Prenatal low-dose Bisphenol A exposure impacts cortical development via cAMP-PKA-CREB pathway in offspring

IF 2.6 3区医学 Q2 BEHAVIORAL SCIENCES

Frontiers in Integrative Neuroscience Pub Date : 2024-08-07 DOI:10.3389/fnint.2024.1419607

Chu Jiang, Jun Guan, Xiangrong Tang, Yichun Zhang, Xiangyu Li, Yuting Li, Zhiheng Chen, Jing Zhang, Jia-Da Li

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Abstract

Bisphenol A (BPA) is a widely used plasticizer known to cause various disorders. Despite a global reduction in the use of BPA-containing products, prenatal exposure to low-dose BPA, even those below established safety limits, has been linked to neurological and behavioral deficits in childhood. The precise mechanisms underlying these effects remain unclear. In the present study, we observed a significant increase in the number of cortical neurons in offspring born to dams exposed to low-dose BPA during pregnancy. We also found that this prenatal exposure to low-dose BPA led to increased proliferation but reduced migration of cortical neurons. Transcriptomic analysis via RNA sequencing revealed an aberrant activation of the cAMP-PKA-CREB pathway in offspring exposed to BPA. The use of H89, a selective PKA inhibitor, effectively rescued the deficits in both proliferation and migration of cortical neurons. Furthermore, offspring from dams exposed to low-dose BPA exhibited manic-like behaviors, including hyperactivity, anti-depressant-like responses, and reduced anxiety. While H89 normalized hyperactivity, it didn't affect the other behavioral changes. These results suggest that the overactivation of PKA plays a causative role in BPA-induced changes in neuronal development. Our data also indicate that manic-like behaviors induced by prenatal low-dose BPA exposure may be influenced by both altered neuronal development and abnormal PKA signaling in adulthood.

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产前低剂量双酚 A 暴露通过 cAMP-PKA-CREB 通路影响后代大脑皮层的发育

双酚 A（BPA）是一种广泛使用的塑化剂，已知会导致各种疾病。尽管全球范围内都在减少含双酚 A 产品的使用，但产前接触低剂量的双酚 A（即使低于既定的安全限值）仍与儿童期的神经和行为缺陷有关。这些影响的确切机制尚不清楚。在本研究中，我们观察到在孕期暴露于低剂量双酚 A 的母体所生后代的大脑皮层神经元数量显著增加。我们还发现，产前暴露于低剂量双酚 A 会导致大脑皮层神经元增殖增加，但迁移减少。通过 RNA 测序进行的转录组分析表明，暴露于双酚 A 的后代体内 cAMP-PKA-CREB 通路被异常激活。使用 H89（一种选择性 PKA 抑制剂）可有效缓解大脑皮层神经元增殖和迁移的缺陷。此外，母体暴露于低剂量双酚 A 的后代表现出类似狂躁症的行为，包括多动、抗抑郁样反应和焦虑减少。虽然H89能使多动正常化，但并不影响其他行为变化。这些结果表明，PKA 的过度激活在双酚 A 诱导的神经元发育变化中起着致病作用。我们的数据还表明，产前低剂量双酚 A 暴露诱发的躁狂症样行为可能同时受到神经元发育改变和成年后 PKA 信号异常的影响。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Frontiers in Integrative Neuroscience Neuroscience-Cellular and Molecular Neuroscience

CiteScore

4.60

自引率

2.90%

发文量

148

审稿时长

14 weeks

期刊介绍： Frontiers in Integrative Neuroscience publishes rigorously peer-reviewed research that synthesizes multiple facets of brain structure and function, to better understand how multiple diverse functions are integrated to produce complex behaviors. Led by an outstanding Editorial Board of international experts, this multidisciplinary open-access journal is at the forefront of disseminating and communicating scientific knowledge and impactful discoveries to researchers, academics, clinicians and the public worldwide. Our goal is to publish research related to furthering the understanding of the integrative mechanisms underlying brain functioning across one or more interacting levels of neural organization. In most real life experiences, sensory inputs from several modalities converge and interact in a manner that influences perception and actions generating purposeful and social behaviors. The journal is therefore focused on the primary questions of how multiple sensory, cognitive and emotional processes merge to produce coordinated complex behavior. It is questions such as this that cannot be answered at a single level – an ion channel, a neuron or a synapse – that we wish to focus on. In Frontiers in Integrative Neuroscience we welcome in vitro or in vivo investigations across the molecular, cellular, and systems and behavioral level. Research in any species and at any stage of development and aging that are focused at understanding integration mechanisms underlying emergent properties of the brain and behavior are welcome.