Neurotoxicology Research Group, Division of Toxicology, Faculty of Veterinary Medicine, Institute for Risk Assessment Sciences (IRAS), Utrecht University, P.O. Box 80.177, NL-3508 TD, Utrecht, The Netherlands.
Arch Toxicol. 2024 Nov;98(11):3837-3857. doi: 10.1007/s00204-024-03840-0. Epub 2024 Aug 20.
Developmental exposure to carbamates, organophosphates, and pyrethroids has been associated with impaired neurodevelopmental outcomes. Sex-specific differences following chronic insecticide exposure are rather common in vivo. Therefore, we assessed the chronic effects of in vitro exposure to different carbamates (carbaryl, methomyl and aldicarb), organophosphates [chlorpyrifos (CPF), chlorpyrifos-oxon (CPO), and 3,5,6,trichloropyridinol (TCP)], and pyrethroids [permethrin, alpha-cypermethrin and 3-phenoxy benzoic acid (3-PBA)] on neuronal network development in sex-separated rat primary cortical cultures using micro-electrode array (MEA) recordings. Our results indicate that exposure for 1 week to carbaryl inhibited neurodevelopment in male cultures, while a hyperexcitation was observed in female cultures. Methomyl and aldicarb evoked a hyperexcitation after 2 weeks of exposure, which was more pronounced in female cultures. In contrast to acute MEA results, exposure to ≥ 10 µM CPF caused hyperexcitation in both sexes after 10 days. Interestingly, exposure to 10 µM CPO induced a clear hyperexcitation after 10 days of exposure in male but not female cultures. Exposure to 100 µM CPO strongly inhibited neuronal development. Exposure to the type I pyrethroid permethrin resulted in a hyperexcitation at 10 µM and a decrease in neuronal development at 100 µM. In comparison, exposure to ≥ 10 µM of the type II pyrethroid alpha-cypermethrin decreased neuronal development. In female but not in male cultures, exposure to 1 and 10 µM permethrin changed (network) burst patterns, with female cultures having shorter (network) bursts with fewer spikes per (network) burst. Together, these results show that MEA recordings are suitable for measuring sex-specific developmental neurotoxicity in vitro. Additionally, pyrethroid exposure induced effects on neuronal network development at human-relevant concentrations. Finally, chronic exposure has different effects on neuronal functioning compared to acute exposure, highlighting the value of both exposure paradigms.
发育过程中接触氨基甲酸酯类、有机磷和拟除虫菊酯类杀虫剂与神经发育受损有关。在体内，慢性杀虫剂暴露后出现的性别特异性差异相当常见。因此，我们评估了体外暴露于不同氨基甲酸酯（西维因、灭多威和涕灭威）、有机磷（毒死蜱、氧乐果和三氯吡啶醇）和拟除虫菊酯（氯菊酯、氯氰菊酯和 3-苯氧基苯甲酸）对雄性和雌性大鼠原代皮质培养物神经元网络发育的慢性影响，采用微电极阵列（MEA）记录。我们的结果表明，西维因暴露 1 周会抑制雄性培养物的神经发育，而在雌性培养物中观察到兴奋过度。甲萘威和涕灭威暴露 2 周后会引起兴奋过度，在雌性培养物中更为明显。与急性 MEA 结果相反，≥10µM 毒死蜱暴露 10 天后，在两性中均引起兴奋过度。有趣的是，10µM 氧乐果暴露 10 天后在雄性培养物中引起明显的兴奋过度，但在雌性培养物中没有。100µM 氧乐果强烈抑制神经元发育。Ⅰ型拟除虫菊酯氯菊酯在 10µM 时引起兴奋过度，在 100µM 时降低神经元发育。相比之下，≥10µM 的Ⅱ型拟除虫菊酯氯氰菊酯降低神经元发育。在雌性培养物中，但不在雄性培养物中，暴露于 1 和 10µM 氯菊酯改变（网络）爆发模式，雌性培养物的（网络）爆发更短，每个（网络）爆发的尖峰更少。总之，这些结果表明，MEA 记录适用于测量体外的性别特异性发育神经毒性。此外，拟除虫菊酯暴露在人类相关浓度下对神经元网络发育产生影响。最后，慢性暴露与急性暴露相比对神经元功能有不同的影响，突出了这两种暴露模式的价值。
