Exploratory Toxicogenomic Analysis of Parasite-Related Th2 Immune Response

Abstract

Helminth parasites infect mammalian hosts through complex life cycles, mostly triggering T helper type 2 (Th2) immune responses characterized by interleukin-4 (IL4), interleukin-5 (IL5), and interleukin-13 (IL13) production. Environmental chemical exposures may modulate these immune pathways, potentially affecting infection outcomes. Using The Comparative Toxicogenomics Database (CTD), we analyzed chemical–gene interactions affecting IL4, IL5, and IL13 genes to identify chemicals capable of modulating Th2 immunity and their associated expression profiles. Accordingly, a total of 818 chemicals can interact with IL4, IL5 and/or IL13, with 145 chemicals showing the potential of affecting all three genes. These 145 chemicals include air pollutants (8.3%), allergens (2.7%), bioactive molecules (8.3%), industry-related chemicals (14.5%), medicinal drugs (21.4%), metal and metal-containing chemicals (8.3%), pesticides (3.4%), plant compounds (12.4%), and others (20.7%). We observed a greater number of chemicals associated with increased (n = 95) gene expression compared to decreased (n = 14) gene expression, suggesting a Th2 pathway hyperactivation caused by chemicals capable of affecting IL4, IL5 and IL13. Eight classes of parasitic diseases were observed among chemical-associated conditions. Environmental chemicals extensively modulate Th2 immune responses through diverse molecular mechanisms. The trend concerning upregulation of Th2 pathways may enhance antiparasitic protection but, on the other hand, could predispose individuals to allergic diseases, among other Th2-related conditions. These exploratory findings suggest that chemical pollution may influence the susceptibility and pathogenesis of helminth infections and highlight the need for the incorporation of exposome-based approaches in parasitology research.

1. Introduction

Helminth parasites are organisms characterized by complex life cycles and the ability to establish long-standing, chronic infections that can persist for decades, challenging the immune system in a fundamentally different manner than rapidly replicating infectious agents [1]. More than 1.5 billion people worldwide show helminth infections [2]. Although these infections do not necessarily result in major disease or death, they are associated with high morbidity rates, and the chronic condition can culminate in anemia and malnutrition [2,3]. Beyond human health impacts, helminth infections have large negative impacts on livestock mammals [4] and influence multiple aspects of wild mammalian ecology, including host behavior, body condition, reproductive success, population dynamics, and susceptibility to concurrent infections [5].

The establishment and persistence of helminth infections are influenced by a complex interplay of host genetics, parasite characteristics, and environmental factors [6]. Notably, the totality of environmental exposures that an individual experiences throughout their lifetime, including chemical pollutants, pathogens, dietary components, lifestyle factors, and socioeconomic conditions can collectively be termed “exposome” [7]. In the context of helminth infections, the exposome plays a critical role in determining susceptibility, establishment and chronicity of infections. Environmental factors such as sanitation infrastructure, water quality, soil contamination, and climate conditions directly influence helminth transmission dynamics and larval survival in the environment [8]. Additionally, host nutritional status, concurrent infections, stress levels, and exposure to immunomodulatory compounds can significantly alter immune responses to helminths, potentially facilitating parasite establishment or, conversely, enhancing resistance [3]. The exposome framework is particularly relevant for helminth ecology as these parasites often require specific environmental conditions for their complex life cycles. Furthermore, their transmission is intimately linked to human behavior, agricultural practices, and ecosystem health [8].

Helminth infections in mammals typically trigger T helper type 2 (Th2) immune responses, which are characterized by recruitment of eosinophil, basophil and mast cells, IgE production, and the proliferation of type 2 innate lymphoid (ILC2) and type 2 helper (Th2) cells [1,9,10]. Once activated, both ILC2s (driving the innate response) and Th2 cells (driving the adaptive response) secrete key type 2 cytokines that orchestrate antiparasitic defenses, collectively promoting helminth expulsion [10,11,12,13].

The cytokines involved in those responses includes interleukin-4 (IL4), interleukin-5 (IL5), and interleukin-13 (IL13) [13]. IL4 is a key cytokine in Th2 response, promoting T cell differentiation into Th2 cells, stimulating the development of alternatively activated macrophages (AAMs, which are immune cells crucial in combating parasitic infections and promoting wound healing), and inducing immunoglobulin class switching to IgE in B cells, which binds to high-affinity IgE receptors (FcεRI) on mast cells and basophils, priming them for degranulation upon subsequent antigen exposure [14]. IL13 acts synergistically with IL4 in IgE responses, acting on epithelial cells, goblet cells, smooth muscle cells, and macrophages to enhance mucus production, reinforce barrier integrity, increase smooth muscle contractility, accelerate epithelial turnover, and stimulate the production of anthelmintic molecules such as resistin-like molecule-β (RELM-β), thereby promoting intestinal protection and facilitating worm expulsion [10,11,12,13]. IL5 specifically triggers eosinophilia, which is a key marker of helminth infection in multiple host species, being also a common feature of antiparasitic immunity through the induction of eosinophil-related mediators and cytotoxic products [15]. Collectively, IL4, IL5 and IL13 orchestrate the characteristic features of Th2 immunity, including tissue remodeling, enhanced barrier function, and expulsion mechanisms that are crucial for helminth clearance but, on the other hand, can contribute to allergic pathology when dysregulated [13,14].

Given the critical role of Th2 immunity in helminth infection outcomes and the established influence of the exposome on both parasite transmission and host immune function, there is a need to investigate how environmental pollutants (i.e., chemicals) may modulate helminth-related immune response. Considering that diverse types of chemical exposure have already been described as capable of significantly influence immunogenetic expression and alter the balance of cytokine production and Th2 response [16,17], environmental contaminants within the exposome may have profound impacts on the effectiveness of Th2 responses against helminth parasites.

Chemical pollutants, including toxic metals, persistent organic compounds, and endocrine-disrupting chemicals, have been shown to modulate immune cell function and cytokine signaling pathways [18], potentially compromising the host’s ability to mount an adequate Th2 response. Furthermore, exposome-associated factors may disrupt the delicate coordination between innate and adaptive immunity, affecting both ILC2 and Th2 cell responses that are essential for helminth expulsion. Therefore, understanding the potential impacts of chemical exposures on Th2 immune responses is essential for comprehending the complex relationship between environmental factors, susceptibility and pathogenesis of helminth infections, particularly in populations facing high burdens of both chemical contamination and parasitic diseases. In this sense, this work used a toxicogenomic approach to explore how chemical agents interact with IL4, IL5 and IL13 genes, potentially influencing their expression patterns and helminth infection outcomes.

2. Materials and Methods

2.1. Gene Selection

While numerous genes orchestrate the Th2 response, we targeted three genes for this exploratory analysis: IL4, IL5, and IL13. The selection of these genes for analyzing the impacts of chemical compounds on Th2 responses is based on the central role of IL4, IL5 and IL13 in orchestrating and maintaining Th2 immune responses. IL4 represents the primary inducer of naive T cell differentiation into Th2 cells, in addition to promoting immunoglobulin class switching to IgE and contributing to development of AAMs, constituting an early and fundamental marker of Th2 polarization [14]. IL5 acts specifically on eosinophil differentiation, activation and survival, being considered the main mediator of eosinophilia, which is a classical marker of allergic and parasitic responses [15]. IL13, in turn, contributes to mucus production, tissue remodeling, maintenance of chronic Th2 inflammation and worm expulsion [11,12]. Collectively, the genes that encode these three cytokines represent key responses of molecular effectors in the Th2 immunity, enabling a comprehensive evaluation of the modulatory effects of xenobiotics on this helminth-related immune response.

2.2. Chemical Data Source and Chemical–Gene Interactions

Data on chemicals interacting with the IL4, IL5 and IL13 genes were obtained from The Comparative Toxicogenomics Database (CTD) on 16 August 2025, Revision 17899M [19]. The CTD is a platform that brings together biological information based on chemical–gene interactions, aggregating data from several studies involving multiple species [20].

First, using the function “gene search” at CTD, raw data of the chemicals interacting with each of the genes were downloaded (Excel files), the number of chemicals interacting with each gene was collected, and then the top 20 chemicals interacting with each of the genes were ranked based on the number of chemical–gene interactions (first ranking criterion) and the number of organisms that supported such interactions (second ranking criterion, applied if necessary). Finally, the chemicals interacting with each of the genes were grouped into an Excel file and duplicate chemical names were removed, allowing calculating the number of chemicals interacting with the IL4, IL5 and IL13 (with one of them, with two and with all three).

2.3. Chemical Intersection, Chemical Classification and Expression Profile

To identify chemicals capable of interacting specifically with all three genes targeted by this study (IL4, IL5 and IL13), a Venn diagram was generated using CTD’s Venn Viewer function [21], considering curated gene associations and any chemical–gene interaction type (“increases”, “decreases”, “affects (degree unspecified)”). Then, the chemicals identified at the intersection of the three genes were obtained and arbitrarily classified into the following categories: “air pollutants”, “allergens”, “bioactive molecules”, “industry-related chemicals”, “medicinal drugs”, “metal and metal-containing chemicals”, “pesticides”, “plant compounds”, and “others”. Of note, the classification of chemicals into these categories was defined arbitrarily, based primarily on information obtained from PubChem [22,23]. We emphasize that many chemicals may be classified by other authors into different categories or may even fit into more than one category. However, we use our best knowledge and judgment to classify chemicals most appropriately. Furthermore, this classification aims only to identify the main groups of chemicals with the ability to affect genetic pathways that affect the immune response in parasitic infections. In other words, this classification is merely exploratory and should be interpreted as such.

Subsequently, to identify the gene expression profile stimulated by the total chemicals, two additional Venn diagrams were generated. The first considered only “increases expression” and the second considered only “decreases expression”. This was performed using the “chemical–gene interaction type” filter of CTD’s Venn Viewer function [21].

2.4. Enriched Diseases

Using CTD’s Set Analyzer function [24], enriched diseases associated with the set of chemicals identified at the intersection of the three genes generated in the first Venn diagram (described in the previous section) were identified, considering corrected p-value of <0.001 as threshold. Diseases were first filtered using the disease category “infection” and then the subcategory “parasitic diseases”. Diseases were ranked based on corrected p-values, from lowest to highest. The number of annotated genes linking the chemicals to each disease was also collected.

3. Results

3.1. Chemical–Gene Interactions

Table 1. Top 20 gene-interacting chemicals.

IL4 (n = 675 Interacting Chemicals)			IL5 (n = 326 Interacting Chemicals)			IL13 (n = 330 Interacting Chemicals)
Top 20 Chemicals	Number of Chemical–Gene Interactions	Organism Number	Top 20 Chemicals	Number of Chemical–Gene Interactions	Organism Number	Top 20 Chemicals	Number of Chemical–Gene Interactions	Organism Number
Poly I-C	111	2	Ovalbumin	97	2	Ovalbumin	107	1
Ovalbumin	104	2	Toluene 2,4-diisocyanate	34	2	Particulate matter	46	4
Lipopolysaccharides	85	4	Dexamethasone	26	2	Ozone	38	3
Toluene 2,4-diisocyanate	83	3	Antigens, dermatophagoides	25	3	Lipopolysaccharides	35	4
Tetradecanoylphorbol acetate	60	5	Particulate matter	24	2	Toluene 2,4-diisocyanate	28	1
Ionomycin	50	5	Ozone	22	3	Antigens, dermatophagoides	24	1
Mercuric chloride	45	4	Tetradecanoylphorbol acetate	16	3	Vehicle emissions	21	3
Particulate matter	45	3	Vehicle emissions	15	2	Metformin	19	1
Bisphenol A	39	3	Bisphenol A	14	3	Dexamethasone	18	4
1-Methyl-4-phenylpyridinium	35	1	Lipopolysaccharides	14	3	Tetradecanoylphorbol acetate	18	3
Dinitrochlorobenzene	28	1	Calcimycin	12	1	Nanotubes, carbon	14	2
Ketoconazole	28	1	1-Methyl-3-isobutylxanthine	11	1	Dinitrophenyl-bovine serum albumin	12	1
Dexamethasone	26	3	Tetrachlorodibenzodioxin	11	3	Air pollutants	11	2
Antigens, dermatophagoides	25	2	Bucladesine	10	1	Calcimycin	11	3
4-(5H-dibenzo(a,d)cyclohepten-5-ylidene)-1-(4-(2H-tetrazol-5-yl)butyl)piperidine	24	1	Colforsin	10	1	Dust	11	2
Itraconazole	23	1	Itraconazole	10	1	Alisol B 23-acetate	10	1
Terbinafine	23	1	Ketoconazole	10	1	Calcitriol	10	1
Vehicle emissions	22	3	Miconazole	10	1	Fidarestat	10	2
Calcimycin	21	2	Nanotubes, carbon	10	2	Plant extracts	10	2
Dinitrophenyl-human serum albumin conjugate	21	1	Terbinafine * and Tolnaftate *	10	1	Resveratrol	10	3

Data from The Comparative Toxicogenomics Database. Number of chemical–gene interactions: first ranking criteria. Organism number: second ranking criteria. * Chemicals in the last position with the same numbers of chemical–gene interactions and organism number.

details the top 20 gene-interacting chemicals for each targeted gene. A total of 675 chemicals can interact with the IL4 gene (Supplementary List S1), 326 with IL5 (Supplementary List S2), and 330 with IL13 (Supplementary List S3). A wide variety of chemical classes, from environmental pollutants to pharmaceuticals, are ranked among the top 20 chemicals interacting with the three genes (Table 1). Removing duplicate chemical names, resulted in a total of 818 chemicals (Supplementary List S4) that have the potential to interact with at least one of the genes IL4, IL5, or IL13.

3.2. Chemical Intersection, Chemical Classification and Expression Profile

Figure 1 shows the Venn diagram with the intersection of chemicals that have the ability to interact with all the three target genes (IL4, IL5 and IL13), which form a set of 145 chemicals (Supplementary List S5) that are divided into the following chemical categories: air pollutants (8.3%), allergens (2.7%), bioactive molecules (8.3%), industry-related chemicals (14.5%), medicinal drugs (21.4%), metal and metal-containing chemicals (8.3%), pesticides (3.4%), plant compounds (12.4%), and others (20.7%) (Figure 1).

Figure 2 shows Venn diagrams considering the chemicals associated specifically with increased or decreased gene expression. Considering chemicals that can interact with all the three target genes (IL4, IL5 and IL13), we identified a total of 95 chemicals associated with increased gene expression (Supplementary List S6), and only 14 chemicals associated with decreased expression (Supplementary List S7).

3.3. Enriched Diseases

Considering the set of chemicals identified at the intersection of the three genes (Figure 1, panel (a)), we identified a total of 64 infectious diseases associated with chemical-gene interactions.

Table 2. Enriched parasitic diseases based on chemicals (n = 146 *) that interact with IL4, IL5 and IL13 genes.

Disease	Corrected p-Value	Annotated Genes Quantity
Parasitic diseases	4.65 × 10−42	62
Protozoan infections	6.18 × 10−29	44
Malaria	1.22 × 10−13	23
Euglenozoa infections	3.47 × 10−12	21
Leishmaniasis	3.47 × 10−12	21
Skin diseases, parasitic	1.51 × 10−8	16
Leishmaniasis, visceral	2.30 × 10−6	13
Helminthiasis	1.23 × 10−5	12

Data from The Comparative Toxicogenomics Database. The nomenclature and standardization were maintained according to the information available on the database. Diseases filtered by disease category of “parasitic disease”, a subcategory of “infection”, considering corrected p-values < 0.001. * One more chemical than in the original list of 145 chemicals because the Comparative Toxicogenomics Database expanded the list to include a chemical (i.e., Polychlorinated dibenzodioxins) closely related to Tetrachlorodibenzodioxin.

shows only the parasitic diseases (n = 8; 12.5%) included in this set of infectious diseases.

4. Discussion

Our analysis identified 818 chemicals capable of interacting with the core Th2 immunity genes IL4, IL5 and/or IL13, demonstrating the susceptibility of Th2 immune pathways to modulation by environmental chemicals. The number of chemical–gene interactions identified (675 for IL4, 326 for IL5, and 330 for IL13) indicates that Th2 immune responses operate within a molecular environment where multiple xenobiotics can influence cytokine production and cellular differentiation pathways. In brief, these findings suggest that the effectiveness of antiparasitic immune responses may be highly influenced by the exposome.

The regulation of Th2 immune responses is controlled by key transcription factors and cytokines that determine cell fate and function. IL4 drives naive CD4+ T cells to differentiate in Th2 cells upon antigen encounter by activating the transcription factor GATA-binding protein 3 (GATA-3) which, in turn, drives the production of IL4, IL5, and IL13 [25]. This differentiation is promoted by signal transducer and activator of transcription 6 (STAT6) signaling and is inhibited by Th1-promoting factors such as interferon gamma (IFN-γ) [26,27]. Once established, Th2 responses are maintained through IL4-mediated positive feedback loops and are regulated by suppressive mechanisms including regulatory T cells and anti-inflammatory cytokines like interleukin-2 (IL2) and transforming growth factor beta (TGF-β) [14]. These regulatory networks ensure that Th2 responses effectively combat extracellular pathogens and mediate allergic reactions while preventing excessive inflammatory damage to tissues. Chemicals may modulate Th2 cytokine production through these various molecular pathways that influence cellular signaling and gene expression regulation. For instance, the aryl hydrocarbon receptor (AhR) pathway, known to be activated by numerous metabolites and xenobiotics, has been demonstrated to modulate Th2 immune responses by repressing Th2 cytokine production [28,29], potentially explaining why diverse chemical classes converge on similar transcriptional outcomes.

The heterogeneous nature of the chemical classes identified in this study (e.g., pharmaceuticals, metals, pesticides, industrial compounds) reveals that Th2 modulation occurs through diverse biological mechanisms and exposure routes. This chemical diversity suggests that the traditional approach of studying single chemical exposures may be insufficient to capture the complexity of environmental impacts on antiparasitic immunity. Also, it reinforces the importance of using exposome approaches when evaluating helminth infection and immune–environment interactions, here employed with the aid of toxicogenomic tools.

The identification of 145 chemicals capable of modulating the core Th2 immunity genes suggests the need for an integrated risk assessment approach that considers not only the individual toxicological effects of these compounds, but also their synergistic or antagonistic interactions in the context of antiparasitic immune responses. This is particularly relevant considering that 95 chemicals were associated with increased gene expression versus only 14 with decreased expression, suggesting a trend toward hyperactivation of Th2 pathways. For instance, an individual living in an industrialized area may simultaneously experience exposure to air pollutants, toxic metals from multiple environmental sources, pesticide residues in food, and pharmaceuticals in water, all of which could collectively influence their capacity to mount effective Th2 responses against helminth infections. This issue extends beyond human health, as wildlife and domestic mammals facing similar helminth–chemical co-exposures may experience comparable disruptions in their antiparasitic immune responses. Considering that CTD data are compiled from studies conducted with multiple species [20], our findings can be, with caution, extrapolated to non-human animals.

Enhanced Th2 immune responses could theoretically provide improved antiparasitic protection, particularly in environments with high helminth transmission rates where robust IL4, IL5, and IL13 production would facilitate more efficient worm expulsion through enhanced mucus secretion, smooth muscle contractility, and eosinophil-mediated cytotoxicity. However, chronic upregulation of these pathways may come at a significant physiological cost, potentially predisposing individuals to allergic diseases, asthma and tissue fibrosis, conditions that have indeed increased in prevalence alongside industrialization and chemical contamination [30]. While initial helminth exposures typically trigger strong allergic inflammatory responses, chronic infections lead to tightly controlled immune regulation. These long-term infections generate potent regulatory effects that result in “modified” Th2 responses, allowing parasite survival while simultaneously protecting the host from damaging immune-mediated pathology [31]. In this sense, helminths would serve as potent immunomodulators, suppressing host Th2 inflammatory pathways associated with allergic reactions, thereby potentially decreasing allergic disease susceptibility during chronic infection [31,32].

This observation aligns with the “hygiene” or “old friend” hypothesis, which posits that reduced exposure to co-evolved microorganisms and helminths in early life disrupts the normal development of immune regulatory mechanisms [33,34]. In line with this hypothesis, in more sanitized environments, the decreased stimulation of Th2 responses by helminths would result in immune dysregulation, causing heightened allergic or autoimmune reactions [34,35]. Additionally, exposure to environmental chemicals can directly modulate Th2 responses by altering cytokine production or immune cell function, as suggested by our toxicogenomic results. These chemicals may exacerbate or trigger aberrant Th2-driven inflammation, compounding the effects of reduced microbial and parasitic exposure. Thus, while Th2 immunity is crucial for protection against parasitic infections, its role may be double-edged, being influenced heavily not only by modern urban living habits but also by widespread chemical exposure. Understanding these combined environmental impacts on immune response is essential for developing strategies to prevent or treat immune-mediated diseases linked to altered Th2 immunity.

Furthermore, the observation of parasitic diseases among the infectious conditions linked to chemical–gene interactions emphasize the potential clinical relevance of these findings. It suggests that environmental chemical exposures might modulate host susceptibility to helminth infections by influencing cytokine-mediated defense pathways. In areas with high parasite burden, simultaneous exposure to immune-modulating chemicals could either enhance protection or disrupt effective immunity, depending on the timing, dose, and combination of exposures. Indeed, this connection is complex. For instance, different helminth species may either promote or suppress inflammatory responses. The development of asthma, which has been associated with Ascaris lumbricoides infection, is also influenced by community infection levels and environmental context [31,32]. This might partly explain the heterogeneous outcomes observed in epidemiological studies of parasite infections and allergic diseases across different geographic and socio-environmental contexts [32,36,37].

Some limitations of this study warrant consideration. First, the datasets available on CTD are influenced by the frequency of research on certain chemicals or genes, variability in experimental design of the studies included in the database, and potential reporting biases. This set of factors may affect the representativeness of chemical–gene interactions identified in toxicogenomic studies [38]. Second, some chemicals identified in our analysis are pharmaceuticals or experimental compounds with known immunosuppressive activity, which should be carefully considered when interpreting their effects on Th2 cytokine expression. Third, the correlations identified in this toxicogenomic approach do not necessarily indicate causality, and the exploratory nature of these in silico findings requires validation through experimental studies. Fourth, while we focused on the three core Th2 cytokines (IL4, IL5, and IL13), other important cytokines involved in antiparasitic responses (e.g., IL-9, IL-10, IL-25, IL-33) [13] were not considered, potentially limiting the comprehensiveness of our analysis. Fifth, immune responses to different helminth species are highly complex and involve multiple host-associated factors and exposome features, which may explain the heterogeneous outcomes observed in experimental studies; our toxicogenomic approach can help elucidate this complexity and generate new hypotheses, but cannot fully capture all biological interactions. Finally, toxicogenomic data from multiple species were analyzed in a pooled manner, which may generalize results and overlook species-specific differences in dose–response relationships, detoxification mechanisms, and evolutionary adaptations to chemical exposures [38]. We stress that these limitations should be considered when analyzing our results.

Incorporating chemical exposure assessments into parasitology and immunology research across mammalian species may improve our understanding of the environmental determinants of immune-related outcomes, ultimately guiding public health interventions aimed at reducing the burden of helminth infections and immune-mediated diseases. In this sense, our study showed that toxicogenomic tools are useful for exploring these biological complexities. However, it is crucial to highlight that biases in the data available on platforms like CTD (e.g., more studies focused on classical genes or chemicals, or experimental variability between studies) can influence the results obtained. On the other hand, data retrieved from CTD are highly relevant for exploratory and hypothesis-free studies, as they unify information from thousands of studies and different species, bringing robustness to the trends found [38].

5. Conclusions

This study identified 818 chemicals capable of interacting with the core Th2 immunity genes IL4, IL5, and/or IL13, with 145 chemicals demonstrating potential for interaction with all three genes. The predominance of chemicals associated with increased, as compared to decreased, gene expression (95 versus 14) suggests a general tendency toward Th2 pathway hyperactivation following chemical exposure. The diverse chemical classes identified indicate that Th2 immune modulation occurs through multiple exposure routes and molecular mechanisms, highlighting the complexity of environmental impacts on antiparasitic immunity.

The presence of parasitic diseases among conditions linked to chemical–gene interactions demonstrates the potential clinical relevance for helminth infection outcomes. While enhanced Th2 responses may improve antiparasitic protection, chronic upregulation could predispose individuals to allergic diseases and other Th2-related pathological conditions. Our results suggest that single-chemical exposure studies may be insufficient to capture the complexity of environmental impacts on immune function, particularly in populations experiencing concurrent chemical contamination and parasitic disease burden.

Future research should incorporate exposome-based assessments into parasitology and immunology studies to better understand the environmental determinants of immune responses and health of humans and other animals. The chemical–gene interaction network identified in this study suggests that populations with high burdens of both environmental contamination and helminth infections may experience complex, bidirectional relationships between chemical exposures, and multiple parasitic disease outcomes. This could partially explain the geographical clustering of helminth infections in regions with environmental contamination and inadequate sanitation infrastructure, creating a “perfect storm” of compromised immunity and increased parasite exposure. Understanding these multifaceted exposome–helminth interactions is essential for developing comprehensive control strategies that address not only the parasites themselves but also the environmental and social determinants that sustain transmission cycles.