Codeine alters female reproductive function by targeting ovarian steroidogenesis and folliculogenesis via the induction of oxidative stress, inflammation, and apoptosis

Akhigbe, R.E.; Ebiwonjumi, O.S.; Ajayi, Lydia Oluwatoyin; Ajayi, Ayodeji Folorunsho

doi:10.1016/j.reprotox.2022.02.001

Cited by 11 publications

(10 citation statements)

References 36 publications

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“…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 [ 11 , 12 ]. L-arginine was administered at 300mg/kg as previously reported [ 14 ].…”

Section: Methodsmentioning

confidence: 99%

“…Studies have also revealed that codeine induces testicular damage by promoting testicular oxidative damage [ 10 ], suppressing testicular HER2, Ki67, and circulating testosterone [ 11 ], and upregulating caspase 3 signaling and p53/Bcl-2 pathway [ 10 , 11 ]. In addition, codeine has been reported to impair ovarian steroidogenesis and folliculogenesis by inducing oxidative stress, inflammation, and apoptosis [ 12 ]. Despite these available shreds of evidence on the negative effects of codeine on male reproductive function, the transgenerational effect of codeine is not yet known.…”

Section: Introductionmentioning

confidence: 99%

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

2022

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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.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

2022

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“…The animals were nulliparous and the oestrous cycle of all animals was assessed daily by vaginal smear technique using 0.1% Crystal violet stain and viewed by light microscopy [ 24 ]. Animals were monitored for three consecutive cycles, and only those with a regular cycle and at the same phase of cycle were selected for the study [ 25 ].…”

Section: Methodsmentioning

confidence: 99%

“…Also, the ovarian levels of TNF-α (Elabscience Biotechnology Inc., U.S.A.), IL-6 (Elabscience Biotechnology Inc., U.S.A.), 8OHdG (Elabscience Biotechnology Inc., U.S.A.), and VCAM-1 (Elabscience, Wuhan, China) as well as the activity of caspase 3 (Elabscience Biotechnology Inc., U.S.A.) were determined using ELISA kit following the manufacturers’ guidelines. Ovarian DNA fragmentation index was determined by diphenylamine methods as previously reported [ 25 ].…”

Section: Methodsmentioning

confidence: 99%

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Atorvastatin-mediated downregulation of VCAM-1 and XO/UA/caspase 3 signaling averts oxidative damage and apoptosis induced by ovarian ischaemia/reperfusion injury

Afolabi

Hamed²,

Anyogu

et al. 2022

Redox Report

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Background Oxidative damage is critical in the pathogenesis of ovarian ischaemia/reperfusion (I/R) injury, and statins have been reported to exert antioxidant activity. However, the role of VCAM-1 and xanthine oxidase (XO)/uric acid (UA) in ovarian I/R injury is not known. Also, whether or not atorvastatin exerts antioxidant activity like other statins is unclear. Objectives This study investigated the involvement of VCAM-1 and XO/UA in ovarian I/R injury and the likely protective role of atorvastatin. Methods Forty female Wistar rats were randomized into sham-operated, ischaemia, ischaemia/reperfusion (I/R), ischaemia and atorvastatin, and I/R and atorvastatin. Results In comparison with the sham-operated group, atorvastatin blunted ischaemia and I/R-induced distortion of ovarian histoarchitecture and follicular degeneration. Also, atorvastatin alleviated ischaemia and I/R-induced rise in XO, UA, and malondialdehyde, which was accompanied by inhibition of ischaemia and I/R-induced reductions in reduced glutathione level, enzymatic antioxidant activities and increase in myeloperoxidase activity and TNF-α and IL-6 levels by atorvastatin treatment. Additionally, atorvastatin blocked ischaemia and I/R-induced increase in VCAM-1 expression, caspase 3 activity, 8-hydroxydeoxyguanosine level and ovarian DNA fragmentation index. Conclusion For the first time, this study revealed that atorvastatin-mediated downregulation of VCAM-1 and XO/UA/caspase 3 signaling averts oxidative injury, inflammation, and apoptosis induced by ovarian ischaemia/reperfusion injury.

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Zinc normalizes hepatic lipid handling via modulation of ADA/XO/UA pathway and caspase 3 signaling in highly active antiretroviral therapy-treated Wistar rats

Hamed

Akhigbe

Aremu

et al. 2022

Chemico-Biological Interactions

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Codeine alters female reproductive function by targeting ovarian steroidogenesis and folliculogenesis via the induction of oxidative stress, inflammation, and apoptosis

Cited by 11 publications

References 36 publications

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

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

Atorvastatin-mediated downregulation of VCAM-1 and XO/UA/caspase 3 signaling averts oxidative damage and apoptosis induced by ovarian ischaemia/reperfusion injury

Zinc normalizes hepatic lipid handling via modulation of ADA/XO/UA pathway and caspase 3 signaling in highly active antiretroviral therapy-treated Wistar rats

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