Trem2-Mical1-Erk1/2 signaling defines a macrophage-Leydig cell axis essential for testicular descent under DEHP exposure

However, the mechanisms by which environmental endocrine disruptors disrupt the crosstalk between macrophages and Leydig cells remain insufficiently defined. In this study, it was demonstrated that prenatal exposure to DEHP induces cryptorchidism and defective spermatogenesis in C57BL/6 male offspring, accompanied by marked reductions in Leydig cell quantity, testosterone production and steroidogenic enzyme expression.

Notably, Trem2, an immunoregulatory receptor expressed on testicular macrophages, was significantly downregulated following DEHP exposure. Further investigation revealed that MEHP-activated macrophages exacerbate the inhibitory effects of MEHP on Leydig cell proliferation and steroidogenic function. Transcriptomic profiling of macrophages with Trem2 overexpression identified Mical1 as the most significantly upregulated gene.