As a worldwide human health problem, infertility is estimated to affect 8%–12% of couples globally. Male infertility contributes to more than half of all cases of global childlessness (Agarwal et al., 2021). It is noteworthy that the rate of male infertility is still on the rise and may have a severe negative impact on social development (Vollset et al., 2020). To date, the cause of male infertility has not been fully elucidated yet. Still, most of the time, it can be related to overweight, diabetes (Service et al., 2023), and poor lifestyle habits such as smoking (Sharma et al., 2016) and alcohol consumption (Basic et al., 2023), which may impair spermatogenesis and eventually lead to the production of abnormal spermatozoa. Moreover, It was reported that more than 2% of infertile men exhibit abnormal spermatozoa (Kumar and Singh, 2015). Asthma is one of the most common chronic inflammatory diseases, which has affected nearly 334 million patients worldwide at any age (Papi et al., 2018). It is characterized by a range of respiratory symptoms and airflow limitation to varied degrees, which can be generated by a range of airway inflammation and bronchospasm (Papi et al., 2018). As illustrated in animal models, male mice with asthma were related to abnormal spermatozoa and testicular structure (Xu et al., 2016; Deng et al., 2021; Wang et al., 2021; Feng et al., 2022). Moreover, a cross-sectional study in humans showed that men with asthma had lower spermatozoa concentration and total spermatozoa count compared with non-asthmatic men (Pedersen et al., 2023). The findings from the above studies have proved a negative correlation between asthma and spermatozoa quality. However, the underlying mechanisms linking asthma to spermatozoa quality are poorly understood. As reported, asthma can induce systemic inflammation and immune responses, leading to elevated levels of pro-inflammatory factors in the peripheral blood and excessive production of reactive oxygen species (Papi et al., 2018). These factors can adversely affect reproductive cells and interfere with spermatozoa production and maturation (Hasan et al., 2022).

Due to variances in the exposure to risk factors such as smoking, obesity, and alcohol consumption between humans and animals, the reliability of animal studies needs to be further investigated, and the conclusions may be biased. Additionally, considering the scarcity of relevant human studies, the presence of reverse causation, and the impact of confounding factors, it is exceedingly challenging to determine causality based on observational studies. Mendelian randomization (MR), utilizing genetic associations to investigate the causal impact of a risk factor on an outcome (Smith and Ebrahim, 2003), is a powerful and effective method for gauging causal inference. This approach can limit reverse causality and significantly reduce the likelihood of residual confounding (Davies et al., 2018). Therefore, we employed MR to circumvent limitations observed in previous research endeavors and to assess potential genetic causal associations between genetically predicted asthma and the risk of abnormal spermatozoa, intending to provide some insights into future prevention and treatment strategies.

To the best of our knowledge, this is the first study to evaluate the potential causal associations of asthma with abnormal spermatozoa based on the MR. This MR study consistently suggests that genetically predicted asthma was associated with an increased risk of abnormal spermatozoa. Furthermore, The causal inference was further supported by consistent direction and magnitude from distinct MR models. Moreover, we found that AOA has positive causal effects on the risk of abnormal spermatozoa rather than COA.

Our finding on the association between asthma and abnormal spermatozoa risk is consistent with previous studies. Recently, Multiple mouse model studies consistently indicate an association between asthma and spermatozoa quality, primarily characterized by significantly lower spermatozoa concentration and motility in the asthma mouse group compared to the control group (Xu et al., 2016; Deng et al., 2021; Wang et al., 2021; Feng et al., 2022). Xu et al. (2016) propose that asthma could activate the mitochondrial apoptosis signaling pathway in the mouse testis, thereby impacting spermatozoa quality. Similarly, Feng et al. (2022) argue that asthma can modulate the HIF-1 signaling pathway, resulting in increased expression of IL6, Stat3, HIF-1α protein, and mRNA, ultimately leading to spermatozoa apoptosis. Additionally, Deng et al. (2021) suggest that asthma can induce the production of abnormal spermatozoa by upregulating the expression of IL-6, vascular endothelial growth factor A, and mRNA while inhibiting albumin expression levels. In addition, only one cross-sectional study in humans found a potential association between self-reported asthma patients and reduced testicular function, primarily manifested by decreased spermatozoa concentration and total spermatozoa count. However, no significant differences were observed in semen volume, spermatozoa motility, or spermatozoa morphology (Pedersen et al., 2023). The findings from the above studies have proved a negative correlation between asthma and spermatozoa quality.

Although the underlying mechanisms of these associations are poorly understood, there are still some potential mechanisms that can be used to explain their possible connection. Asthma is characterized by reversible airflow obstruction, bronchial hyperresponsiveness, and airway inflammation. Th17 cells, a subset of CD4⁺ T cells, have been associated with asthma phenotypes (Newcomb and Peebles, 2013). These cells produce IL-17, driven by TGF-β, IL-1β, IL-6 and IL-23. In the synergistic action of TNF-α, IL-17 stimulates the secretion of IL-1β, IL-6, and GM-CSF by airway epithelial cells, endothelial cells, and fibroblasts, leading to neutrophil recruitment ultimately (Alcorn et al., 2010). Additionally, IFN-γ, a pleiotropic Th1 cytokine, also plays a crucial role in asthma pathogenesis (Raundhal et al., 2015). The pro-inflammatory state is activated in response to invading pathogens, and a significant amount of pro-inflammatory cytokines, such as IL-1, IL-6, and TNF-α, are secreted by Th1 cells, CD4⁺ T cells, macrophages, and dendritic cells (Turner et al., 2014). These cytokines stimulate, recruit, and amplify immune cells, driving an inflammatory reaction. In addition to their role in the pathogenesis of asthma, IFN-γ, IL-6, TNF-α, and other cytokines have also been implicated in the development of decreased spermatozoa quality. Studies have demonstrated that seminal plasma from men with poor spermatozoa motility had higher concentrations of IFN-γ, TNF-α, and IL-10 (Ulcova-Gallova et al., 2009). Similarly, IFNγ, IL-17, and IL-1β can impair spermatozoa motility and viability (Paira et al., 2022). Several previous studies have shown that pro-inflammatory cytokines such as IL-6, IFN-γ, IL-1β, and TNF-α can induce the overproduction of reactive oxygen species, leading to the formation of oxidative stress. This negatively affects the process of spermatogenesis and maturation ultimately (Lampiao and du Plessis, 2008; Dobrakowski et al., 2017; Aitken et al., 2022). There is a very complex relationship between asthma and sperm homeostasis. Recent studies have indicated that the genetic structures of COA and AOA are somewhat distinct. Interestingly, variants that are linked to obesity and smoking appear to have a more significant contribution to the risk of AOA than COA (Ferreira et al., 2019). Additionally, several studies (Toskala and Kennedy, 2015; Agarwal et al., 2021) suggest that asthma and spermatozoa quality are influenced by various common factors, such as diabetes, obesity, and smoking. However, the MVMR study confirmed that the effect of genetically predicted asthma on abnormal spermatozoa remained after accounting for diabetes, BMI, and smoking.

In summary, It appears that asthma may increase the risk of abnormal spermatozoa through the mechanism of inflammatory processes and oxidative stress. Future advancements should focus on further research and conducting large-scale prospective human studies to elucidate their underlying mechanisms and identify potential therapeutic targets.

The major strength of this study is the MR method, which is less susceptible to potential confounding factors and other biases, thus reinforcing the causal inference. Second, we assessed the potential associations using summary statistics from several large GWAS. In addition, the results remained overall consistent across several sensitivity analyses. Moreover, our findings were unlikely to be impacted by population structure bias since the analyses were restricted to individuals of European ancestry. Limitations need to be considered in this study. First, the nonlinear connection between asthma and the risk of abnormal spermatozoa cannot be eliminated due to the linear effect assumption in MR analysis. Furthermore, our study is mainly based on Europeans. Thus, the generalization of the findings to other ethnic groups needs to be cautious. Furthermore, due to the absence of suitable GWAS data, we refrained from conducting further analysis on various subtypes of asthma. Finally, there are other possible unmeasured and residual confounding factors, like environmental factors, asthma medications, allergic diseases, or other pulmonary conditions, which might drive the bias of the overall estimates.

To summarize, the MR study provides evidence supporting a causal relationship between genetically determined asthma and the increased risk of abnormal spermatozoa, and similar results are obtained in AOA. Our research findings hold significant implications for public health and epidemiological prevention. Clinical practice should emphasize early prevention and preconception counseling. Additionally, we should promote multidisciplinary collaboration to formulate comprehensive guidelines, strengthening reproductive health management for asthmatic men of childbearing age, aiming to achieve early detection and timely prevention.