Phthalate-Induced Uterine Wall Remodeling Alters Organ-Level Biomechanics

Abstract Phthalates are endocrine-disrupting chemicals associated with adverse reproductive outcomes and uterine extracellular matrix remodeling. However, whether such remodeling alters organ-level uterine mechanics remains unknown. Uterine horns from mice exposed to a phthalate mixture (0, 0.15, 1.5, or 1500 ppm for one year) underwent balloon inflation testing to characterize mechanical behavior and second harmonic generation imaging to quantify wall geometry and collagen microstructure. Exposure reduced endometrial (Em) area, increased circumferential myometrial (CM) thickness, and decreased Em:CM area and thickness ratios, while increasing inflation stiffness, work, and resistance. Lower Em ratios correlated with greater inflation resistance. An image-informed, three-layer finite element model showed that geometric redistribution alone, with constitutive properties unchanged, reproduced experimental inflation trends, reduced deformation, and redistributed layer-specific stresses and strains. Within the investigated ranges, geometric remodeling influenced inflation mechanics more than twofold CM stiffening, identifying uterine wall geometry as a key determinant of passive biomechanics following phthalate exposure.