Tepraloxydim metabolite exposure disrupts placental function revealed by single-cell sequencing and metabolomics.

The impact of pesticide exposure on pregnancy outcomes is of increasing concern, yet the effects of a metabolite of the relatively new herbicide tepraloxydim (DMP) on placental development remain poorly understood. This study combining single-cell RNA sequencing with metabolomics, to systematically investigate the effects of DMP on placental cellular composition, transcriptional programs, and metabolic homeostasis in a mouse model. We found that DMP crosses the placental barrier and is detected in placental tissue with subcellular distribution patterns suggestive of endoplasmic reticulum association, inducing extensive reprogramming of the placental metabolic network, with the branched-chain amino acid (BCAA) degradation pathway emerging as a central node of metabolic disruption. Single-cell transcriptomic analysis further revealed that DMP exposure altered the differentiation trajectories and functional states of major placental cell types, including fibroblasts, trophoblasts, endothelial cells, and macrophages. Specifically, fibroblasts exhibited a pro-fibrotic phenotypic shift, trophoblast differentiation pathways were redirected, endothelial cells showed reduced metabolic plasticity, and macrophages underwent pro-inflammatory polarization. Key metabolic genes such as Cyb5a, LDHA, and MDH1 were upregulated in their respective cell types, suggesting their potential role in DMP-induced placental dysfunction. This study provides the first systematic evidence of the mechanisms by which DMP disrupts placental structure and function through metabolic reprogramming and altered cell fate, offering important experimental basis for assessing its health risks during pregnancy.