Monosodium Glutamate (MSG)-Induced Male Reproductive Dysfunction: A Mini Review

Reproductive dysfunction is often characterized by malfunction of the reproductive tissues, which may lead to disruption of the synergistic rhythm that should bring about a progression of sexual events and the conception of new life. This may therefore result in the sexual dysfunction and infertility that can be seen in couples having prolonged biological difficulty in reproducing their offspring after having unrestricted sexual intercourse for at least twelve months. Several factors have been implicated in the cause and progression of reproductive dysfunction, including poor nutrition, drug side effects, disease states, and toxicant ingestion. A well-known food additive that has been found to be potent at initiating reproductive anomalies in males is monosodium glutamate (MSG). This regular flavor enhancer is widely used as a taste enhancer in several diets. The different mechanisms by which it may induce reproductive dysfunctions include spermatogenic alteration resulting in a low sperm count, high sperm abnormality, reduced live sperm and decreased sperm pH, oxidative damage (increased lipid peroxidation and reduced antioxidant enzyme activities), histological alteration (blood hemorrhage, distorted germ and Sertoli cells), as well as gonadotropin imbalance (reduced testosterone, luteinizing hormone, and follicle-stimulating hormone concentrations). Therefore, this review discusses various established mechanisms through which MSG may induce reproductive dysfunction and the treatment strategies to ameliorate its toxic effects.


Introduction
The adult male reproductive system consists of two testes, each joined to its own epididymis and connected to the penis via the vas deferens, and functioning majorly in the production and transportation of sperm for the fertilization of an ovum, leading to the development of an offspring [1]. Germ cells develop in the testes and travel through the epididymis (caput to cauda) where they mature and gain motility [2]. During copulation, sperm is released as semen into the female reproductive tract, where the final stages of maturation takes place (capacitation) and leave the sperm ready for fertilization should an ovum be present [3].
Male reproductive dysfunction describes a condition where one or more of the components of the male reproductive system is malfunctioning or performs below its expected capability. This may have a debilitating effect on the individual and may result in other secondary conditions [4]. Some of the implicated factors for male reproductive dysfunction include hormonal disorders, reactive oxygen species, testicular inflammation, endocrinal disturbance, genital infection, heat, smoking and alcohol, illness, injury, chronic health problems, heavy metals, genetic defects, exposure to radiation, lifestyle, and diet [5].
The German chemist Karl Heinrich Ritthausen discovered monosodium glutamate. MSG is a subset of glutamate which is an important but "non-essential" amino acid found in several foods, including beef, milk, tuna, and vegetables, and plays an important role in human metabolism [6]. MSG is formulated from water, glutamate, and sodium, and it is a major food flavor enhancer, which serves to exaggerate the inherent flavor of foods. The induction of myriad undesirable conditions such as weakness, numbness, muscle pain, headaches, dizziness, and flushing have been associated with MSG consumption [7]. Pre-clinical studies revealed that repeated MSG ingestion may also trigger asthma, cancer-induced obesity, diabetes, and oxidative stress. Toxicities such as hepatotoxicity, genotoxicity, reproductive toxicity, and renal toxicity, as well as neurotoxic effects have also been reported to accompany MSG intake. MSG ingestion has also been linked with Parkinson's disease, Alzheimer's disease, addiction, brain trauma, anxiety, stroke, depression, and epilepsy [6,8]. MSG has also been associated with male reproductive dysfunction by triggering a hemorrhage in the testis as well as deterioration of sperm cell structure and production [9]. Glutamate, a major component of MSG, is present in large quantities in the body and is sourced from dietary protein or food containing free glutamate (MSG/hydrolyzed protein). Glutamate is metabolized mainly in the small intestine, where other amino acids (aspartate and glutamine) are catabolized. It is a major substrate for the synthesis of protein, as it is contained in 20-40% of most proteins. Excitatory amino acid carrier 1 (EAAC-1) (intestine), glutamate/aspartate transporter-1 (GLAST-1), and glutamate transporter-1 (GLT-1) (stomach) respectively, are the major glutamate and glutamine active transporters. These transporters are dependent on sodium ion concentration, and can be inhibited competitively [9].
Glutamate can be metabolized into free amino acids absorbed into the gut for further breakdown [7]. The metabolized products include α-ketoglutarate via transamination (alanine transferase and aspartate transferase) and deamination using glutamate dehydrogenase, glutamine substrate through glutamine synthetase, and precursors for glutathione and N-acetylglutamine generation. The product, α-ketoglutarate, enters the tricarboxylic acid (TCA) cycle in the mitochondrial matrix for the production of energy and release of CO 2 . Therefore, increased glutamate in the diet could increase energy generation by increasing the level of transamination and deamination, conversion of amino acids into glucose (gluconeogenesis), and conversion to other products like glutathione, GABA, N-acetylglutamate, and γ-carboxyglutamine [8].
Neurotransmitters are chemical messengers carrying information between nerve cells to influence each other in the central nervous system (CNS). Neurotransmitters are found at the terminal buttons of transmitting nerves and they inhibit or excite cell targets. Glutamate is a major excitatory neurotransmitter, which enables the rapid transmission of synapses. It is also a precursor to γ-butyric acid (GABA), another important neurotransmitter. Memory, cognition, and sensation (taste, hearing, and sight) are the consequences of glutamate neurotransmission. Glutamate also has a trophic role in developing the CNS and so controls reproduction, movement, and the survival of neuronal progenitors [8,9].

MSG and the Induction of Reproductive Dysfunction
Several investigations have documented the induction of different modes of reproductive injury by MSG in laboratory animals. These studies are summarized in Table 1. A few other studies have also documented the treatment of these MSG-induced alterations with natural products ( Table 2).

Mechanism of MSG-Induced Testicular Alteration
The action of MSG on the male reproductive morphology and function may be as a result of its diverse influence on cells, thereby initiating spermatogenic alterations, oxidative damage, histological alteration, and gonadotropin imbalance which may eventually culminate into reproductive abnormalities in the males as shown in Figure 1. There seems to be a scarcity of empirical data on the evaluation of MSG intake on human male reproductive functions; mostly, available animal model studies are extrapolated to humans.

Oxidative Stress
The organs of the reproductive system are targets of reactive oxygen species (ROS) because of adipose tissue present in these organs [13]. Studies have revealed an increase in the lipid peroxidation (malondialdehyde, MDA) and decreased antioxidant activity (reduced glutathione, GSH) as well as noticeable increase in testicular oxidative stress and a corresponding reduction in antioxidant/antioxidant enzyme activities after MSG administration [7,13,19]. Increased production of free radicals caused by MSG could lead to lipid peroxidation and sperm membrane dysfunction, sperm DNA damage, and impaired sperm movement. The abundance of unsaturated fat (plasma membrane) and low levels of antioxidants (cytoplasm) make the testes and sperm cells susceptible to oxidative stress [20]. Patients with asthenozoospermia were found to have a high ROS generation in seminal plasma as well as sperm membrane damage mediated by MSG [7,19]. The direct implication of this ROS-induced damage on membrane integrity are impaired sperm motility and viability [20]. Therefore, therapeutic agents such as antioxidants may be useful in reversing MSG-induced reproductive toxicity.

Neurotoxicity
The neurotoxic effect of MSG causes excitotoxicity in the brain through disruption of the hypothalamic-pituitary-axis pathway (HPA) [13]. Glutamate is an excitatory neurotransmitter, and a high influx of neuron intracellular calcium caused by high glutamate may lead to neuronal death. HPA disruption may reduce levels of sex hormones, including testosterone, follicle-stimulating hormone, and luteinizing hormone. This ultimately leads to alterations in sperm quality [21]. Spermatogenesis is totally dependent on the sex hormones and androgen-dependent organs of the reproductive system, which include the prostate gland, epididymis and seminal vesicles. Any androgen hormone (i.e., testosterone, luteinizing hormone, and follicle-stimulating hormone) disorder will therefore have a negative impact on the reproductive tissues [7].

Glutamate Receptor Dysfunction
Another mechanism of MSG-induced male reproductive toxicity is via glutamate receptors, as MSG directly affects the glutamate transporter on the epithelium of seminiferous tubules. Glutamate receptors are found in different organs and tissues, including the endocrine glands, hypothalamus, thymus, ovaries, liver, kidney, and testis. The testis has been found to exhibit morphological alterations subsequent to MSG treatment due to mal-expression of glutamate receptor in the testis [7,10,21].

Brief Clinically Observed Adverse Effect of MSG
Clinical trials conducted in the past have revealed the interplay between MSG and hunger and food intake. In one study, 32 volunteers were screened for the effect of MSG on food intake. It was observed that those who consumed soup containing MSG had increased hunger and food intake when compared to those who took soup without MSG [8,23]. In another study involving 100 French men given an MSG-added diet, an obvious increase in food intake was noticed [8,24]. There have been clinical reports on the direct relationship between MSG intake and obesity in humans [8,[25][26][27]. Clinical trials have also shown that the consumption of MSG could result in certain allergic reactions in humans [8].

Conclusions
MSG may induce male reproductive toxicity via different mechanisms (e.g., oxidative damage, histomorphological alterations, hormonal dysfunction, and reduced sperm quality). Further studies should be focused on providing a more comprehensive mechanism for MSG-induced reproductive dysfunctions in order to generate a better management strategy for the condition. Clinical studies on human subjects to evaluate the adverse effects of MSG on the male reproductive system are also advocated.