L-arginine improves prenatal and pre-pubertal codeine-induced steroidogenesis deregulation by suppressing oxidative stress-dependent signaling in male wistar rats.

This study investigated the impact of prepubertal L-arginine on prepubertal and maternal codeine-induced testicular toxicity in F1 male offspring. Forty female rats were randomized at weaning into either vehicle-treated control or codeine-treated groups (n = 20 rats/group). After 8 weeks of treatment, the animals were matched with healthy, sexually developed male rats. During pregnancy and lactation, the female rats continued their pre-pregnancy treatments. The female rats delivered at term and 20 male FI offspring from each group (the control and codeine-treated groups) were divided into four groups by randomization after weaning: the control, codeine-treated, L-arginine-treated, and codeine + L-arginine-treated groups (n = 10 rats per group). Prepubertal codeine use significantly reduced testicular weight and gamma-glutamyl transferase and sorbitol dehydrogenase activities, increased testicular injury markers (lactate dehydrogenase and lactate), and distorted testicular histoarchitecture. These findings were associated with decreased activities of steroidogenic proteins (StAR, 3β-HSD, and 17β-HSD) and male reproductive hormones (LH, FSH, and testosterone). More so, codeine increased pro-inflammatory (myeloperoxidase, TNF-α, IL-1β) and pro-apoptotic (Bax and caspase 3 activity) genes and proteins, and reduced antioxidant cytoprotective genes and proteins. These negative effects were associated with the modulation of transcription factors (Nrf2 and NF-kB) and were more profound in animals whose dams were also exposed to codeine compared with those whose dams were not exposed to codeine. Nonetheless, codeine-induced perturbations were attenuated by prepubertal L-arginine administration. Our results revealed that L-arginine protected the testis and preserved testicular steroidogenesis in codeine-exposed rats by suppressing oxidative stress, inflammation, and apoptosis.