Elser Benjamin A, Hing Benjamin, Eliasen Samuel, Afrifa Malik A, Meurice Naomi, Rimi Farzana, Chimenti Michael, Schulz Laura C, Dailey Michael E, Gibson-Corley Katherine N, Stevens Hanna E
Interdisciplinary Graduate Program in Human Toxicology, Graduate College, The University of Iowa, Iowa City, Iowa, USA.
Department of Psychiatry, Carver College of Medicine, The University of Iowa, Iowa City, Iowa, USA.
bioRxiv. 2025 Mar 17:2025.03.16.643434. doi: 10.1101/2025.03.16.643434.
Pyrethroid insecticides represent a broad class of chemicals used widely in agriculture and household applications. Human studies show mixed effects of maternal pyrethroid exposure on fetal growth and neurodevelopment. Assessment of shared pyrethroid metabolites as a biomarker for exposure obscures effects of specific chemicals within this broader class. To better characterize pyrethroid effects on fetal development, we investigated maternal exposure to permethrin, a type I pyrethroid, and α-cypermethrin, a type II pyrethroid, on fetal development in mice. Pregnant CD1 mice were exposed to permethrin (1.5, 15, or 50 mg/kg), α-cypermethrin (0.3, 3, or 10 mg/kg), or corn oil vehicle via oral gavage on gestational days (GD) 6-16. Effects on fetal growth, placental toxicity, and neurodevelopment were evaluated at GD 16. Cypermethrin, but not permethrin, significantly reduced fetal growth and altered placental layer morphology. Placental RNAseq analysis revealed downregulation of genes involved in extracellular matrix remodeling in response to α-cypermethrin. Both pyrethroids induced shifts in fetal dorsal forebrain microglia morphology from ramified to ameboid states; however, effects of α-cypermethrin were more pronounced. The α-cypermethrin transcriptome of fetal dorsal forebrain implicated altered glutamate receptor signaling, synaptogenesis, and c-AMP signaling. Coregulated gene modules in individual placenta and fetal dorsal forebrain pairs were correlated and overlapped in biological processes characterizing synapses, mitotic cell cycle, and chromatin organization, suggesting placenta-fetal brain shared mechanisms with α-cypermethrin exposure. In summary, maternal type II pyrethroid α-cypermethrin exposure but not type I pyrethroid permethrin significantly affected placental development, fetal growth, and neurodevelopment, and these effects were linked.
拟除虫菊酯类杀虫剂是一类广泛应用于农业和家庭的化学物质。人体研究表明，母体接触拟除虫菊酯对胎儿生长和神经发育的影响存在差异。将共同的拟除虫菊酯代谢物作为暴露生物标志物进行评估，会掩盖这一广泛类别中特定化学物质的影响。为了更好地表征拟除虫菊酯对胎儿发育的影响，我们研究了母体接触 I 型拟除虫菊酯氯菊酯和 II 型拟除虫菊酯高效氯氰菊酯对小鼠胎儿发育的影响。在妊娠第 6 - 16 天，通过口服灌胃法将怀孕的 CD1 小鼠暴露于氯菊酯（1.5、15 或 50 mg/kg）、高效氯氰菊酯（0.3、3 或 10 mg/kg）或玉米油载体中。在妊娠第 16 天评估对胎儿生长、胎盘毒性和神经发育的影响。氯氰菊酯而非氯菊酯显著降低了胎儿生长并改变了胎盘层形态。胎盘 RNA 测序分析显示，响应高效氯氰菊酯，参与细胞外基质重塑的基因表达下调。两种拟除虫菊酯均诱导胎儿背侧前脑小胶质细胞形态从分支状转变为阿米巴样状态；然而，高效氯氰菊酯的影响更为明显。胎儿背侧前脑的高效氯氰菊酯转录组涉及谷氨酸受体信号传导、突触发生和 c - AMP 信号传导的改变。单个胎盘和胎儿背侧前脑对中的共调控基因模块在表征突触、有丝分裂细胞周期和染色质组织的生物学过程中相关且重叠，表明高效氯氰菊酯暴露存在胎盘 - 胎儿脑共享机制。总之，母体接触 II 型拟除虫菊酯高效氯氰菊酯而非 I 型拟除虫菊酯氯菊酯会显著影响胎盘发育、胎儿生长和神经发育，且这些影响相互关联。
