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. 2020 Nov 24;6(11):e05589.
doi: 10.1016/j.heliyon.2020.e05589. eCollection 2020 Nov.

In vivo exposure to codeine induces reproductive toxicity: role of HER2 and p53/Bcl-2 signaling pathway

A F Ajayi  1 , R E Akhigbe  1   2   3
Affiliations

In vivo exposure to codeine induces reproductive toxicity: role of HER2 and p53/Bcl-2 signaling pathway

A F Ajayi et al. Heliyon. .

Abstract

Several studies have implicated codeine use in the aetiopathogenesis of male infertility. The purpose of this study was to investigate the role of HER2, Ki67, oestrogen and p53/Bcl-2 signaling pathways and the possible outcome of codeine cessation on codeine-induced reproductive toxicity. Thirty adult male Wistar rats of comparable ages and weights were randomly allocated into 5 groups. The control animals received distilled water per os (p.o), while animals in the low-dose (LDC) and high dose (HDC) codeine-treated groups received 2 and 5 mg/kg/day of codeine respectively p.o for 6 weeks. The animals in the low-dose codeine recovery (LDC-R) and high-dose codeine recovery (HDC-R) groups received treatment as LDC and HDC respectively followed by another drug-free six weeks, recovery period. Cessation of codeine exposure led to a partial reversal of codeine-induced poor sperm quality, reduced litter size and weight, increased oxidative testicular injury, testicular apoptosis, and testicular DNA damage caused by codeine administration. Codeine-induced gonado-spermotoxicity was associated with a reduction of circulatory testosterone, suppression of testicular HER2, Ki67, and Bcl-2 expression, down-regulation of oestrogen signaling, and upregulation of testicular caspase 3 activities and p53 signaling pathway. Conclusion: Upregulation of oestrogen signaling associated with enhanced testicular HER2 and Ki67 expression during the recovery period is seemingly beneficial in protecting against codeine-related testicular injury and infertility.

Keywords: Bcl-2; Biological sciences; Chemistry; Environmental science; HER2; Health sciences; Ki67; Opioid; Oxidative stress; Veterinary medicine; p53.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Experimental protocol chart.
Figure 2
Figure 2
Effect of low-dose codeine (LDC) and high-dose codeine (HDC) and their cessation during the recovery period (-R) on sperm count (a), sperm motility (b), sperm viability (c), normal sperm morphology (d), litter size (e), and litter weight (f) in wistar rats. Values are expressed as mean ± SD of 6 rats per group. Data were analyzed by one-way ANOVA followed by Tukey's post hoc test. ∗p < 0.05 vs control, #p < 0.05 vs LDC, + p < 0.05 vs HDC, ~ p < 0.05 vs LDC-R.
Figure 3
Figure 3
Effect of low-dose codeine (LDC) and high-dose codeine (HDC) and their cessation during the recovery period (-R) on testicular H2O2 generation (a), MDA (b), AGE (c), GSH (d), SOD (e), catalase (f), GPx (g), and GST (h) in wistar rats. Values are expressed as mean ± SD of 6 rats per group. Data were analyzed by one-way ANOVA followed by Tukey's post hoc test. ∗p < 0.05 vs control, #p < 0.05 vs LDC, + p < 0.05 vs HDC, ~ p < 0.05 vs LDC-R.
Figure 4
Figure 4
Effect of low-dose codeine (LDC) and high-dose codeine (HDC) and their cessation during the recovery period (-R) on testicular MPO (a), NO (b), TNF-α (c), IL-1β (d), Na+-K+-ATPase (e), and Ca2+-ATPase (f) in wistar rats. Values are expressed as mean ± SD of 6 rats per group. Data were analyzed by one-way ANOVA followed by Tukey's post hoc test. ∗p < 0.05 vs control, #p < 0.05 vs LDC, + p < 0.05 vs HDC, ~ p < 0.05 vs LDC-R.
Figure 5
Figure 5
Effect of low-dose codeine (LDC) and high-dose codeine (HDC) and their cessation during the recovery period (-R) on testicular Ki67 expression in the negative control (a), LDC (b), HDC (c), LDC-R (d), and HDC-R (E)groups in wistar rats. Values are expressed as mean ± SD of 6 rats per group. Data were analyzed by one-way ANOVA followed by Tukey's post hoc test. ∗p < 0.05 vs control, #p < 0.05 vs LDC, + p < 0.05 vs HDC, ~ p < 0.05 vs LDC-R. 1: original image; 2: Immunoratio pseudo image. Spermatogenic cells (LINE) of the seminiferous tubules (ST) and leydig cells (arrow head).
Figure 6
Figure 6
Effect of low-dose codeine (LDC) and high-dose codeine (HDC) and their cessation during the recovery period (-R) on testicular HER2 expression in the negative control (a), LDC (b), HDC (c), LDC-R (d), and HDC-R (E)groups in wistar rats. Values are expressed as mean ± SD of 6 rats per group. Data were analyzed by one-way ANOVA followed by Tukey's post hoc test. ∗p < 0.05 vs control, #p < 0.05 vs LDC, + p < 0.05 vs HDC, ~ p < 0.05 vs LDC-R. 1: original image; 2: Immunoratio pseudo image. Spermatogenic cells (LINE) of the seminiferous tubules (ST) and leydig cells (arrow head).
Figure 7
Figure 7
Effect of low-dose codeine (LDC) and high-dose codeine (HDC) and their cessation during the recovery period (-R) on testicular p53 expression in the negative control (a), LDC (b), HDC (c), LDC-R (d), and HDC-R (E)groups in wistar rats. Values are expressed as mean ± SD of 6 rats per group. Data were analyzed by one-way ANOVA followed by Tukey's post hoc test. ∗p < 0.05 vs control, #p < 0.05 vs LDC, + p < 0.05 vs HDC, ~ p < 0.05 vs LDC-R. 1: original image; 2: Immunoratio pseudo image. Spermatogenic cells (LINE) of the seminiferous tubules (ST) and leydig cells (arrow head).
Figure 8
Figure 8
Effect of low-dose codeine (LDC) and high-dose codeine (HDC) and their cessation during the recovery period (-R) on testicular Bcl-2 expression in the negative control (a), LDC (b), HDC (c), LDC-R (d), and HDC-R (E)groups in wistar rats. Values are expressed as mean ± SD of 6 rats per group. Data were analyzed by one-way ANOVA followed by Tukey's post hoc test. ∗p < 0.05 vs control, #p < 0.05 vs LDC, + p < 0.05 vs HDC, ~ p < 0.05 vs LDC-R. 1: original image; 2: Immunoratio pseudo image. Spermatogenic cells (LINE) of the seminiferous tubules (ST) and leydig cells (arrow head).
Figure 9
Figure 9
Graphical abstract of the effects of codeine and codeine cessation in gonado-spermotoxicity.
See this image and copyright information in PMC

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