Trem2-Mical1-Erk1/2 signaling defines a macrophage-Leydig cell axis essential for testicular descent under DEHP exposure
Description
About 1%–9% of full-term male newborns suffer from cryptorchidism, which is one of the most common congenital abnormalities in the male reproductive tract. 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. In vitro, MEHP stimulation led to decreased expression of Trem2, Mical1, and Erk in macrophages. Trem2 overexpression restored Mical1 and Erk signaling and Trem2 activation rescued Leydig cell proliferative capacity, while Trem2 silencing further suppressed Mical1 and Erk expression and exacerbated Leydig cell dysfunction. These findings highlight the Trem2-Mical1-Erk axis as a critical immunoregulatory pathway linking DEHP-induced macrophage activation to testosterone insufficiency. The discovery provides new insights into the etiology of cryptorchidism and identifies potential targets for DEHP-induced cryptorchidism.
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Institutions
- Nantong University