Early gonadotoxic effects of cyclophosphamide on the prepubertal testis and the feasibility of reducing toxicity through combined antioxidant therapy.
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Eskafinoghani A, Palomares AR, Hao X, Mohammadi R, Lundberg A, Rodriguez-Walberg KA
Reprod. Toxicol. 140 (-) 109156 [2025-12-29; online 2025-12-29]
Early chemotherapy-induced gonad toxicity threatens future fertility in boys, yet early in-vivo testicular responses are poorly defined. To characterize acute effects of cyclophosphamide (CPA) on the prepubertal testis and explore whether combined antioxidants (AO; L-carnitine [LC] and N-acetyl cysteine [NAC]) modulate these changes. CBA/B6 F1 male pups (postnatal day 7-9) were randomized to saline control, CPA (100 mg/kg i.p.), AO, or CPA+AO. Testes were collected every 8 h to 48 h for histology/immunostaining and were pooled (n = 3 per group/time point) for bulk RNA-seq per group/time point. Histology showed emerging degeneration from ∼32 h with prominent effects by 48 h after CPA, including reduced germ cell layers, increased γH2AX/CC3, and decreased Ki67. Transcriptionally, CPA perturbed apoptosis/developmental pathways as early as 16 h, preceding overt histological change. AO and CPA+AO groups displayed partial transcriptional shifts toward control profiles, consistent with mitigation of CPA-associated signatures, but not full normalization. In neonatal mouse testis, CPA elicits rapid transcriptomic reprogramming within 16 h, before morphological injury at ∼32-48 h. Concomitant AO shows preliminary, partial protective transcriptional effects. These proof-of-concept data support transcriptomics as an early, sensitive readout of testicular toxicity and motivate follow-up studies with independent validation and long-term outcomes prior to clinical translation.
PubMed 41475676
DOI 10.1016/j.reprotox.2025.109156
Crossref 10.1016/j.reprotox.2025.109156
pii: S0890-6238(25)00327-2