Rituximab alleviates increased disomic sperm in DBA/1J mouse models of rheumatoid arthritis via restoration of redox imbalance.

Abstract

Compared to the general population, patients with arthritis have a higher risk of fertility abnormalities, which have deleterious effects on both reproductive function and pregnancy outcomes, especially in patients wishing to conceive. These may be due to the disease itself or those of drug therapies. Despite the increasing use of rituximab in arthritis, limited data are available on its potential to induce aneuploidy in germ cells. Therefore, the aim of the current investigation was to determine if repeated treatment with rituximab affects the incidence of aneuploidy and redox imbalance in arthritic mouse sperm. Mice were treated with 250 mg/kg rituximab once weakly for 3 weeks, and then sperm were sampled 22 days after the last dose of rituximab. Fluorescence in situ hybridization assay with chromosome-specific DNA probes was used to evaluate the disomic/diploid sperm. Our results showed that rituximab had no aneuploidogenic effect on the meiotic stage of spermatogenesis. Conversely, arthritis induced a significantly high frequency of disomy, and treatment of arthritic mice with rituximab reduced the increased levels of disomic sperm. The occurrence of total diploidy was not significantly different in all groups. Reduced glutathione and8-hydroxydeoxyguanosine, markers of oxidative stress were significantly altered in arthritic animals, while rituximab treatment restored these changes. Additionally, arthritis severity was reduced after rituximab treatment. We conclude that rituximab may efficiently alleviate the arthritis-induced effects on male meiosis and avert the higher risk of abnormal reproductive outcomes. Therefore, treating arthritic patients with rituximab may efficiently inhibit the transmission of genetic anomalies induced by arthritis to future generations.