Mechanistic Insights into Fluoride-Induced Male Reproductive Injury: The Role of Nrf2/FSP1 Pathway-Mediated Ferroptosis.

Abstract

Global environmental fluoride contamination causes damage to multiple organs, with the male reproductive system being particularly susceptible. Nevertheless, the precise pathophysiological mechanisms underlying this vulnerability remain poorly defined. This study aimed to elucidate how excessive fluoride exposure leads to impairment of the male reproductive system. Initially, bioinformatics analyses were conducted to screen for the potential involvement of the ferroptosis pathway in fluoride-induced reproductive toxicity. Subsequently, in vitro and in vivo models confirmed that fluoride exposure elicited reproductive damage through the induction of ferroptosis. The results revealed that fluoride exposure significantly suppressed the activity of the Nrf2/FSP1 antioxidant pathway. This suppression led to elevated levels of malondialdehyde (MDA), a lipid peroxidation marker, and ferrous ions (Fe2+), along with a reduction in coenzyme Q10 (CoQ10), an essential component of the mitochondrial electron transport chain. Concurrently, histological examination of testicular tissue revealed structural alterations, and a decline in epididymal sperm quality was observed in the fluoride-exposed group. Intervention with Ferrostatin-1 (Fer-1, a ferroptosis inhibitor) and Tert-butylhydroquinone (TBHQ, an antioxidant) partially alleviated the inhibitory effects of fluoride exposure on the Nrf2/FSP1 pathway. This intervention reduced the incidence of ferroptosis, as indicated by decreased levels of MDA and Fe2+, and consequently mitigated the reproductive damage caused by fluoride exposure. In conclusion, excessive fluoride exposure inhibited the Nrf2/FSP1 pathway, resulting in a marked increase in reactive oxygen species (ROS) generation and subsequent lipid peroxidation. This cascade of events induced ferroptosis in the testicular tissue of Sprague-Dawley rats and GC-1 spermatogonial cells, ultimately leading to reproductive dysfunction.

Key Findings

• Excessive fluoride exposure suppresses the Nrf2/FSP1 antioxidant pathway in testicular tissue.
• Suppression of Nrf2/FSP1 leads to increased lipid peroxidation markers (MDA), elevated ferrous ions (Fe2+), and decreased CoQ10 levels.
• Inhibition of ferroptosis via Ferrostatin-1 and antioxidant TBHQ mitigates fluoride-induced reproductive damage.

Clinical Significance

Citation

Wang Yan, Li Chunxiang, Fu Xiaoliet al.. Mechanistic Insights into Fluoride-Induced Male Reproductive Injury: The Role of Nrf2/FSP1 Pathway-Mediated Ferroptosis. The Journal of nutritional biochemistry. 2026-Jun-12.