Synergistic Impact of Environmental Pollution and Occupational Stress on Sperm DNA Integrity Unveiling Hidden Drivers of Male Infertility

Exposure to pesticides and its impact on male fertility

Pesticides, including herbicides, insecticides, and fungicides, are crucial in agriculture and public health. However, their use has been linked to harmful effects on human and environmental health. Certain pesticides, like organochlorines, are persistent pollutants that can accumulate in the food chain.^[12] Humans are exposed to pesticides and their residues by consuming contaminated food, water, and soil or through inhalation and skin contact. Pesticides are known to disrupt endocrine function and have been connected to various reproductive problems. The United Nations Environment Programme (UNEP) stated that nine of the twelve most harmful persistent organic pollutants (POPs) are pesticides used in agriculture. These POPs have been recognised globally as serious threats to human and wildlife health.^[13] Humans may be exposed to pesticides through work or environmental routes. An example of a harmful reproductive chemical is 1,2-dibromo-3-chloropropane (DBCP), used since the mid-1950s. Its harmful effects on human sperm were only recognised in 1977.

Dichloro-diphenyl trichloroethane, commonly referred to as DDT, is a pesticide widely known for its links to possible negative effects on fertility. DDT and its metabolite DBCP have demonstrated estrogenic effects in males by blocking androgen receptors.^[14,15] This identifies DBCP as a strong male reproductive toxicant that directly harms testicular tissue and spermatogenesis.^[16] A study in India looked at male workers exposed to various pesticides, including DDT, benzene hexachloride (BHC), endosulfan, various organophosphates, and synthetic pyrethroids like fen valerate and cypermethrin during mixing and spraying tasks. These workers faced negative reproductive outcomes, such as abortions, stillbirths, neonatal deaths, and congenital defects. However, it is challenging to assign these effects to a specific pesticide, as they likely result from cumulative exposure to multiple chemicals.^[17] Research on greenhouse workers has shown that exposure to pesticides may negatively impact testicular function and male fertility, especially during manual plant handling. A significantly higher risk of cryptorchidism (undescended testicles) was noted in the sons of women employed in gardening.^[18] Studies involving agricultural and chemical industry workers have further linked pesticide exposure to reduced fertility in both men and women. This exposure also raised risks of spontaneous abortion, birth defects, and other negative pregnancy outcomes.^[19] Specifically, agricultural pesticide exposure has been associated with declines in semen quality, lower sperm count, reduced motility, and higher rates of Teratospermia.^[20] Given the reproductive risks seen among workers and applicators exposed to certain pesticides, it is essential to promote integrated pest management, develop safe alternatives, and educate farmers and workers on the proper handling and use of these chemicals to lessen reproductive health risks. Emerging evidence suggests that certain pesticides can induce epigenetic marks in sperm that persist for three generations, even without continued exposure. Unlike DNA mutations, these epimutations affect DNA methylation and histone retention patterns, altering spermatogenesis in offspring. This transgenerational impact has not been incorporated into most reproductive toxicity models and represents a significantly underexplored contributor to unexplained male infertility in populations with ancestral pesticide exposure.^[21,22]

Exposure to metals & its impact on fertility

Occupational exposure to metals, such as lead and solvents, among painters and construction workers, has been linked to negative effects on both male and female reproductive health. A study observed a decline in sperm count in a population from Bangalore, India, corresponding with rising pollution levels, including suspended particulate matter (PM), sulphur dioxide, and lead.^[23] Research by Dawson et al. indicates that environmental lead exposure may disrupt regular spermatogenesis.^[24] Even moderate lead exposure (blood levels <400 µg/dL) can significantly harm semen quality, although solid evidence for its negative effects on male reproductive endocrine function is still lacking.^[25] These studies suggest that lead exposure at levels near 40 µg/dL may adversely affect spermatogenesis and male reproductive hormone function. Additionally, paternal lead exposure has been studied in relation to low birth weight and premature births. Although no significant differences in birth weight or gestational age were found between exposed and control groups, workers with elevated blood lead levels for over five years had a higher risk of fathering children with low birth weight or premature birth.^[26] While traditional metal toxicity is well documented, new data indicate that metal nanoparticles (NPs) from industrial paints, welding fumes, and electronics manufacturing can accumulate in seminiferous tubules, causing physical compression of the germinal epithelium and limiting nutrient diffusion and oxygen exchange. This mechanical biological hybrid mechanism has not been included in classical fertility toxicology, but may explain infertility in men exposed to nano-industry environments despite normal conventional lead or cadmium levels.^[27,28]

Environmental pollution and sperm DNA damage

Single and double-strand DNA breaks due to dietary patterns

Consumption of processed meat, artificial sweeteners, alcohol, caffeine, and full-fat dairy products has been identified as a risk factor for male infertility. Therefore, it is important to investigate the relationship between diet and sperm chromatin integrity in order to develop potential nutritional interventions that can optimise sperm quality, improve male fertility, and support embryonic development. Different dietary patterns may influence spermatogenesis, thereby affecting sperm chromatin integrity and ultimately male reproductive health. Two complementary but biologically distinct approaches to assess this integrity are DNA fragmentation, which reflects double-strand breaks (DSBs), and chromatin Deprotamination, which reflects reduced protamine DNA binding.^[31] Evidence indicates that DSBs have a greater negative effect on reproductive outcomes, including fertilisation, implantation, miscarriage, pregnancy, and live birth rates, than single-strand breaks (SSBs). However, these effects can be partially overcome through the use of intracytoplasmic techniques (ICSI). In sperm, SSBs are irreversible, whereas DSBs can be repaired by homologous recombination, non-homologous end joining (NHEJ), and alternative NHEJ pathways.^[32]

Effect of packaged food on male fertility

Ultra-processed foods (UPFs) are ready-to-eat items, such as carbonated drinks, sugary beverages, snacks, and instant meals, often replacing healthier dietary options.^[33] Recent lifestyle changes and advances in food processing technology have increased the demand for affordable, convenient foods, especially highly processed ones. While food processing extends shelf life by slowing microbial growth, it often leads to harmful byproducts and significant nutrient loss.^[34] Eating UPFs is linked to greater oxidative stress, changes in gut microbiota, and inflammatory responses. These issues mostly stem from high caloric content, saturated and trans fats, high Glycaemic index, and low fibre levels.^[35,36] Common UPFs include dairy drinks, sweets, bread, non-dairy beverages, oils, sauces, processed meats, fast food, cakes, cookies, and more. Parabens, a group of preservatives in cosmetics, are also used in food products to extend shelf life. Human exposure mostly comes from skin contact or ingestion.^[37] A study involving 200 healthy men showed that higher UPF consumption is linked to lower sperm count, concentration, and motility.^[38] Similarly, a case-control study of men with asthenozoospermia found a direct link between high UPF intake and reduced sperm motility.^[39] Another study with 115 men facing infertility identified an indirect relationship between sperm motility and the Artuklu Sperm Quality Index (ASQI), reflecting unhealthy diet patterns.^[40] Overall, UPFs have been reported to negatively affect various aspects of semen quality. A meta-analysis of observational studies discovered that following a Western dietary pattern characterised by high intake of fatty dairy products and processed meats, along with low consumption of vegetables, whole grains, and fruits, was inversely related to sperm concentration. However, this dietary pattern did not show significant links to abnormal sperm motility or morphology.^[41] Given the different nutritional profiles and additives found in UPF categories across populations, their effects on sperm may differ.^[42,43]

While the connection between UPF intake and infertility is still under-researched, several mechanisms have been suggested. UPFs are high in sugar, salt, and unhealthy fats, which can contribute to weight gain and obesity.^[44-46] Obesity can harm reproductive health by leading to insulin resistance, elevated leptin and oestrogen levels, sexual dysfunction, and triggering oxidative and inflammatory pathways. This results in diminishing spermatogenesis and worsening sperm quality in obese individuals.^[47,48]

Unhealthy eating habits, such as high consumption of sugars, fats, and UPFs, are linked to higher production of ROS in sperm, lower antioxidant defences, and greater fertility issues. Consequently, oxidative stress has damaging effects on sperm quantity and quality in various ways.^[49] Moreover, UPFs, despite their high levels of sugars, fats, and calories, often lack vital nutrients like fibre, proteins, vitamins A, C, D, E, B3, and B12, along with minerals such as zinc, phosphorus, magnesium, and potassium.^[50,51]

The role of nutrients in maintaining sperm quality and quantity is well-documented. For example, zinc, selenium, and antioxidant minerals and vitamins are associated with improved fertility by reducing inflammation and oxidative harm. Antioxidants can enhance sperm count, motility, viability, lessen DNA fragmentation, and help maintain normal morphology. The presence of zinc, copper, magnesium, and vitamins E and C in semen, along with the beneficial effects of fat-soluble vitamins on sperm, suggests that cutting back on UPF intake may improve male fertility. Beyond low nutrient density, UPFs include cosmetic additives, packaging contaminants, hydrogenated oils, modified starches, and hydrolysed proteins, all of which can negatively affect various aspects of health, including reproductive function.^[52-56]

UPF-derived advanced glycation end products (UPF-AGEs) are especially found in extruded snacks and reheated oils. UPF-AGEs can cross the blood-testis barrier, bind to RAGE receptors on spermatozoa, and trigger DNA fragmentation and chromatin condensation defects.^[57,58]

Focus on urban dietary patterns, UPFs, and sperm DNA integrity

The effect of work stress on male fertility

Job stress threat factors encompass job complexity, workload, shift schedules, time constraints, job demands, degree of job control, social support at the plant, environmental and cerebral hazards present at work, low ménage income, imbalance between trouble and price, individual characteristics, weekly working hours, leave availability, employment status, physical and socio- profitable conditions, behavioural factors related to work, collapse, and job satisfaction.

The impact of occupational stress on fertility is a significant yet less honoured consequence. Job stress ranks among the most current occupational health issues, posing a serious threat to workers' well- being. Studies from advanced nations reveal that nearly 30 of workers witness job- related stress.^[61]

This stress can lead to severe behavioural, physical, and cerebral issues. Occupational threat factors for job stress include aspects such as job control, conflicts at work, job satisfaction situations, cerebral demands, physical plant conditions, social support deficiency, and workload intensity.^[62]

Infertility may arise as a result of physiological goods convinced by job stress, which can negatively affect semen quality in men. Also, stress can reduce luteinizing hormone (LH) and testosterone storage, inhibit spermatogenesis, and diminish sperm quality.^[63,64] Acute stress may negatively impact testicular function.^[65] Habitual stress is associated with further profound consequences; elevated glucocorticoid situations due to sustained stress can spark apoptosis in colourful testicular cells, including origin cells, Sertoli cells, and Leydig cells.^[66,67] High job stress situations also contribute to increased oxidative stress.^[68,69]

Occupational stress and environmental toxicants

Late-night sleep and its impact on male fertility

Late-night sleep patterns disturb the core circadian rhythm, which regulates testicular clock genes such as BMAL1, PER1, Period Circadian Regulator 2 (PER2), Cryptochrome Circadian Regulator 1 (CRY1), and Circadian Locomotor Output Cycles Kaput (CLOCK). Disruption of these genes leads to impaired regulation of spermatogenesis, abnormal hormone cycling, and reduced germ cell survival.^[90]

Testosterone secretion follows a strong nocturnal rhythm, peaking during early sleep cycles. Sleeping late shortens deep sleep phases, reducing total nighttime testosterone output. Chronically reduced nocturnal testosterone suppresses Leydig cell activity, impacting sperm count and motility.^[91] Late-night sleep is usually accompanied by excessive light exposure, suppressing melatonin secretion. Melatonin is a major gonadal antioxidant, and its deficiency increases testicular ROS production, leading to sperm DNA damage, lipid peroxidation, and reduced motility.^[92] The pulsatile release of LH and FSH depends on synchronised sleep-wake cycles. Late-night sleep disrupts hypothalamic GnRH rhythm, causing weaker LH pulses and misaligned FSH release. This reduces Sertoli cell support function and weakens spermatogenic efficiency. Studies are beginning to show that poor sleep contributes to disorders of the testicular hormonal axis, including hypogonadism, infertility, and erectile dysfunction.^[93] Staying awake late increases evening cortisol, which should naturally decline at night. Chronic elevation of nighttime cortisol is linked to:

Leydig cell apoptosis

Reduced steroidogenesis

Sertoli cell dysfunction

Oxidative injury to developing sperm.^[94]

Sleep delay impairs mitochondrial biogenesis genes and increases mitochondrial ROS. This reduces ATP production, which is essential for progressive sperm motility. Studies show that men with late-night sleep patterns have significantly compromised mitochondrial membrane potential.^[95] Late-night routines often involve prolonged sitting (gaming, phones, laptops), which elevates scrotal temperature. Even a 1-2°C increase negatively affects spermatogenesis, leading to DNA fragmentation, reduced sperm count, and abnormal morphology.^[96] Excess screen time at night exposes the testes to prolonged electromagnetic field (EMF) radiation at a time when DNA repair activity in germ cells is highest. EMF exposure is associated with increased ROS formation and mitochondrial stress in spermatozoa.^[97] Sleeping late is associated with late-night eating, glucose intolerance, and insulin resistance. Chronic hyperinsulinemia reduces SHBG (sex hormone-binding globulin) and increases free oestradiol. Creating a hormonal imbalance detrimental to spermatogenesis. Sleep deprivation stimulates the hypothalamic-pituitary-adrenal (HPA) axis, resulting in increased cortisol production. Elevated cortisol decreases GnRH production, negatively impacting FSH, LH, and testosterone.^[98] New evidence shows that disrupted sleep reduces levels of seminal antioxidants such as selenium, zinc, vitamin C, and catalase. This results in lower sperm viability and higher susceptibility to oxidative injuries.^[99]

Emerging evidence from recent human studies supports the synergistic detrimental impact of environmental pollution, occupational exposures, and poor diet on sperm DNA integrity. Prolonged exposure to air pollutants and heavy metals induces oxidative stress, leading to epigenetic alterations and increased DNA damage in sperm cells, as shown by altered methylation patterns. High levels of UPFs are associated with significantly elevated sperm DNA fragmentation, emphasising lifestyle contributions to genomic instability. Additionally, contemporary clinical data reveal that both single and double-strand DNA breaks are strongly correlated with total DNA fragmentation, emphasising the need for research focusing on molecular DNA damage endpoints rather than conventional semen parameters alone.