Department of Psychology and Health Research Center (CEINSA), Laboratory of Psychobiology, University of Almería CeiA3, Carretera de Sacramento s/n, La Cañada de San Urbano, 04120, Almería, Spain.
Biomolecular Mass Spectrometry and Proteomics Group, Faculty of Science, Utrecht University, 3584 CS, Utrecht, The Netherlands.
Mol Neurobiol. 2022 Sep;59(9):5835-5855. doi: 10.1007/s12035-022-02933-0. Epub 2022 Jul 8.
Based on previous reports, exposure to pesticides could be linked to the prevalence increase of autism spectrum disorders (ASD). Gestational exposure to chlorpyrifos (CPF) has been associated with ASD diagnosis in humans and ASD-like behaviors in rodents. However, ASD severity degree results from the complex relationship between genetic background and environmental factors. Thus, animals with a genetic vulnerability and prenatally exposed to CPF could have a more severe ASD-like phenotype. Fragile X syndrome is one of the most common monogenic causes of ASD, characterized by a mutation in the X chromosome which alters the expression of the fragile X mental retardation protein (FMRP). Based on this, some fmr1 knockout (KO) rodent models have been developed to study the physiological and genetic basis of ASD. Both fmr1-KO and wild-type male rats (F2 generation) were used in the present study. F1 pregnant females were randomly exposed to 1 mg/kg/mL/day of CPF (s.c.) from GD12.5-15.5 or vehicle. Different behavioral, developmental, and molecular variables were analyzed in F2 males. KO rats were heavier, emitted altered USVs, were socially inefficient, reacted more to a novel stimulus, were hyperactive when exploring a new context, but hypoactive when exploring anxiety-inducing environments, and had an upregulated hippocampal expression of the grin2c gene. When exposed to low doses of CPF during gestation, these KO rats showed decreased climbing capacity, dysfunctional social interaction, and increased hippocampal expression for kcc1 and 5ht2c genes. Gestational CPF exposure increased the ASD-like phenotype in those animals with a genetic vulnerability, although its effect was less generalized than expected. It is the first time that this additive effect of CPF exposure and the fmr1-KO genetic vulnerability model is explored concerning social traits or any other behavior.
基于先前的报告，接触农药可能与自闭症谱系障碍（ASD）的流行率增加有关。在人类中，妊娠期接触氯蜱硫磷（CPF）与 ASD 诊断有关，而在啮齿动物中则与 ASD 样行为有关。然而，ASD 的严重程度是由遗传背景和环境因素之间的复杂关系决定的。因此，具有遗传易感性并在妊娠期暴露于 CPF 的动物可能具有更严重的 ASD 样表型。脆性 X 综合征是 ASD 最常见的单基因病因之一，其特征是 X 染色体上的突变改变了脆性 X 智力迟钝蛋白（FMRP）的表达。基于此，一些 fmr1 敲除（KO）啮齿动物模型被开发出来，用于研究 ASD 的生理和遗传基础。本研究同时使用了 fmr1-KO 和野生型雄性大鼠（F2 代）。F1 孕鼠从 GD12.5-15.5 天每天接受 1mg/kg/mL 的 CPF（皮下注射）或溶剂处理。在 F2 雄性大鼠中分析了不同的行为、发育和分子变量。KO 大鼠体重增加，发出改变的 USV，社交效率降低，对新刺激反应过度，在探索新环境时过度活跃，但在探索引起焦虑的环境时活动减少，海马中 grin2c 基因的表达上调。在妊娠期接触低剂量 CPF 时，这些 KO 大鼠表现出攀爬能力下降、社交功能障碍，以及海马中 kcc1 和 5ht2c 基因表达增加。在具有遗传易感性的动物中，妊娠期 CPF 暴露增加了 ASD 样表型，尽管其影响不如预期的那样广泛。这是首次探索 CPF 暴露和 fmr1-KO 遗传脆弱性模型对社会特征或任何其他行为的这种附加效应。
