Tire rubber-derived contaminants 6PPD and 6PPD-quinone differentially perturb decidualization-associated phenotypes and gene expression in an immortalized human endometrial stromal cell line

Decidualization of endometrial stromal cells is essential for endometrial receptivity and the establishment of early pregnancy. The tire rubber–derived chemical N-(1,3-dimethylbutyl)-N′-phenyl-p-phenylenediamine (6PPD) and its oxidative derivative 6PPD-quinone (6PPDQ) are ubiquitous environmental contaminants that are frequently detected in human biospecimens. However, their effects on uterine stromal function remain poorly understood. In this study, we investigated whether 6PPD and 6PPDQ influence decidualization-associated responses in an immortalized human endometrial stromal cell line (tHESC). Both chemicals exhibited dose-dependent reductions in cell viability of tHESCs, and exposure conditions that did not significantly reduce cell viability were selected for subsequent analyses. Under these conditions, 6PPD and 6PPDQ exerted distinct effects on decidualization-associated stromal responses. Phenotypic analyses showed that the two chemicals altered decidualization-associated morphometric parameters in different directions. At the transcript level, 6PPD increased the expression of classical decidualization markers but also downregulated several stromal regulatory genes. In contrast, 6PPDQ produced a broader suppression of decidualization-associated gene expression. Together, these findings indicate that 6PPD and 6PPDQ differentially perturb morphometric and transcriptional decidualization-associated responses in an immortalized human endometrial stromal cell line. Specifically, 6PPD exhibited an internally discordant pattern of program-level dysregulation, whereas 6PPDQ showed a more consistently suppressive profile under decidualizing conditions. These results provide insights into the distinct effects of 6PPD and 6PPDQ on stromal decidualization-associated responses.