L-Arginine reverses maternal and pre-pubertal codeine exposure-induced sexual dysfunction via upregulation of androgen receptor gene and NO/cGMP signaling

Abstract

Background Although codeine has been reported to enhance sexual activity by improving penile reflexes, it has been shown to impair fertility indices. Also, codeine impairs ovarian steroidogenesis and folliculogenesis. Nonetheless, whether or not codeine exerts an epigenetic effect remains unclear. On the other hand, arginine has been speculated to enhance penile reflexes by upregulating NO/cGMP Signaling. Aim The study evaluated the effect of maternal codeine exposure and prepubertal codeine and arginine treatments on F1 male sexual function and fertility indices, as well as the outcome of F2 progenies. In addition, the epigenetic programming mechanism was also explored. Methods Forty three-week-old female rats were randomized into two groups (n = 20 rats/group); the control that received 0.5 ml of distilled water and the codeine-treated that received 5 mg/kg of codeine via gavage for eight weeks. Afterward, the female rats were paired for mating with sexually mature male rats. Rats were maintained on their pre-pregnancy treatments throughout pregnancy and lactation. FI progenies from each cohort (control and codeine-treated cohorts) were weaned at three weeks and randomized into four groups; the control, codeine-treated, L-arginine-treated (300mg/kg), and codeine + L-arginine-treated (n = 10 rats/group). Administration commenced a week post-weaning and lasted for eight weeks via gavage. Key findings Maternal codeine exposure did not alter body weight, but significantly reduced anogenital distance and anogenital index of F1 male offspring. Also, maternal codeine delayed preputial membrane separation, impaired male sexual competence, and penile reflexes of F1 male offsprings. These were associated with reduced dopamine, gonadotropins, and testosterone levels as well as suppressed expression of androgen receptor mRNA. In addition, maternal codeine downregulated NO/cGMP signaling, impaired fertility indices, and reduced the litter size, weight, and survival of F2 progenies. These alterations were observed to be aggravated by prepubertal codeine exposure but improved by prepubertal arginine treatment. Significance In conclusion, codeine programmed sexual dysfunction by suppressing the levels of dopamine and testosterone, as well as repressing the expression of androgen receptor mRNA. In addition, codeine-induced epigenetic reprogramming was expressed in the F2 offsprings as reduced litter size and weight, and survival rate. Notably, these observations were worsened by prepubertal codeine exposure, but dampened by prepubertal arginine treatment.

L-Arginine abrogates maternal and pre-pubertal codeine exposure-induced impaired spermatogenesis and sperm quality by modulating the levels of mRNA encoding spermatogenic genes

“…It is credible to construe that codeine-induced alteration in testosterone levels and the decrease in AR may directly impair spermatogenesis ( 35 ). The present finding that codeine reduces testosterone levels aligns with previous reports that demonstrated that opioids such as tramadol and codeine lower testosterone level ( 14 , 17 , 18 , 26 , 44 ). Arginine supplementation blocked the codeine-induced decrease in testosterone and AR concentrations possibly by upregulating endocrine signaling pathways, especially the hypothalamic-pituitary-testicular axis evidenced by increased LH and FSH, which culminates in increased testosterone production and release, enhanced AR expression, and consequently improved spermatogenesis and sperm count.…”

“…The administration was via gavage. The dose of codeine used is the submaximal peak dose obtained from the dose-response curve of our pilot study as previously reported ( 18 , 26 , 27 ) and that of arginine was as previously reported ( 28 ). Animals were culled at 12 weeks via euthanasia using intraperitoneal ketamine (4 mg/kg bw) and xylazine (40 mg/kg bw).…”

“…The intake of arginine has been shown to enhance its concentrations in the plasma and tissue ( 24 ) and to promote the biosynthesis of nitric oxide, which is an important vasodilator ( 25 ). Although there is a scarcity of data on the effect of arginine on codeine-induced male reproductive dysfunction, our previous study ( 26 ) revealed that arginine attenuated codeine-induced delay in puberty attainment and impaired penile and sexual function. This effect of arginine on codeine-exposed rats was demonstrated to be associated with the upregulation of circulating testosterone and androgen receptor in the testis ( 26 ).…”

“…Although there is a scarcity of data on the effect of arginine on codeine-induced male reproductive dysfunction, our previous study ( 26 ) revealed that arginine attenuated codeine-induced delay in puberty attainment and impaired penile and sexual function. This effect of arginine on codeine-exposed rats was demonstrated to be associated with the upregulation of circulating testosterone and androgen receptor in the testis ( 26 ). Given these properties of arginine and the knowledge that codeine impairs male fertility via an oxidative stress-dependent pathway, the present study investigated whether or not maternal and prepubertal codeine exposure reprograms spermatogenesis and sperm quality in adult male of F1 generation to study the effect that codeine may have during recreational use in humans, as well as to demonstrate the possible mechanisms involved and the likely role of prepubertal arginine supplementation.…”

Systemic metabolomics characterization of the ascending and descending property

“…A related study showed that arginine can treat endocrine disorders, delayed sexual maturity, and sexual dysfunction induced by codeine [37], and it can signi cantly increase the sperm density, total sperm count, and effective sperm count of the body [38,39]. Arginine is a precursor of nitric oxide (NO), which is an important signal and effector molecule in the body, plays an important role in the male reproductive system, and can promote vasodilation and penile smooth muscle relaxation.…”