Di Re Jessica, Koff Leandra, Avchalumov Yosef, Singh Aditya K, Baumgartner Timothy J, Marosi Mate, Matz Lisa M, Hallberg Lance M, Ameredes Bill T, Seeley Erin H, Buffington Shelly A, Green Thomas A, Laezza Fernanda
Department of Pharmacology & Toxicology, University of Texas Medical Branch, Galveston, TX 77555, USA; NIEHS Environmental Toxicology Training Program, University of Texas Medical Branch, USA.
Department of Pharmacology & Toxicology, University of Texas Medical Branch, Galveston, TX 77555, USA.
J Hazard Mater. 2025 Mar 5;485:136893. doi: 10.1016/j.jhazmat.2024.136893. Epub 2024 Dec 16.
Environmental exposure to pesticides at levels deemed safe by regulatory agencies has been linked to increased risk for neurodevelopmental disorders. Yet, the mechanisms linking exposure to these disorders remain unclear. Here, we show that maternal exposure to the pesticide deltamethrin (DM) at the no observed adverse effect level (NOAEL) disrupts long-term potentiation (LTP) in the hippocampus of adult male offspring three months after exposure, a phenotype absent in female offspring. Clonazepam, a GABAa receptor agonist, rescued this deficit, indicating impaired hippocampal GABAergic signaling. Recordings from CA1 pyramidal neurons, complemented by MALDI mass spectrometry imaging, showed an imbalance in excitatory/inhibitory tone. Using a combination of parvalbumin (PV)-Cre transgenic mice and hippocampal injection of designer receptors exclusively activated by designer drugs (DREADDs), we show that developmental DM exposure reduces hippocampal PV interneuron intrinsic firing. DREADD activation rescued both PV interneuron firing and LTP deficits. Complementary behavioral experiments revealed a deficit in social memory, a behavior relevant to autism spectrum disorder (ASD) symptomatology, which was restored by DREADD activation. Overall, these results establish a novel mechanistic link between maternal exposure to DM at the NOAEL and known cellular, circuital, and behavioral vulnerabilities, indicating it is a potential driver in the exposome of ASD.
监管机构认为安全水平的环境农药暴露与神经发育障碍风险增加有关。然而，将暴露与这些疾病联系起来的机制仍不清楚。在此，我们表明，母体在未观察到不良反应水平（NOAEL）下暴露于农药溴氰菊酯（DM），会在成年雄性后代暴露三个月后的海马体中破坏长期增强（LTP），而雌性后代则不存在这种表型。氯硝西泮，一种GABAa受体激动剂，挽救了这一缺陷，表明海马体GABA能信号受损。CA1锥体神经元的记录，辅以基质辅助激光解吸电离质谱成像，显示兴奋/抑制平衡失调。结合小白蛋白（PV）-Cre转基因小鼠和海马体注射仅由设计药物激活的设计受体（DREADDs），我们表明发育过程中暴露于DM会降低海马体PV中间神经元的固有放电。DREADD激活挽救了PV中间神经元放电和LTP缺陷。补充行为实验揭示了社交记忆缺陷，这是一种与自闭症谱系障碍（ASD）症状相关的行为，DREADD激活可恢复该缺陷。总体而言，这些结果在母体在NOAEL下暴露于DM与已知的细胞、环路和行为易感性之间建立了一种新的机制联系，表明它是ASD暴露组中的一个潜在驱动因素。
