Environmental and microbiome determinants of sperm quality: a narrative review on male health

Introduction

The global issue of infertility is becoming increasingly severe, affecting approximately 8–12% of couples of childbearing age, with male factors accounting for about half of these cases (1).

According to World Health Organization (WHO) guidelines, normal testosterone levels in male fertility assessment are typically ≥12 nmol/L. The 2021 Manual for the Examination and Processing of Human Semen (6th Edition) provides a reference lower limit based on the fifth percentile of approximately 3,500 men of reproductive age; specific values include: semen volume ≥1.4 mL, sperm concentration ≥16×10⁶/mL, total sperm count ≥39×10⁶/ejaculate, proportion of forward-moving sperm ≥30%, total motility ≥42%, and normal morphology ≥4%. These data indicate potential risks of reduced fertility but do not represent absolute thresholds for distinguishing “fertile” from “infertile”. Clinical assessment requires a comprehensive analysis of multiple indicators (2).

Declining sperm quality is one of the primary manifestations of male infertility. In the general fertile population, the prevalence of asthenospermia, azoospermia, and oligoasthenospermia is significantly higher than in the general population. Globally, sperm count and concentration have been declining significantly since the 1970s, with the rate of decline accelerating particularly since the 21st century (3). Multiple studies indicate that over the past four decades, semen quality and total sperm count in healthy Chinese men have decreased over time (4,5). The state of sperm quality is a concern.

Numerous factors influence sperm quality, including environmental factors (6), lifestyle factors (7), and age-related factors (8). Among these, environmental factors play a significant role in deteriorating semen quality, primarily encompassing physical factors, chemical factors, biological factors, and air pollution.

Traditional environmental factors include high temperatures, heavy metals, pesticides, viruses, and bacteria. These primarily impact spermatogenesis through mechanisms such as oxidative stress, endocrine disruption, and direct cellular damage, leading to reduced sperm count, decreased motility, morphological abnormalities, and DNA damage. In recent years, rapid advancements in production and daily life have introduced numerous emerging environmental factors, such as radiofrequency electromagnetic radiation (RF-EMR), perfluorinated compounds [perfluorooctanoic acid/perfluorooctanesulfonic acid (PFOA/PFOS)], and air pollution. Modern men are highly exposed to these emerging environmental factors, which exert extensive and profound effects on male reproductive health. Existing research often focuses on single environmental factors while overlooking the synergistic effects of multiple factors. This paper conducts a systematic analysis of both traditional and emerging environmental factors and summarizes the combined impact of multiple environmental factors on male human population.

Although assisted reproductive technologies or therapeutic interventions offer hope to many couples, environmental factors continue to influence reproductive outcomes (9,10). Further research is urgently needed to investigate the impact of environmental factors on male sperm quality and to promote equitable access to global reproductive health services, thereby providing evidence for preventing and controlling male infertility. We present this article in accordance with the Narrative Review reporting checklist (available at https://tau.amegroups.com/article/view/10.21037/tau-2025-aw-833/rc).

Methods

A comprehensive literature search was conducted in PubMed from its inception to June 25, 2025, for articles on the effects of traditional environmental factors on male sperm quality. The search included all articles containing the following keywords: “sperm quality”, “environmental factors”, “temperature”, “heavy metals”, “pesticide”, “phthalate”, “viruses”, “bacteria”, “Radiofrequency Electromagnetic Radiation (RF-EMR)”, “Per- and Polyfluoroalkyl Substances (PFAS)”, “air pollution”, “Benzo[a]pyrene (BaP)”, and “microbiome”. From a total of 250 articles reviewed, we included all the studies in English that provided strong evidence or were most relevant to the topic of interest. Eighty-two retrieved articles were reviewed to summarize the effects of environmental factors on male sperm quality. A complete search strategy for article selection can be found in Table 1. No prior registration protocol or ethical approval is required for the present review.

Traditional environmental factors

Temperature

Multiple epidemiological studies in the Americas and Asia have confirmed a negative correlation between high-temperature exposure and semen quality (11,12).

The temperature of mammalian testes needs to be 4–5 ℃ lower than the core body temperature (36–38 ℃) to maintain normal physiological function. High temperatures (>40 ℃) can disrupt the testicular spermatogenic microenvironment, induce heat stress (HS), and lead to germ cell apoptosis and the arrest of spermatogenesis (13).

From a structural perspective, HS can lead to seminiferous tubule dysplasia, atrophy of Sertoli cells, a reduction in Leydig cells, and disruption of the blood-testis barrier (BTB). From a neuroendocrine axis standpoint, HS results in suppression of the hypothalamic-pituitary-gonadal (HPG) axis and activation of the hypothalamic-pituitary-adrenal (HPA) axis, consequently leading to a significant decrease in plasma testosterone levels. From a microenvironmental viewpoint, pro-inflammatory factors such as interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α) in the plasma are significantly elevated, inducing a local inflammatory response in the testes and damaging the spermatogenic microenvironment. HS also induces increased reactive oxygen species (ROS) production, leading to peroxidation of sperm membrane lipids and mitochondrial membranes, which in turn causes mitochondrial dysfunction. Concurrently, ROS can directly attack DNA or inhibit the function of DNA repair enzymes. Specifically, 8-oxoguanine DNA glycosylase (OGG1) recognizes and excises oxidative base damage such as 8-oxoguanine, initiating the base excision repair pathway; poly(ADP-ribose) polymerase (PARP), sensing DNA strand breaks, catalyzes protein poly(ADP-ribosylation) to recruit repair proteins and coordinate DNA repair with chromatin remodeling. When these key repair enzymes are inhibited, DNA damage accumulates, ultimately elevating the DNA fragmentation index (Figure 1) (13-15).

Figure 1 Environmental factors such as extreme temperatures, heavy metals, BPA, air pollution, PFAS, RF-EMR, bacteria, and viruses primarily reduce sperm motility and concentration, damage sperm DNA, and cause abnormalities through pathways including oxidative stress, inflammatory responses, endocrine disruption, epigenetic effects, disruption of the blood-testis barrier, and DNA fragmentation. These ultimately lead to male infertility. 5-hmC, 5-hydroxymethylcytosine; BPA, bisphenol A; DFI, DNA fragmentation index; FSH, follicle-stimulating hormone; GnRH, gonadotropin-releasing hormone; IL-6, interleukin-6; LH, luteinizing hormone; OGG1, 8-oxoguanine DNA glycosylase; PARP, poly(ADP-ribose) polymerase; PFAS, per- and polyfluoroalkyl substances; RF-EMR, radiofrequency electromagnetic radiation; ROS, reactive oxygen species; RRBS, reduced representation bisulfite sequencing; TNF-α, tumor necrosis factor-α.

In addition to high-temperature exposure, low-temperature exposure can also lead to a decrease in sperm concentration and total count. A study by Wang et al. in a Northern Chinese cohort revealed that low-temperature exposure (<9.2 ℃) inflicts particularly pronounced impairment on sperm motility during the epididymal storage phase (0–37 days pre-ejaculation), and older men are more vulnerable to this effect (16).

Extreme temperatures in both hot regions (such as sub-Saharan Africa, North Africa, and the Middle East, with annual average temperatures exceeding 24 ℃) and cold regions (such as Europe and parts of East Asia, with annual average temperatures below 10 ℃) are detrimental to male fertility. Research indicates that environmental temperature exhibits a U-shaped relationship with male infertility rates, with an optimal temperature of 15.7 ℃. Moreover, the greater the deviation from long-term average temperatures, the higher the risk of infertility (17). The effects of temperature on male sperm quality are summarized in Table 2.

Heavy metals

The effects of various heavy metals on male sperm quality are summarized in Table 2. Heavy metals are defined as metals with a density greater than 5 g/cm³ and are common contaminants in food and drinking water (18,19). Metals, including lead, cadmium, and copper, can markedly decrease sperm concentration, motility, and morphological integrity via mechanisms involving oxidative stress, endocrine interference, and epigenetic modulation (20).

Professional exposure to lead results in increased blood lead concentration, diminished sperm number, impaired sperm motility, and elevated prolactin levels, whereas testosterone and other hormones show no significant changes. Pb²⁺ regulates the levels of intracellular cAMP and Ca²⁺ in sperm cells through L-type calcium channels, and triggers spontaneous or premature acrosome reaction (AR) by enhancing protein tyrosine phosphorylation and reducing mitochondrial membrane potential. Furthermore, lead notably exacerbates DNA fragmentation and apoptotic cell death (21). Elevated blood lead concentrations in puberty correlate with decreased seminal volume later in adult life (22).

Cadmium exposure is significantly associated with male infertility, reduced total semen volume, and decreased sperm motility (23,24). Cadmium metal disrupts the fusion of autophagosomes with lysosomes, leading to impaired autophagy, accumulation of cellular waste, and exacerbated damage (25). Furthermore, cadmium induces testicular oxidative stress and activates the absent in melanoma 2 (AIM2) inflammasome, triggering pyroptosis in testicular cells; oxidative stress can also damage DNA, induce germ cell degeneration or apoptosis, and increase the rate of sperm malformation (26). Cadmium exposure in the paternal generation interferes with cholesterol metabolism and markedly inhibits critical enzymes [steroidogenic acute regulatory protein (StAR), cytochrome P450 side-chain cleavage (P450scc)] for testosterone production in the next generation (27).

Elevated seminal plasma copper levels are positively correlated with the risk of abnormal semen quality. In terms of energy generation, copper suppresses the activity of lactate dehydrogenase within sperm mitochondria, resulting in a elevated NAD⁺/NADH ratio, halted glycolysis, disrupted rapid adenosine triphosphate (ATP) production, and consequently an immediate reduction in sperm motility; the inhibition of lipid synthesis leads to inadequate long-term ATP provision, thus diminishing sperm motility and compromising sperm function (28). At the cellular division level, Yi et al. discovered that high copper ions reduce retinol dehydrogenase 10 (RDH10), thereby inhibiting retinoic acid synthesis; since retinoic acid is an essential signal for initiating spermatocyte meiosis, high copper consequently impedes the initiation of spermatogenesis (29).

Arsenic inhibits key mitochondrial enzymes [pyruvate dehydrogenase (PDH) and succinate dehydrogenase (SDH)] in the testes, reduces ATP production, disrupts histone acetylation (upregulating H3K9ac, downregulating H4K5ac), and damages BTB proteins (COL1A1, RAB13), ultimately leading to decreased sperm motility and fertility (30).

Whole blood chromium concentration in exposed men was negatively correlated with sperm concentration and total count. Their animal studies revealed that chromium (VI) diminishes the copy number of 5S/45S ribosomal DNA (rDNA), resulting in impaired seminiferous tubule structure and reduced sperm motility. The rDNA copy number may thus be utilized as a new biomarker for assessing chromium-induced reproductive toxicity (31).

Pesticide

Evidence from the past three decades consistently indicates that environmental or occupational pesticide exposure significantly increases the risk of male fertility decline, reducing sperm concentration and motility while damaging DNA. Among these effects, the association between sperm motility and DNA damage is the most consistent (32,33).

Pesticide exposure substantially impairs male sperm quality. Among these, organochlorine and organophosphate pesticides pose the highest risk for reduced total sperm count, motility, and morphological abnormalities. Pyrethroid pesticides are closely associated with elevated sperm DNA fragmentation indices and increased chromosomal aneuploidy risk (33). Lismer et al. demonstrated through cross-cohort studies that long-term exposure to dichlorodiphenyltrichloroethane (DDT) and its metabolite dichlorodiphenyldichloroethylene (DDE) induces significant epigenetic alterations in male sperm, including abnormal DNA methylation and histone modifications. These changes may increase offspring health risks by disrupting gene expression related to embryonic development (34).

Pyridine-containing organophosphate metabolites (PhOP), a metabolite of the pesticide pyridine, reduces proliferating cell nuclear antigen (PCNA), inhibits cell proliferation, promotes apoptosis (BAX/Bcl2 imbalance), elevating oxidative stress [ROS/superoxide dismutase (SOD)/malondialdehyde (MDA)], disrupting BTB integrity, and interfering with key testosterone synthesis pathways [SF1/StAR/cytochrome P450 family 11 subfamily A member 1 (CYP11A1)/3β-hydroxysteroid dehydrogenase (HSD3)]. This multi-pathway synergistic action—involving oxidative stress, apoptosis, hormonal disruption, and barrier damage—impairs male fertility (35). Changes in male sperm quality due to plastic exposure are summarized in Table 2.

Bisphenol A (BPA)

BPA ranks among the world’s most widely produced chemicals. BPA is present in polycarbonate plastics and epoxy resins used in manufacturing numerous plastic products (36).

Bisconti et al.’s proteomics analysis revealed that pollutants like BPA, through regulation of the oxidative stress-inflammation axis, reduced sperm flagellar motor protein (DNAH17) expression by 67%, directly impairing sperm forward motility (37,38) (Table 2). Castellini et al.’s meta-analysis showed a significant negative correlation between elevated urinary BPA concentrations and sperm motility, though this association weakened after adjusting for publication bias, suggesting potentially limited clinical relevance (39). However, Martínez et al.’s meta-analysis found no significant association between BPA exposure and sperm concentration (40).

Phthalate

Phthalate is a widely used class of synthetic compounds primarily added to plastics as plasticizers to enhance flexibility, transparency, and durability. Phthalates inhibit spermatogenesis by disrupting the testosterone/androgen receptor (T/AR) signaling pathway, an effect antagonized by lycopene (41). As shown in Table 2, directly acting on Leydig cells in the testes, they downregulate StAR9 (which transports cholesterol to the inner mitochondrial membrane) and P450scc, Cyp17a1, 3β-HSD, and 17β-HSD (key enzymes catalyzing cholesterol conversion to testosterone) in Leydig cells, reducing testosterone synthesis within the testes. This severely disrupts the microenvironment for spermatogenesis, leading to impaired spermatogenesis. Additionally, elevated levels of ROS and MDA, coupled with reduced SOD activity, induce lipid peroxidation and damage sperm DNA. This results in decreased sperm motility, morphological abnormalities, and induces spermatocyte apoptosis (42).

Viruses

Human papillomavirus (HPV) infection can impair sperm motility and compromise DNA integrity. While the prevalence of HPV infection in semen reached 14.9%, it showed no significant association with parameters such as sperm concentration or progressive motility (43). However, HPV infection rates were significantly higher in infertile men compared to the general population (44). Moreover, infection with high-risk HPV genotypes is strongly associated with sperm morphological abnormalities, significantly reduced progressive motility, and elevated DNA fragmentation indices (45,46) (Table 2). HPV infection correlates with reduced in vitro fertilization pregnancy rates and increased miscarriage rates, leading to adverse reproductive outcomes (47).

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection also negatively impacts sperm quality. Large-scale meta-analyses further indicate that post-infection sperm volume, concentration, total count, normal morphology rate, and motility significantly decline compared to healthy states, while the risks of oligospermia, asthenospermia, and teratospermia markedly increase (48,49). Coronavirus disease 2019 (COVID-19) can increase sperm DNA fragmentation through oxidative stress mechanisms, particularly pronounced in men over 35 years of age (Table 2). However, vaccination against SARS-CoV-2, especially booster doses, can improve post-recovery sperm quality, suggesting this damage may be partially reversible (50).

Bacteria

Ureaplasma, Enterococcus, Mycoplasma, and Prevotella were negatively correlated with sperm concentration, progressive motility, and morphology (Table 2). while Lactobacillus exerted a protective effect on sperm quality (51).

Increased microbial α-diversity in semen of infertile men was observed, with Prevotella abundance negatively correlated with sperm concentration and positively correlated with oligospermia; increased staphylococci and group A Streptococci in semen were significantly associated with reduced total sperm motility and count, respectively; Pseudomonas species showed a positive correlation with total motile sperm count (52,53); and Xanthomonas species were significantly associated with abnormal semen parameters (54).

While Lactobacillus counts are commonly believed to correlate positively with semen quality, increased Lactobacillus paracasei was associated with reduced sperm concentration (55). Enrichment of the acetyl-CoA fermentation to butyrate II and purine nucleotide degradation I pathways in samples with high DNA fragmentation index (HDFI). Excessive butyrate concentration may induce oxidative stress reactions, directly attacking sperm DNA and causing fragmentation (56).

Therefore, specific bacteria such as Prevotella, Ureaplasma, Enterococcus, and Lactobacillus inertum negatively impact sperm quality, while Lactobacillus species may exert protective effects. This suggests that regulating the microbiota could emerge as a novel strategy for improving male fertility.

Emerging environmental factors

RF-EMR

RF-EMR emanates from numerous human-invented electronic devices such as mobile phones, Wi-Fi, and microwave ovens, exerting far-reaching effects on human health (57). The effects of RF-EMR on male sperm are summarized in Table 2.

Substantial epidemiological evidence supports the adverse impact of RF-EMR on sperm quality. A cross-sectional study confirmed a negative correlation between average daily mobile phone usage duration and sperm progressive motility (58). A cohort study involving 1,454 men indicated that each additional hour of daily electronic device use was associated with an 8.0% reduction in sperm concentration and a 12.7% decrease in total sperm count. Furthermore, using earphones during calls further exacerbated the decline in sperm motility (59).

Effects vary across radiation sources: WiFi radiation (2.4 or 5 GHz) significantly harms sperm, whereas no significant effects were observed with 4G/5G exposure. RF-EMR possesses both thermal and non-thermal effects. Non-thermal effects may induce increased ROS production, leading to oxidative stress in the testes. Excessive ROS can damage sperm DNA, causing apoptosis; disrupt mitochondrial function, impairing sperm energy supply and reducing motility; and potentially alter the cell cycle, affecting sperm maturation and function (60).

Although animal studies indicate RF-EMF reduces conception rates and sperm counts, the quality of evidence from human sperm in vitro studies is generally low. RF-EMR may cause minor impairment to sperm motility but shows no significant effect on DNA changes (21).

PFAS

Perfluorinated compounds (PFOA/PFOS) exhibit reproductive toxicity by reducing testosterone levels, disrupting the BTB, inducing oxidative stress, and impairing sperm motility and fertilization capacity (61). Sun et al. reported population-based evidence showing that PFOS/PFOA exposure reduces sperm concentration by 21.7%, increases the risk of asthenospermia by 3.2-fold, shrinks sperm head area, significantly elevates DNA fragmentation rates, and increases abnormal sperm proportions. Sperm plasma antioxidant enzyme catalase (CAT) activity was inhibited by 38.2% (62). Moreover, the toxicity correlation strength of PFAS in seminal plasma is 1.3–3.1 times higher than in serum, suggesting its superior sensitivity as an exposure biomarker.

Perfluorinated compounds also exhibit intergenerational effects. A study of a mother-infant cohort demonstrated that fetal exposure to maternal PFAS mixtures resulted in an 8% reduction in adult sperm concentration and a 10% decrease in total sperm count. Among these compounds, perfluoroheptanoic acid (PFHpA) exerted the most significant impact despite its lower serum concentration. Maxwell et al. first demonstrated through animal studies that paternal exposure to PFAS mixtures can transgenerationally impact offspring’s metabolic health. PFAS mixtures can cross the BTB and accumulate in testicular tissue, potentially disrupting epigenetic reprogramming during spermatogenesis. By altering sperm DNA methylation, primarily enriched in RRBS (Figure 1) and Illumina (related to lipid metabolism, phospholipid metabolism, and cellular signaling), they cause liver/adipose tissue transcriptomic abnormalities in offspring, particularly cholesterol metabolism disorders and heightened inflammatory responses in male progeny (63). The reproductive toxicity of PFAS is summarized in Table 2.

Other endocrine disruptors

Parabens are widely used as antimicrobial preservatives in cosmetics, pharmaceuticals, and food and beverage processing due to their broad-spectrum activity, inertness, and low cost. Exposure to a mixture of parabens reduces sperm motility, with methylparaben (MeP) exhibiting the most pronounced effect (64).

BaP is generated through incomplete combustion of organic matter (OM) and thermal cracking/polymerization of fats in food at high temperatures. BaP exposure causes testicular histopathological damage, increased sperm abnormalities, and reduced motility in mice (65,66). Mechanistically, BaP upregulates oxidative stress markers [heme oxygenase-1 (HO-1), MDA], suppresses antioxidant enzymes [SOD, CAT, glutathione (GSH)], and significantly alters testicular histone modifications (e.g., downregulation of H4K5ac and H4K12ac), disrupting sperm DNA integrity (66). Combined transcriptomic and proteomic analyses revealed that BaP downregulates key metabolic proteins (e.g., ALDH1A1, CYB5R3) by inhibiting PI3K-Akt and mitogen-activated protein kinase (MAPK) signaling pathways, leading to a significant increase in sperm DNA fragmentation index (DFI) (Figure 1).

As health risks associated with traditional endocrine disrupting chemicals (EDCs) have become increasingly recognized, many countries and regions have restricted their use. Diisononyl phthalate (DINP), diisononyl cyclohexane-1,2-dicarboxylate (DINCH), diethylene glycol dibenzoate (DGD), and glycerol triacetate (GTA), as phthalate alternatives, pose substantially reduced risks to sperm. However, DINP at high doses (e.g., 600 mg/kg/d in rat studies) can decrease testosterone levels, reduce sperm count and motility, and shorten the agonal generation duration (AGD). Rat studies indicate that extremely low doses of DINCH (1 mg/kg/d) can upregulate steroid synthesis gene expression (Star, Cyp11a1) in offspring testes while decreasing testosterone levels, suggesting low-dose endocrin (67) e-disrupting effects.

The complexity of emerging environmental factors

RF-EMR and air pollution involve high exposure levels that are unavoidable in modern urban living. However, due to individual variations and parameter complexity, experimental settings cannot fully replicate real-world conditions. The impact of RF-EMF on male sperm quality is likely mediated through thermal effects, inducing HS-like responses (13-15). However, the temperature changes from daily electronic device use are too minimal to trigger thermal effects, resulting in generally low-quality evidence from in vitro human sperm studies on RF-EMF. Regarding the epidemiologically observed association between RF-EMR exposure and declining reproductive health and sperm quality, the underlying drivers are most likely behavioral and lifestyle factors associated with device use (such as sedentary behavior, sleep deprivation, psychological stress, etc.), rather than RF-EMR itself (68,69). Future studies must employ more refined designs to isolate these confounding effects, with recommendations to control for temperature variables induced by RF-EMF and to focus on psychological state changes associated with RF-EMR content.

Endocrine disruptors exhibit environmental persistence, making them extremely difficult to degrade in natural settings, and possess bioaccumulative properties that allow them to accumulate within organisms through the food chain. Endocrine disruptors such as pesticides, BPA, and phthalates act as exogenous ligands for the aryl hydrocarbon receptor (AhR). By activating the AhR signaling pathway, they impair male sperm quality at multiple levels, constituting a key pathophysiological mechanism in environmentally associated infertility (70). The AhR pathway-mediated toxicity primarily manifests as disruption of the BTB integrity. Excessive AhR activation disrupts supporting cell function, leading to abnormal expression and distribution of tight junction proteins (e.g., claudins, occludin). This disintegrates the barrier structure, allowing harmful substances to infiltrate the seminogenic microenvironment and directly damage germ cells. Regarding sperm morphogenesis and maturation, AhR signaling disruption directly impairs sperm cell differentiation. Studies confirm that AhR knockout mice exhibit abnormal sperm head and tail morphology, with significant downregulation of key genes (e.g., Prm1, Prm2) involved in sperm nuclear protein condensation and morphogenesis in their testes (71,72). Exposure to environmental AhR ligands [e.g., 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), BaP] similarly increases sperm abnormalities and impairs chromatin condensation. Furthermore, sustained AhR activation induces abnormal expression of cytochrome P450 enzymes (e.g., CYP1A1), triggering oxidative stress that diminishes sperm mitochondrial membrane potential and elevates ROS levels, thereby impairing sperm motility and survival. Notably, natural AhR antagonists like resveratrol demonstrate potential to protect sperm quality by inhibiting this pathway and mitigating oxidative stress (70).

The harm caused by endocrine disruptors may extend beyond directly exposed individuals. DNA methylation involves the addition of methyl groups to CpG islands within gene promoter regions, typically resulting in transcriptional silencing of genes. Male rats exposed to low-dose BPA during the neonatal period exhibited abnormal hypermethylation in the promoter regions of the estrogen receptor alpha (ERα) and beta (ERβ) genes within their testes, accompanied by elevated expression of DNA methyltransferases (Dnmt3a/b). This results in persistent suppression of receptor expression after sexual maturation, potentially disrupting normal estrogen regulation and impairing the function of testicular supporting cells and stromal cells, ultimately damaging spermatogenesis (67). Exposure during pregnancy may also impart similar effects to offspring (35). Future research must not overlook their intergenerational impacts and should track their bioaccumulation effects. Effects of parabens, BaP, and novel plasticizers are summarized in Table 2.

Systemic interference and synergistic effects

The preceding sections examined the direct reproductive toxicity of environmental factors. However, in the real world, their effects do not operate in isolation. This chapter will focus on two representative systemic disruptors—microbiota and air pollution—which exert synergistic effects far exceeding simple addition by reshaping the body’s systemic homeostasis.

Microbiome

Studies (73-75) validated in human populations that the abundance of Bacteroides and Prevotella is negatively correlated with sperm motility. It was also found that high-fat diet (HFD)-induced gut dysbiosis triggers metabolic endotoxemia and epididymitis, leading to insulin resistance that suppresses testicular gene expression and significantly reduces spermatogenesis efficiency and sperm motility. The study also revealed elevated aromatase activity in adipose tissue, leading to excessive conversion of testosterone into estrogens. This, coupled with HPG axis suppression via mechanisms like leptin resistance, resulted in functional hypogonadism. Visceral fat accumulation due to obesity elevated scrotal temperature; concurrent impairment of the BTB allowed harmful substances to more readily disrupt spermatogenesis.

Hyperinsulinemia and insulin resistance disrupt testicular energy metabolism; adipose tissue releases pro-inflammatory factors, triggering systemic and localized testicular chronic inflammation and oxidative stress. The gut-inflammatory factor-testicular axis theory is proposed to clarify the relationship between gut microbiota dysbiosis, systemic inflammation, insulin resistance, and impaired testicular function.

Dysbiosis and poor diet damage the tight junctions between intestinal epithelial cells, leading to increased intestinal permeability and forming “leaky gut”. Lipopolysaccharide (LPS), the primary component of Gram-negative bacterial cell walls, crosses the intestinal barrier in large quantities into the bloodstream, causing “metabolic endotoxemia”. LPS entering the bloodstream binds to Toll-like receptor 4 (TLR4) on immune cells (e.g., macrophages), activating inflammatory signaling pathways like nuclear factor kappa B (NF-κB). This triggers massive release of pro-inflammatory cytokines such as TNF-α and IL-6. This represents the “inflammatory bridge” connecting the gut to the testes. Inflammatory factors interfere with insulin signaling, exacerbating systemic insulin resistance. Conversely, insulin resistance itself further worsens the inflammatory state, creating a vicious cycle. Local insulin signaling pathways exist within the testes, and systemic insulin resistance may impair testicular energy metabolism, further damaging spermatogenesis and hormone synthesis functions.

Within the intricate network of gut microbiota influencing male fertility, beyond the classic “inflammation-metabolism” pathway, the exosome-mediated direct communication axis and metabolite-mediated indirect regulatory axis are emerging as new frontiers in mechanistic research. Research indicates that gut dysbiosis alters the miRNA profile of circulating exosomes derived from the intestine. These exosomes can remotely target the testes, directly suppressing the expression of key meiotic genes (such as Meioc) in spermatogenic cells, thereby disrupting spermatogenesis (76). Simultaneously, the microbiota exerts core regulatory effects through metabolites. For example, Akkermansia muciniphila modulates secondary bile acid metabolism, influencing intestinal retinol absorption and local testicular retinoic acid levels, thereby supporting normal spermatogenesis (77).

Sperm quality is also closely linked to the semen microbiome (75), with the male lower genital tract microbiota interacting with the female reproductive tract microbiota. Under certain conditions (e.g., prostatitis), this can lead to increased diversity of microbial communities in semen, affecting reproductive health (78). This suggests potential value in microbiota regulation for the prevention and treatment of male infertility (79). The role of gut and semen microbiomes in male fertility is summarized in Table 2.

Air pollution

The health effects of fine particulate matter (PM2.5) primarily manifest through two core mechanisms: oxidative stress and inflammatory responses. Exposure to PM2.5 leads to sustained and unregulated production of ROS, which in turn triggers systemic inflammatory responses, resulting in cellular damage and tissue dysfunction. Within the respiratory system, this damage manifests as airway inflammation, reduced lung function, and increased risk of chronic obstructive pulmonary disease (COPD). In the cardiovascular system, particulate-induced systemic inflammation and oxidative stress impair vascular endothelial function, contributing to serious cardiovascular events such as arrhythmias, non-fatal heart attacks, and myocardial ischemia (80).

In the male reproductive system, the toxic effects of PM2.5 are particularly pronounced on testicular and sperm development. Recent studies consistently demonstrate that air pollution increases the risk of male infertility (81), exerting significant negative impacts on sperm quality across multiple parameters including concentration, morphology, and DNA integrity. Components in PM2.5 such as Cl⁻, NO3⁻, and NH4⁺ are significantly correlated with reduced sperm count and motility (82), while OM and black carbon (BC) exert particularly pronounced negative effects on sperm density and total motility (83).

Exposure to environmental air pollution reduces total sperm count (84,85), sperm concentration, and motility (86) in males, while impairing sperm morphology (87,88) and DNA integrity. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and sperm chromatin dispersion (SCD) are two methods for assessing sperm DNA fragmentation. The TUNEL assay labels broken DNA strands using terminal deoxynucleotidyl transferase, allowing the detection of labeled signals under a fluorescence microscope to calculate the fragmentation ratio. The SCD test employs a processing method that causes intact DNA to form a halo, while fragmented DNA lacks this halo. The presence or absence of the halo is used to determine DNA integrity (89).

Additionally, air pollution correlates with offspring health risks, with epigenetic mechanisms extensively explored. Paternal preconception exposure to PM2.5 and NO₂ reduces offspring birth weight and impacts offspring health through altered sperm DNA methylation. A study (90) indicated that PM10 exposure reduces 5-hydroxymethylcytosine (5-hmC) levels in sperm DNA, suggesting that epigenetic alterations may represent a key pathway through which pollution affects sperm function (Figure 1).

PM2.5 induces massive ROS to suppress the expression of BTB-associated proteins (such as occludin, claudin-11, connexin-43, N-cadherin) by activating the p38 MAPK pathway. This barrier disruption leads to an imbalance in the spermatogenic microenvironment and abnormal sperm development.

Excessive ROS also induces phosphorylation and activation of the c-Jun N-terminal kinase (JNK) pathway, synergizing with p38 MAPK to jointly reduce the Bcl-2/Bax ratio and activate Caspase-3. This promotes the mitochondrial-dependent apoptosis pathway, accelerating programmed cell death in spermatogenic cells. JNK may regulate inflammatory mediators like NF-κB, activate the NLR family pyrin domain containing 3 (NLRP3) inflammasome, and target Forkhead box O1 (FOXO1) via the miR-183/96/182 cluster, resulting in testicular inflammation and diminished sperm quality.

The extracellular signal-regulated kinase (ERK) pathway, typically associated with cell proliferation and survival, is activated by excessive ROS, potentially disrupting normal germ cell cycle and proliferation signaling. AMP-activated protein kinase (AMPK) inhibits mammalian target of rapamycin (mTOR), inducing autophagy and cell death.

PM2.5 exposure induces endoplasmic reticulum stress, activating the ER-mediated apoptosis pathway, leading to germ cell apoptosis and increased sperm abnormalities (1).

The systemic oxidative stress and inflammatory background induced by PM2.5 acts like “adding fuel to the fire”, significantly amplifying the reproductive toxicity of chemicals such as heavy metals and PFAS. For instance, an individual already exposed to PFAS becomes more susceptible to DNA damage caused by air pollution. This cross-exposure synergistic effect represents a critical gap in risk assessment that urgently needs to be addressed. The impact of PM2.5 and other pollutants on sperm quality is summarized in Table 2.

Conclusions

In summary, environmental factors (such as chemical pollutants, physical agents, and biological agents) enter the human body through inhalation, ingestion, or skin contact. They first affect systemic organs and subsequently cause indirect or direct damage to male reproductive function. These environmental factors significantly reduce sperm concentration, motility, morphological integrity, and DNA stability through multiple mechanisms and systemic effects—including oxidative stress ROS, endocrine disruption, DNA damage, and inflammatory responses—thereby impairing male fertility.

Current research has established significant associations between pollutants such as high temperatures, heavy metals, pesticides, and PM2.5 and declining sperm quality, with important advances made at the molecular mechanism level. However, real-world exposures typically involve mixtures (e.g., PM2.5 + PFAS + heavy metals), whereas existing studies predominantly focus on single pollutants. This discrepancy between experimental conditions and actual exposure scenarios limits the extrapolation of experimental results to real-world settings. It is recommended that experiments integrate environmental monitoring data to establish real-world exposure profiles; multi-omics integration analysis should combine metabolomics, microbiomics, and epigenomics to identify key interactive pathways (e.g., oxidative stress + inflammation). Using human sperm primary cultures or organoid models to validate the synergistic damage of mixtures to the BTB, mitochondrial function, and DNA integrity will enhance the extrapolation and authenticity of experimental exposures, thereby providing more accurate references for improving male reproductive health. Environmental impacts still require leveraging modern evidence-based medical systems to conduct multicenter prospective cohort studies, clinical research, and animal experiments. Relying on cutting-edge technologies such as genomics and proteomics, we must deeply explore mechanisms like epigenetics. This will provide more valuable references for developing targeted interventions, helping to address fertility issues caused by declining male sperm quality and alleviating the burden on families and society.

Acknowledgments

None.

Footnote

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