A Review on Effect of Para-nonylphenol on Male Reproductive System

Para-nonylphenol (p-NP) is a term that can be applied to a wide range of isomeric compounds with the general formula C₉H₁₂ (OH) C₆H₄ (Figure-1). p-NP is an organic compound of the alkylphenol group. Alkylphenols are a small group of substances known as Xenostrogen [1]. If the position of the hydrocarbon chain linking to phenol in nonylphenol be para, it is referred to as p-NP or 4-nonyl phenol [1].

Figure 1: Chemical structure of Para-nonylphenol.

p-NP has higher estrogenic activity than other alkylphenols and this effect has been observed in the male reproduction system including mice [1,2]. p-NP has been proposed to act as estrogen mimics by direct action at the estrogen receptor [3]. Estrogen was considered as a female hormone, it is also present in males and is responsible for performing some physiological functions such as maintenance of the skeletal system, normal function of testis and prostate [4]. On the other hand, p-NP can reduce the biosynthesis of testosterone by inhibiting the activity of the 17α-HSD enzymes and the cAMP pathway of Leydig cells [5-15]. Many studies have shown that estrogenic activity disrupts sex hormones such as testosterone [6], estrogen and progesterone [7], which can decrease the chance of fertility (Table-1).

p-NP can induce oxidative stress on germ cells [8] and reduces the level of antioxidant defense system [9] and also increased lipid peroxidation [10] in the testicular tissue [11]. Also, p-NP by increasing Reactive Oxygen Species (ROS) levels that cause increasing active box and the cytochrome exhaust from the mitochondria that leads to activation of the Apaf1/Caspase-9 complex. Activation of this Caspar cascade results in apoptosis [12] of germinal and Sertoli cells [10]. According to the researches presented in Table 1, it can be concluded that this pollutant increases ROS and causes apoptosis in the male reproductive system (Table-2).

Table 1: Evaluation of the adverse effect of p-NP on different species of laboratory animal (male reproductive system).

NIMRI: Naval Medical Research Institute; SD: Sprague-Dawley; NAC: N- acetylcysteine; p-NP: para-nonylphenol; T: testosterone; E: Estrogen; TMDA: Tissue Malondialdehyde; MDA: Malondialdehyde; LH: Luteinizing hormone; FSH: Follicle-stimulating hormone; AEA: Antioxidant; Enzyme Activities; ↑: Increase; ↓: Decrease; +: positive effect on p-NP

Table 2: Evaluation of the adverse effect of p-NP on different species of laboratory animal (testicular tissue).

NIMRI: Naval Medical Research Institute; SD: Sprague-Dawley; NAC: N- acetylcysteine; p-NP: para-nonylphenol; Ap: Apoptosis; CC: Caspase; Cascade; OS: Oxidative Stress; +T: Positive-TUNEL in germinal cells; ↑: Increase; ↓: Decrease; +: positive effect on p-NP.

NP can destroy the linkage of Gap junction by reducing the expression of connexin 43 protein, causing a defect and apoptosis in spermatogenic and Sertoli cells that may be a reason for the reduction in epithelial layer [6,13], as well as disruption of the blood-testicle barrier and the production of tissue edema. On the other hand, NP by stopping the B type spermatogonia in the G1 stage of mitosis because of the product of the XPB1 gene, inhibits the expression of cyclin 1 protein, which is one of the necessary factors for mitosis [5]. These studies listed in Table 2 demonstrates the adverse effect of this pollutant on testicular tissue.

p-NP can induce apoptosis in germinal and Leydig cells [6] and decrease testosterone levels [5], as well as, leads to a decrease in the count and production of sperm daily [5,7]. The middle part of the sperm contains a large number of mitochondria that is responsible for movement and ROS reduces the progressive sperm motility by degenerating these mitochondria [14]. ROS by lipid peroxidation causes a decrease in membrane fluidity, damage to proteins and DNA, and eventually, abnormalities occur in sperm morphology [10]. Table 3 shows the studies of the adverse effect of p-NP on spermatogenesis.

Table 3: Evaluation of the adverse effect of p-NP on different species of laboratory animal (Spermatogenesis).

NIMRI: Naval Medical Research Institute; SD: Sprague-Dawley; NAC: N- acetylcysteine; p-NP: para-nonylphenol; Mot: Motility; Abn: Abnormality; Cou: Count; DSP: Daily sperm production; Via: Vaibility; Ant-E: Antioxidant Effect; ↑: Increase; ↓: Decrease; +: positive effect on p-NP.

This study, by collecting various studies using stereological [5], histological [15], biochemical [15-18] and andrological [7] methods, showed that p-NP at different doses and duration of treatment on laboratory animals can induce oxidative stress and apoptosis in germinal cells. This pollutant also reduces the chances of fertility by disrupting the endocrine system [2,7]. Humans are constantly exposed to p-NP through water, soil, food and vegetables. Many studies have shown that the use of antioxidants can prevent the adverse effects of oxidative stress caused by this pollutant in the male reproductive system [5].

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