Spatiotemporal Progression of Breast Cancer Deterioration and Metastasis‐Associated Metabolic Dyshomeostasis Induced by Exposure of Bisphenol S during Pregnancy

Abstract As a non‐genetic factor, exposure to environmental pollutants, such as bisphenol A and its replacement chemicals (e.g., BPS), is one of the major risk factors for the occurrence and development of breast cancer. The heterogeneous spatiotemporal progression of multifocal breast cancer at the microscale plays an infamous role in phenotype variation and malignant degree increase. However, prenatal bisphenol exposure‐induced heterogeneous features of offspring during breast cancer progression are far from elucidated. Using a noninvasive ultrasound elastography (UE) guided‐spatiotemporal metabolomics strategy, the study obtains the BPS‐treated comprehensive fingerprints and characteristic crosstalk of tumors at the microscale by integrating elasticity‐histopathology‐metabolism in multifocal tumorigenesis across the entire progression of breast cancer and also evaluates the degrees of malignancy and metastasis. Prenatal exposure to BPS (10 µg/kg bw/day) significantly shortens the breast tumor latency of female offspring in multiple primary foci and accelerates the lung metastasis using a spontaneous transgenic model of breast cancer. Prenatal BPS exposure changes the intra‐ and inter‐tumor heterogeneity in histopathological characteristics and induces the spatial dyshomeostasis of lipid metabolism by enlarging the micro‐area of neoplasm and necrosis, also promoting the infiltration of inflammation cells in lung metastasis. The results contribute to the uncovering of insights in the new toxicity of environmental pollutant at microscale and related targeting interventions for disease reversal.