and epigenetic factors in ASD pathophysiology. The study underscores the critical role of early-life stressors, such as MD, in exacerbating neurodevelopmental disorders, particularly when combined with neurotoxic environmental factors like VPA. The sex-specific differences observed in behavioural outcomes suggest the importance of considering biological sex in future ASD research and therapeutic strategies.
自闭症谱系障碍（ASD）是一种神经发育障碍，其特征为持续存在的社交沟通缺陷以及局限的、重复的行为，且与焦虑相关症状存在显著重叠。遗传和环境因素均对ASD的发展有影响，早期生活应激源，如母婴分离（MS），以及接触神经毒性物质，如丙戊酸（VPA），是关键的环境影响因素。本研究调查了母婴剥夺（MD）和产后VPA暴露对雄性和雌性大鼠自闭症样行为及神经发育结局的联合影响。从出生后第2天至第4天暴露于MD的大鼠在社交互动和焦虑样行为方面表现出显著变化，雌性大鼠比雄性大鼠对MD更敏感。产后VPA暴露导致了类似的行为改变，包括焦虑增加和社交障碍，这与先前关于VPA诱导的神经发育缺陷的研究结果一致。MD和VPA暴露相结合加剧了雌性大鼠的焦虑样行为，表明早期生活应激和环境毒素可协同影响神经发育。我们的结果进一步表明，这些暴露的影响可能因性别而异，雌性大鼠对MD和VPA诱导的应激均表现出更高的敏感性。这些发现为ASD病理生理学中遗传、环境和表观遗传因素之间的复杂相互作用提供了有价值的见解。该研究强调了早期生活应激源，如MD，在加剧神经发育障碍方面的关键作用，特别是当与VPA等神经毒性环境因素相结合时。在行为结局中观察到的性别特异性差异表明在未来的ASD研究和治疗策略中考虑生物性别的重要性。
