Impact of the Environmental Endocrine Disruptor Flutamide on Cryptorchidism: Molecular Mechanisms Involving Connexin-43 and p38-MAPK Signaling.
Cryptorchidism, a condition associated with male infertility, is exacerbated by exposure to environmental endocrine disruptors such as flutamide. This study investigates the molecular mechanisms of cryptorchidism and potential interventions targeting endocrine disruptor-induced testicular damage. A rat model of congenital cryptorchidism was established via prenatal flutamide exposure, and testes were harvested at postnatal day 90. Testicular histology, transcriptome sequencing, bioinformatic analysis, sperm analysis, immunohistochemistry, and lentiviral vector transfection were conducted. Cryptorchid testes exhibited impaired seminiferous tubule development, significant reductions in sperm count, and increased sperm abnormalities. Tight and gap junction proteins essential for blood-testis barrier (BTB) integrity, including Claudin-11, Occludin, and Connexin-43, were markedly downregulated. Transcriptomic analysis revealed activation of the p38 MAPK signaling pathway and excessive apoptosis in cryptorchid testes. Overexpression of Connexin-43 restored BTB integrity and suppressed the p38 MAPK pathway, rescuing spermatogenesis. These findings underscore the role of environmental anti-androgens in cryptorchidism pathogenesis and highlight Connexin-43 as a potential therapeutic target for mitigating testicular damage caused by endocrine disruptors.