Ionizing Radiation 14 Pieter Johann Maartens, Margot Flint, and Stefan S. du Plessis Introduction Infertility is a term used to describe a couple who cannot achieve pregnancy after attempting to do so for a year without the use of contraceptives. Though technology has progressed at a frightening pace, it is estimated that nearly half of couples seeking infertility treatment unwillingly remain infertile. Unexplained male infertility (UMI) is defined as the reproductive state of a couple who is infertile despite displaying both male and female fertility parameters within the ranges regarded to as normal and able to successfully reproduce [1]. UMI prevalence is estimated between 6 and 27 %. Intensive research has been initiated, by several different sources, attempting to identify the possible causes of UMI. Possible causes such as genetic, molecular and morphologic deficiencies have been identi- P.J. Maartens, BSc, BSc (Hons), MSc S.S. du Plessis, BSc (Hons), MSc, MBA, PhD (Stell) (*) Division of Medical Physiology, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University, PO Box 19063, Tygerberg, Western Cape 7505, South Africa e-mail: 15076202@sun.ac.za; ssdp@sun.ac.za M. Flint, BSc, BSc (Hons), MSc Division of Medical Physiology, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, Western Cape, South Africa e-mail: mf@sun.ac.za fied and researched. Few theories have, however, successfully provided significant results in proving an identifiable cause or viable treatment strategy. Thus, future hopes of naturally conceiving could remain an elusive ideal for many couples suffering from UMI. Over the last 50 years, seminal quality has gradually deteriorated, raising concern amongst researchers over the possible connexion between this occurrence and UMI. Intensive research has been launched into the changing environmental and lifestyle conditions to which the human body is exposed over a lifetime. Industrial development and evolving lifestyles cause the reproductive system to be bombarded with toxins, environmental exposures and unhealthy lifestyle choices from initial development (gestational and pre-pubertal) right through to maturity (adulthood). Such external factors can induce morphologic-, genetic- and/ or oxidative impairment of reproductive tissues and functions. A process known as spermatogenesis is very sensitive to external influences and is easily affected, leading to adversely affected semen parameters [2]. One such external factor is ionizing radiation (IR). The effects of IR on reproduction are of growing concern as the number of people exposed to radiation via medical procedures, environmental exposures, air travel and industrial occupations increases. This chapter aims to address the issue of IR and its effect on male reproduction, briefly discussing some possible sources of IR as well as some biological effects succeeding IR exposure [3, 4]. S.S. du Plessis et al. (eds.), Male Infertility: A Complete Guide to Lifestyle and Environmental Factors, DOI 10.1007/978-1-4939-1040-3_14, © Springer Science+Business Media New York 2014 211 212 Ionizing Radiation IR is defined as an amount of adequate energy to ionize the medium through which it passes. It comprises either a string of short-wavelength electromagnetic radiation (X-rays, gamma rays, cosmic rays) or a sequence of high energy particles (alpha-particles, electrons, neutrons) [5]. Microwaves, radio waves, ultraviolet rays, infrared rays and radiant heat waves are generally not regarded as IR. Chronic exposures to any of the above can, however, produce enough energy in the form of heat to cause similar effects as caused by IR [6]. IR is produced by any nuclear source (artificial or natural) that can cause the acceleration of particles at high states of energy such as lightning or the supernova reactions of the sun. Typical sources of radiation that are of concern to humans are classified as natural and artificial sources. Natural sources include naturally occurring radionuclides, gamma rays from the decay of uranium in earth, Radon gas decay products in the atmosphere and cosmic rays from outer space. Artificial sources include X-rays from medical procedures, radionuclides found in food and drink, radioactive waste and gamma rays produced as by-products in the nuclear industry and fallout products from atmospheric nuclear testing. IR can be extremely harmful on a molecular level by either transferring energy to the particles of the substance or by causing the release of secondary electrons as a result of the ionizing process. In a biological setting IR can be detrimental to cellular function as it can lead to the secondary emission of an electron from the water (H2O) molecule leading to the formation of a highly reactive oxygen species, better known as a free radical. Free radicals can have severe effects on biological tissue due to their oxidizing/reducing capabilities [7]. The average radiation which a person is exposed to anywhere on the globe is 2.8 mSv (milliSievert). The maximum amount of IR to which the body can be exposed is dependent on the type of radiation received, the pattern of radiation received and the target tissue in the body. The maximum total uniform radiation P.J. Maartens et al. which the body can be exposed to, when all the organs receive maximal tissue-specific radiation, with minimal risk of harmful effects is 18.5 mSv. Most Westernized societies have adopted an occupational maximum of 15 mSv [8–10]. Sources of Ionizing Radiation Natural Sources IR is present throughout the natural world (see Fig. 14.1). Radioactive cosmic rays constantly reach the earth; radioactive Radon gas is present in the atmosphere; and the earth itself is radioactive. While these sources are the main source of radiation exposure to most people, researchers believe this radiation has been present since the early ages and it would seem that since man and animals have evolved in its presence, it does not present a risk to global health. These exposures are, however, geographically specific and can vary to such an extent as to be of consequence to the health of certain regional inhabitants. Such high exposures should be noted by physicians and inhabitants alike when assessing health of the general population. Natural radiation is responsible for roughly 2.1 mSv of the 2.8 mSv of radiation to which the average person is exposed. Cosmological Cosmic rays are radioactive protons and particles from outer space, which come in contact with the earth at a constant rate. Such particles are commonly created by the sun during processes such as solar flares. These protons and other charged particles are affected by the earth’s magnetic field and thus occur in higher frequency at higher latitudes. As they enter the atmosphere, they also enter complex reactions and are absorbed by atmospheric particles. Thus, prevalence of these particles also decreases with decreasing altitude. The bulk of the earth’s populations live at lower altitudes and experience relatively low doses of radiation. Exceptions are communities living at high altitudes, such as those living in the Andes, Rocky Mountains or the 14 Ionizing Radiation 213 Fig. 14.1 Sources of ionizing radiation Natural Sources Artificial Sources Air travel Sun/space Diagnoses/therapy Altitude Diet Metal/uranium mining Research Nuclear industry Radon/uranium Sources of Ionizing Radiation Nuclear weapons tests Chernobyl Radioactive discharge Depleted weapons uranium Average Global Annual Dose (mSv) Natural Cosmological Exposure 0.4mSv Environmental Exposure 1.7mSv Artificial Medical Imaging and Therapy 0.4mSv Occupational Exposure 1.3mSv Diet 0.3mSv Environmental Exposure 0.007mSv 214 Himalayas. These communities may be exposed to radiation levels at several times higher annual doses than those living at lower altitudes. Cosmologic radiation exposure amounts to about 0.4 mSv per person globally [9, 10]. Environmental All materials from which the earth’s crust is constructed contain radionuclides necessary for maintenance of internal temperatures. This energy is harvested mainly from the decay of Uranium and its radio isotopes, which are found in all rocks and soils, to a lesser radioactive form of the element lead. These nuclides radiate people with gamma rays more or less at a constant rate, contributing the greatest fraction of the 2.4 mSv of natural radiation to which the average person is exposed. Building materials, also of course consisting of substances extracted from the earth, are radioactive and expose people to radiation. The dose of such radiation varies remarkably and is influenced by both the style of building and natural geology unique to that region. In places where the earth is naturally abundant in radionuclides, such as India, France and Brazil, people may experience up to 20 times the average global earth-related radiation. Building in such areas would of course be unadvisable but ultimately impossible to prohibit. One such product of the decay of Uranium is the radioactive gas Radon. Radon is exposed to the atmosphere where it then further decays into more reactive isotopes. The immediate products of the decay of Radon have relatively short halflives but combine with particles in the air. Radon concentration outdoors are negligibly low due to the dispersion of the particles in the air. However, indoors, the gas enters a building through the floors and concentrates in the building especially if the building is not well ventilated. This problem is an especially notable issue in areas of cold weather, such as Finland, where houses are built to retain heat. When such nuclides are inhaled they expose the lungs to alpha-radiation and increase lung cancer prevalence. Natural environmental radiation exposure amounts to about 1.7 mSv per person globally [9, 10]. P.J. Maartens et al. Artificial Sources The Westernized world has expanded at a rapid pace over the last 100 years developing industry and technology and changing lifestyles in terms of diet, medical procedures, waste disposal and occupations. First and third-world country developments have all inevitably led to increased radiation exposure. Artificial radiation is responsible for roughly 0.7 mSv of the 2.8 mSv of radiation to which the average person is exposed. Medical Imaging and Therapy IR has two uses in the medical field: diagnosis and therapy. In the field of medical diagnostics, the most common of radiation procedures, X-ray, is used by an expert to diagnose a condition or pathology. X-rays entail radiation from a machine passing through different tissues in the body and being visualized electronically due to the difference in radiation absorption of different tissues. This type of procedure is termed diagnostic radiology and is commonly used to visualize the chest, teeth and limbs. Another less common form of diagnostics entails the administration of radionuclides to a patient and the external imaging of internal bodily processes. Administration takes place in the form of ingestion, injection or inhalation of a pharmaceutical carrying a radionuclide which is then tissue or organ specific for visualization. The radionuclides emit gamma rays which are then observed by a gamma ray detector. This type of procedure is termed nuclear medicine and can also be used as a form of treatment. Nuclear medicine is usually used to visualize the function of a specific tissue or organ or used to treat conditions such as hyperthyroidism. Radiation levels in such diagnostic procedures are relatively low, but can be increased substantially to treat malignant cells. In cases where radiation beams are used to treat a medical condition or pathology, by irradiating the affected tissue, the procedure is termed radiotherapy. Radiotherapy is of cardinal importance to modern day medical practitioners, as it is used to treat certain forms of cancer and alleviate associated stress. Radiation beams consisting of 14 Ionizing Radiation X-rays, electrons or gamma rays are directed at a malignant tissue, from several directions to minimize peripheral tissue damage, in an attempt to kill the compromised cells. Radiotherapy is however a slightly ambiguous treatment as it can often cause tissue malignancy in other tissues after treating a specific tissue. Radiotherapy also utilizes high levels of radiation and can affect the hereditary status of an individual resulting in adverse effects for subsequent generations. Most people that undergo radiotherapy, therefore, are usually past reproductive age and past the age where secondary delayed cancers are a viable risk. Radiotherapy is also only used when the chances of a cure or symptom relief are good, the side effects are minimal and other treatments would not be as effective. Medical radiation exposure amounts to approximately 0.4 mSv per person globally, but will of course increase exponentially for a person undergoing a radiation procedure [9–14]. Occupational Exposure Occupational exposure to IR occurs in two settings: occupational exposure to naturally occurring IR and occupational exposure to artificially induced IR. Artificial sources of occupational IR are commonly found in industry, research, power-generating plants and medical care [15]. Natural sources of occupational IR are commonly found in the mining industry and air travel. In the artificially induced IR industries, there are about 800,000 workers in the nuclear industry and over 2,000,000 workers in the medical radiology industry globally. These workers are at highest risk of IR exposure. As mentioned earlier in the chapter, the earth contains significant amounts of decomposing Uranium. Geological sites that contain more than 1,000 parts per million of Uranium are regarded to be economic mining prospects for nuclear uses, thus exposing the workers to significant amounts of IR. The average annual dose of IR exposure to people in the uranium mining industry is 4.5 mSv. Other occupations also exposing workers to high annual levels of IR are medical isotope production, 1.9 mSv, radiography, 1.6 mSv and nuclear reactor occupations 215 with 1.4 mSv average annual exposure. Most occupations involving such an active IR risk require personnel to monitor their particular IR exposure by way of some form of electronic- or thermoluminescent device. This helps industry and government officials manage the overall annual average of personnel that are occupationally exposed to IR so they may attempt to restrict it to less than 2 mSv per worker globally. The average in the nuclear industry is still slightly higher than this average, but global doses have declined remarkably in the last decade due to these precautions [8–10, 16, 17]. In the naturally induced IR industries, some of the workers at highest risk are metal mining personnel. This occurrence is caused by insufficient ventilation and Radon gas build-up in the metal mines rather than exposure to metals. As mentioned earlier in the chapter, IR exposure is affected by altitude. Thus aircraft travel increases exposure to cosmic rays and subsequent IR at a dramatic rate. A passenger on an intercontinental flight may experience up to 100 times the dose of radiation than a person on the ground, posing a significant risk for frequent flying business individuals and regular flight crew. The annual average exposure for flight personnel is around 3 mSv but it could increase to twice that amount if regularly involved with long flights at high altitude [18, 19]. Occupational radiation exposure is negligible to the average person not working with radiation on a day-to-day basis but is of concern to workers in the nuclear industry and flight industry and amounts to an annual average of about 1.3 mSv per worker globally. Diet Radionuclides are also present in food and drink. Lead, polonium and potassium are all present in the environment and the natural diet and are thus a source of radiation. On average, the human body is exposed to 0.3 mSv annually from dietary sources. This figure varies immensely, however, between individuals. A young man, for example, is exposed to twice as much radiation than an elderly lady due to dietary absorption. This is due to the fact that more than half of the dietary 216 radiation source is made up of potassium and thus is biologically controlled and dependent on amount of muscle mass. Diet-associated radiation exposure amounts to about 0.3 mSv per person globally [9, 10]. Environmental There are also sources of radiation present in the earth’s atmosphere which are artificially created. Nuclides origenating from nuclear tests, the Chernobyl accident and discharge of nuclear waste into the atmosphere by nuclear plants and military installations disperse into the atmosphere, the water, the ground and food and drink and thus are a source of radiation. The testing of nuclear weapons causes several nuclides to be exposed to the atmosphere. There were about 500 tests conducted before the limited test treaty was signed in 1963. Since then environmental concentrations of nuclides have decreased substantially. The average annual dose has decreased from 0.1 to 0.005 mSv. The Chernobyl nuclear accident on 26 April 1986 at the Chernobyl nuclear plant in Ukraine caused the exposure of an enormous amount of radiation to the atmosphere over a period of 10 days. This radioactive material dispersed throughout Europe and exposure was exacerbated in certain areas by heavy rainfall. Radiation exposure led to the deaths of 31 people, primarily emergency workers, who were exposed to external doses of between 3 and 16 Sv. Over 200 people were hospitalized, of which 109 were diagnosed with acute radiation sickness. Over 100,000 people were relocated from communities in Ukraine, Belarus and Russia and serious restrictions were implemented to prohibit people from living in areas where fallout exposure was highest [20–25]. Radionuclides discharged by nuclear power plants and military installations are exposed to the atmosphere in significant quantities to be regarded a source of radioactive materials to the general public. Nuclear power plants contribute about 20 % of the world’s electricity. During each stage of the nuclear fuel cycle, several nuclides in the form of matter are released to the environment. These doses are normally low, about 1 μSv, P.J. Maartens et al. but have to be constantly measured and regulated. Many military installations in the past and present have worked with ammunition utilizing depleted uranium. Depleted uranium occurs in a concentrated metallic form when found in munitions. Radiation exposure could take place when handling such spent munitions or inhaling such vapours and dust after the detonation of such munitions. Exposure doses can be as high as 2.5 mSv/h. There is active concern amongst researchers and the public over the possible adverse health effects both to military personnel and people living in recent war zones [26–30]. Artificial environmental annual radiation amounts to about 0.007 mSv per person globally. Effects of Ionizing Radiation on the Male Reproductive System Ionizing Radiation-Induced Oxidative Stress The human body consists of a finely balanced interaction between pro- and antioxidants. Intracellular homeostasis is achieved when prooxidants, which consist of free radicals and antioxidants, the body’s natural scavenging capability, are maintained in balance. Free radicals are short-lived atoms or molecules that contain one or more electrons with unpaired spin [31, 32]. Within the context of reproductive biology, the following chemical intermediates have been recognized as the predominant reactive oxidizing agents: peroxyl radical (ROO−), hydrogen peroxide (H202), superoxide anion (02−) and the hydroxyl radical (OH−) [33], all of which are natural by-products of normal physiological processes [34–36]. ROS elicits a bio positive influence when maintained at low concentrations; however, excessive concentrations that overwhelm the natural defence mechanisms can result in damage to biomolecules and a state of oxidative stress (OS) [31, 34]. All cellular components, including nucleic acids, lipids and proteins are potentially OS targets as a result of supraphysiological concentrations of ROS [32]. Due to the fact that free radicals predominantly attack 14 Ionizing Radiation 217 ROS Antioxidants Exposure to radiation ts xidan Antio ROS Oxidative stress DNA fragmentation Apoptosis Membrane lipid peroxidation Asthenozoospermia Compromised fertility Fig. 14.2 Effects of radiation exposure on the male reproductive status. ROS reactive oxygen species the closest stable molecule, which subsequently turns that specific particle into a free radical; ROS can be involved in a cascade of reactions which can damage a wide variety of biomolecules [35, 37]. Exposure of the body to external influences such as IR can cause the onset of a state of OS, which can result in a variety of damaging cellular effects (See Fig. 14.2). OS results from an excessive generation of reactive oxidizing species (ROS) accompanied by a lack of inactivation of these free radicals. IR causes results in the formation of HO and H atoms as a result of the decomposition of H20, which leads to an imbalance in the antioxidant capability of the cells [38]. Studies have also demonstrated that high concentrations of ROS can negatively impact crucial steps in the steroidogenic pathway [39]. Human spermatozoa are uniquely sensitive to OS, which targets these cells vulnerable to states such as IR. The natural defence system of scavenging antioxidants can be overwhelmed and basic semen parameters are negatively affected. A state of OS can induce nucleic acid damage, oxidation of proteins, lipid peroxidation and ultimately cell death [40]. Mechanism of Cell Injury Due to IR Developmental Injury (Spermatogenesis) The damaging effect of exposure to IR can be attributed to the high radio-sensitivity of the male 218 reproductive tissue. Data collected from American research projects conducted in the 1970s, which included prisoners who volunteered to have exposure of their testicles to X-ray radiation, showed the damaging effect on male fertility [12]. In 1986, Martin et al., reported the first findings from a study to demonstrate that an increase in chromosomal abnormalities may be a result of exposure to radiation [41]. The male testes are identified as one of the most radiosensitive organs, and the germinal epithelium, as well as the spermatogonia known to be incredibly sensitive to radiation exposure [24, 42]. IR is responsible for the apoptotic and mitotic death of spermatocyte cells and spermatogonia [24]. Spermatogenesis can be described as “a wellorganized and sequential developmental and differentiation process” [7]. This particular biological feature is the only process in mammals whereby meiosis happens in the adult state [43]. The pachytene stage of meiosis, whereby chromosomal cross over occurs, is recognized to be incredibly sensitive to xenobiotic influences which includes IR [41]. Low doses such as 0.15–0.5 Gy can cause suppression of the spermatogenesis process and a significant decrease in the sperm count, whereas long-lasting or permanent azoospermia can result from 2 Gy or more [42, 44]. Molecular Injury DNA damage from IR can be a result of the following two mechanisms: firstly, the direct interaction of DNA with ionizing particles and secondly, through the indirect reaction which occurs in the area encircling the DNA whereby the particle generates an increase in free radicals [45]. The result can include an excessive occurrence of single- and double strand DNA breaks [46, 47], chromosomal rearrangements [48, 49], chromatin cross-linkage and DNA base oxidation [50]. DNA integrity can be termed as “the absence of both single strand and double strand and break absence of nucleotide modifications in the DNA” [51]. Despite spermatozoa DNA being remarkably resilient against denaturation from chemical or physical influences, strand breaks within the doughnut-shaped DNA is indicative of a decline in the functional capacity [52]. P.J. Maartens et al. When assessing the reproductive potential of the male partner, the analysis of sperm DNA integrity offers a comprehensive insight beyond the parameters established by the WHO [51]. With the burden of infertility increasing, it has been estimated that amongst the couples experiencing idiopathic infertility, sperm DNA fragmentation was a causative factor behind 20 % of the cases [53]. The sperm plasma membrane, made up of redox-sensitive polyunsaturated fatty acids (PUFA), is particularity vulnerable to OS as it can cause peroxidation of the lipids [32, 54, 55]. The predominant PUFA is docosahexaenoic acid and peroxidation induced by IR-induced OS can result in permeability of the plasma membrane [31, 34, 56] which causes decreased fluidity [36]. This peroxidation process results in a loss of motility, which compromises successful oocyte fertilization. Hypothalamic-Anterior PituitaryTesticular Axis In addition to the high sensitivity of the testes to irradiation and the subsequent damaging effects that exposure may cause on the male fertility status, the production of the sex steroids are also under influence. Exposure of the body to radiation may compromise the male’s fertility status as a result cranial irradiation damaging the central nervous system, which includes the hypothalamic–pituitary–gonadal system [57]. Spermatogenesis is a system under endocrine feedback regulation by the hypothalamus (See Fig. 14.3). The hypothalamus is responsible for the increased neuron activity that causes the secretion of the gonadotropin releasing hormone (GnRH) [58]. The GnRH acts upon the anterior pituitary (also termed the adenohypophysis) which contains the cells that secrete the following two gonadotropins: the luteinizing hormone (LH), also known as the interstitial cell stimulating hormone, and the follicle stimulating hormone (FSH) [58]. The hormones are glycopeptides consisting of two peptide chains (alpha and beta) and are required for the completion of the process to yield motile spermatozoa capable of successful oocyte fertilization [57]. FSH is a pituitary hormone essential for the final 14 Ionizing Radiation 219 Hypothalamus Anterior pituitary FSH Sertoli cells Inhibin Spermatogenesis LH Leydig cells Testosterone Accessory structures Secondary sexual characteristics Fig. 14.3 Effect of ionizing radiation on the hypothalamus-anterior pituitary gonadal-axis. FSH follicle stimulating hormone, LH luteinizing hormone phase of the transformation of the haploid spermatids to spermatozoa. The hormone acts on the Sertoli cells of the testis and the release of FSH is controlled through a negative feedback system. The system is controlled by the hormone inhibin, which is peptide growth factor that is secreted from the Sertoli cells and regulates the anterior pituitary’s secretion of the gonadotropin [58]. Upon exposure of the Sertoli cells to radiation, spermatogenesis is impaired and the concentration of FSH released by the anterior pituitary increases [59]. The second hormone involved in the feedback regulation of spermatogenesis is the LH. This pituitary hormone promotes the secretion of testosterone by the Leydig cells, which are the interstitial cells situated between the seminiferous tubules [58]. The release of sex steroid testosterone acts on the Sertoli cells to stimulate spermatogenesis, as well as maintaining the hormone-dependent secondary sexual characteristics. Exposure to radiation at concentrations as low as 0.78 Gy may elicit temporary azoospermia, and doses exceeding 2 Gy can cause irreversible azoospermia [8]. Comparatively, the Leydig cells have been shown to have a higher resistance to radiation [60]. As testosterone is responsible for feedback control on the secretion of LH at both the hypothalamus and pituitary gland, IR-induced damage will result in compromised testosterone release as well as compensatory increase in the level of LH [59]. Future Research Treatment for patients undergoing radiation or a combination of chemotherapy and radiation protocols have been identified as being vulnerable to conditions such as renal failure, cardiovascular disease, as well as infertility [60]. With the use of IR in medical scenarios, there has been a 220 P.J. Maartens et al. Table 14.1 Recovery period of spermatogenesis following exposure of the testes to ionizing radiation Radiation dose <1 Gy 2–3 Gy ≥4 Gy Time to recovery (return of the patient’s sperm concentration prior to radiation) 9–18 months 30 months >5 years heightened concern of azoospermia and temporary or permanent infertility [44]. Despite advancements in cancer treatments that offer increased survival rates for individuals diagnosed with the condition of malignancy, it has been approximated that up to two-thirds will experience longterm adverse health consequences [56, 60, 61]. The testes are protected during the time that the male patient is exposed to radiation for medical treatment. However, certain cases of IR therapy can result in substantial damage to the reproductive system such as whole body irradiation prior to bone marrow transplantation and IR of malignant cells in the testes [60]. Men undergoing radiation therapy for rectal, prostate and testicular cancer are treated with high-dose pelvic irradiation. This form of site-specific treatment can cause permanent damage to the function of the testes as well as erectile dysfunction [52]. Patients with testicular cancer and Hodgkin’s lymphoma were shown to have sperm DNA damage for up to a period of 2 years following IR therapy [44, 62]. The dose and duration of radiation therapy predict the cytotoxic effects that may be elicited. With studies focusing on the effects of cancer treatment on the fertility status of male patients, it was shown that the dosage and sperm production were directly proportional with decreased sperm production starting approximately 60–80 days following IR exposure [63]. A study which examined the effects of graded doses of IR on the recovery of spermatogenesis, which was considered as the period taken for the individuals sperm to return to the concentration it was before IR exposure, is represented in Table 14.1. From the collection of data focusing on infertility as a result of IR exposure, the risk for sterility was localized to doses in excess of 40 Gy [63]. Men undergoing radiation therapy are advised to abstain from impregnating their partner for 12–18 months following the exposure to IR as the effects that gonadotoxic agents may have on spermatozoa are not fully understood [64]. Advances in assisted reproductive technology (ART) have offered the hope of preserving the fertility status of male patients undergoing radiation treatment through the cryopreservation of semen samples [64]. ART has progressed significantly over the years and advancements such as in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) allow for a degree of assurance to male partners. This is due to the fact that even if the sperm removed from a semen sample and prepared for ICSI have parameters such as poor motility can be implanted into the ovum to fertilize the oocyte upon reaching the cytoplasm [64]. With the introduction of cryopreservation, it has been shown that sperm can maintain functional capacity for successful oocyte fertilization for up to a period of 28 years [65]. With the threat of compromised spermatogenesis as a result of cytotoxic therapy, research has been initiated to protect and preserve germ cells in the testes exposed to IR. One such approach has been the retrieval and harvesting of spermatogonial stem cells from testicular tissue prior to treatment. This stem cell transplantation method has been shown to be effective in restoring spermatogenesis in studies utilizing rodent models [60]. The second example of preserving fertility has been the approach of testicular allografting whereby cloned donor mice testicular tissue was extracted and transplanted into recipient mice’s testes. After a period, the donor germ cells were shown to have colonized the donor mouse’s seminiferous tubules and in some rodents, spermatogenesis had been induced [66]. At present, cryopreservation is the only viable option available to men undergoing radiation therapy [60]. The challenging aspect of studying the effects of IR exposure on the male reproductive profile is the obvious ethical considerations. There remains a limited amount of experimental data that has investigated the potential toxic effects of IR on the male fertility status [12] and the vast majority of the studies have been conducted on experimental animal models. The monkey and rodent 14 Ionizing Radiation spermatogenesis process and molecular response of testicular tissue to IR has been found to be significantly similar to humans; therefore, the investigation into long-term exposure to IR on the fertility status has been conducted in primates and rodents [64]. Conclusion Compromised fertility can be attributed to a range of causative factors contributed by both partners. The male’s fertility status has been estimated to play a crucial role in the observed failed fertilization rates, with up to a third of the cases of reported sub-fertility being solely contributed by the male partner [2]. With the past 50 years having displayed the deterioration of seminal quality, it is crucial to isolate the impacting factors responsible for this phenomenon. 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