Metabolomics and Lipidomics with Mass Spectrometry Imaging Reveal Mechanistic Insights into Dibutyl Phthalate-Promoted Proliferation of Breast Cancer Cell Spheroids

Dibutyl phthalate (DBP), extensively used as a plasticizer, has endocrine-disrupting properties that may increase the risk of breast cancer at low concentrations. However, previous studies on the effects of DBP on breast cancer mainly focused on the activation of typical intracellular receptors, and the downstream mechanisms at the metabolic level have not been well elucidated. Therefore, our study applied metabolomics, lipidomics, and mass spectrometry imaging (MSI) techniques to investigate the metabolic responses of the MCF-7 breast cancer cell spheroid (CCS) to DBP exposure. The omics results showed that DBP exposure resulted in increased glucose and glutamine uptake and catabolism in breast CCS which supported the production of nucleotides, glycerophospholipids, and amino acids, providing sufficient energy and building blocks for the synthesis of DNA/RNA and the cytomembrane necessary for cell proliferation. These results were further corroborated by the MSI data, showing enhanced abundances of ATP, GMP, UDP, lysophosphatidylcholines, phosphatidylcholines, and phosphatidylethanolamines in CCS treated with DBP. Interestingly, most of these biomolecules were predominantly distributed in the proliferative region. Our result indicated that the enhanced supply of energy and biosynthetic substrates in the peripheral area facilitated the proliferation of breast CCS, shedding new light on the metabolic mechanisms of DBP-promoted breast cancer development.