Open Veterinary Journal, (2026), Vol. 16(4): -2002

Review Article

10.5455/OVJ.2026.v16.i4.3

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Physiological interplay among obesity, male fertility, and aryl hydrocarbon receptor in human and mice: A mini review

Mohammed Kshash^1,2and Hasan Alghetaa^1*

¹Department of Physiology, Biochemistry and Pharmacology, College of Veterinary Medicine, University of Baghdad, Baghdad, Iraq

²Ministry of Agriculture, Veterinary Hospital in Babylon, Babylon, Iraq

*Corresponding Author: Hasan Alghetaa. Department of Physiology, Biochemistry and Pharmacology, College of Veterinary Medicine, University of Baghdad, Baghdad, Iraq. Email: kashifalkitaa [at] covm.uobaghdad.edu.iq

Submitted: 10/12/2025 Revised: 22/02/2026 Accepted: 03/03/2026 Published: 30/04/2026

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ABSTRACT

According to the most recent World Health Organization report in 2022, approximately 16% of people were classified as obese. Obesity is an inflammatory-mediated condition manifested by accelerated lipogenesis and excessive fat accumulation around the viscera and, in some cases, surrounding the male gonads. Thus, obesity is considered a major cause of male infertility. Many environmental toxicants, known as obesogens, are connected to obesity progression by disrupting the hormonal profile, interrupting cellular metabolism, and subsequently leading to the development of sue. Such toxicants, such as bisphenol A, a plastic derivative, and dioxins, which are byproducts of incomplete combustion or industrial processes. Interestingly, these types of toxicants, in addition to others like polycyclic aromatic hydrocarbons (PAHs) and polychlorinated biphenyls, are defined as ligands of aryl hydrocarbon receptor (AhR). AhR has critical roles in immunity, metabolism, reproduction, and cancer biology, and it is expressed in immune cells such as T/B lymphocytes, macrophages, and dendritic cells. The effect of AhR on immunity is dependent on the ligand, which could activate macrophage-induced obesity. Many AhR ligands (e.g., kynurenine and indole derivatives) can be exogenous or endogenous and affect reproductive functions, such as spermatogenesis and oocyte maturation. There are also natural antagonists to AhR, including resveratrol, which have the potential to play a role in fertility. Currently, to connect the roles of AhR in obesity-induced male infertility. This review aims to elucidate the physiological and toxicological roles of AhR in the initiation of obesity and male infertility.

Keywords: Aryl hydrocarbon receptor, Infertility, Metabolic infertility, Obesity.

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Introduction

Obesity is an inflammatory and metabolic disorder that enhances other linked systemic dysfunctions.res. Recently, according to the European Association for the Study of Obesity framework, more than 18% of people were classified as overweight based on their body mass index (BMI); nowadays, they are defined as obese (Dicker et al., 2025). Body adipose tissue (AT) is homeostatically regulated to store metabolic energy through complicated pathways. Any interruption in these pathways may lead to excessive fat accumulation in AT and around the internal viscera, which could impair their homeostatic status and lead to dysfunction (Levin et al., 2025). Leptin and ghrelin are the key hormones that play opposing roles in energy metabolism and lipid tissue. The dysregulation of these hormone signaling pathways is linked to the development of obesity (Skoracka et al., 2025). Obesity is now recognized as a predisposing factor for many chronic health conditions, such as hepatic, renal, and cardiovascular disorders, as well as type 2 diabetes (T2D). In addition, the malfunction of regulatory metabolic hormones, namely leptin and ghrelin, will lead to excessive nutrient intake. This overfeeding stimulates inflammatory responders via the inflammasome and proinflammatory cytokine upregulation, which leads to insulin resistance (IR) and β-cell dysfunction to end up with different organs damage (Tilg et al., 2024; Donath and Drucker, 2025). The interplay of genetic, epigenetic, and environmental factors has a significant role in shaping the pathophysiology of obesity, which in turn affects the susceptibility of individuals to other linked diseases (Tonin et al., 2025).

Lifestyle and environmental factors significantly participate in reproductive-related cancer disorders, for example, endometriosis (Al-Salamy and Alghetaa, 2025; Al-Salamy and Alghetaa, 2026), ovarian cancer, and other gynecologic pathologies in females (Farina et al., 2025) and abnormal histological male reproductive system (Martins et al., 2025). Many researchers have found that environmental factors could lead to internal tissue damage through specific groups of receptors that play pleotropic roles in different tissues, one of which is the aryl hydrocarbon receptor (AhR) (Li et al., 2025).

AhR is a ligand-dependent transcription factor that regulates pathological and physiological functions in various tissues and organs. It was recently reported to enhance the renal damage in obese mice when exposed to environmental pollutant, namely bisphenol-S, through induction of NF-kB signaling (Brito et al., 2025). Furthermore, AhR can support male reproductive health (Bustani and Alghetaa, 2025a,b; Bustani et al., 2025) by ameliorating infertility in rats by upregulating testicular-blood barrier integrity (Bustani and Alghetaa, 2025a,b; Bustani et al., 2025) or even by increasing normospermia percentages (Bustani et al., 2024). Due to a shortage of studies linking the negative impact of AhR signaling with obesity pathogenesis on the one hand and male infertility as a result on the other hand, the current review has been designed to elucidate the pathophysiological roles of AhR in obesity development and, in turn, how this metabolic disorder negatively affects male fertility.

Obesity

It can be recognized as a metabolic-medical status that is manifested by excessive body fat accumulation, which can negatively change health and life expectancy. An individual is considered overweight with a BMI of 25–30 kg/m² and obese if the BMI exceeds 30 kg/m² (Mohajan and Mohajan, 2023). Currently, waist circumference is viewed as a more accurate obesity marker. Rising obesity rates, particularly due to sedentary lifestyles and poor diets (Ross et al., 2020). Additionally, male reproductive potential is reportedly declining, with semen quality set back over the past 50 years, experiencing a reduction in sperm counts by approximately 1.5% per year in the USA. This decline in fertility correlates with rising obesity rates, indicating that male infertility and obesity may be related (Agarwal et al., 2024).

In 2022, the World Health Organization (WHO) reported that 2.5 billion adults aged 18 years and older were overweight, including over 890 million adults living with obesity, while approximately 35 million children under 5 years of age are overweight worldwide (WHO, 2025). More than half of all deaths in the United States are linked to noncommunicable diseases, many of which are associated with overweight, obesity, physical inactivity, tobacco use, and alcohol consumption, leading to metabolic conditions such as hypertension and diabetes (Merzah, 2025).

Gordon Kennedy proposed that AT mass is regulated by homeostatic control affecting food intake and energy balance approximately 50 years ago. Hervey’s experiments showed that ventromedial hypothalamus (VMH) lesions increased a factor that suppresses food intake and weight (Yousefvand and Hamidi, 2021). Genetic studies revealed that mutations in certain genes (ob/ob, db/db, Ay) reveal a hormonal basis for obesity: leptin, produced by fat tissue, plays a crucial role in regulating fat mass via a negative feedback loop (Loos and Yeo, 2022; Friedman, 2025). Human obesity is highly heritable, with polygenic factors also contributing. Diet-induced obesity leads to defects in leptin signaling akin to those seen in genetic models (Lavoie et al., 2023).

The buildup of excessive fat in the scrotum, along with environmental toxins found in the white adipose tissue (WAT) encasing the scrotum, could directly affect sperm generation within the testes in obese men. Oxidative stress likely plays a significant role in the relationship between body fat and male reproductive dysfunction. Mitochondria produce reactive oxygen species (ROS) as a byproduct of metabolic activity during sperm development; excessive ROS production, particularly in conditions of obesity or high-fat diets (HFDs) (Liang et al., 2025).

Pathophysiological mechanisms underlying obesity

Given the considerable individual variability in response to obesity treatment and the complex etiology of obesity, a thorough understanding of the pathophysiological basis of obesity is paramount to developing rational, effective, and cost-effective therapeutic measures. After a thorough review of the literature on the pathophysiology of obesity, the following summary of its pathophysiological mechanisms will serve (Baker et al., 2022).

Metabolic regulation associated with obesity

Energy homeostasis comprises three key elements: energy intake, expenditure, and storage. Long-term energy storage occurs in adipocytes as intracellular droplets of Triglycerides (TG). Adipocytes are typically organized into discrete depots of AT, which can be classified into five general classifications: subcutaneous, visceral or intraperitoneal, pelvic and retroperitoneal, intra or extra pericardial, and intramuscular (Chun, 2021).

Obesity occurs as a result of an imbalance in energy homeostasis, which culminates in unrestrained TG accumulation in WAT and reduced thermogenic capacity of brown AT (BAT)/beige adipose tissue (BeAT) (Kong et al., 2025).

AT is found in two fundamental forms: BAT and WAT, with different physiological functions. Although WAT can be found throughout the body, BAT is mostly localized to the cervical and subscapular area. WAT is generally an energy-storing tissue, converting glucose and FAs into TGs stored in large unilocular lipid droplets that are later released as FFAs from adipocytes (Chernukha et al., 2022). Conversely, BAT is mitochondrial-dependent and is necessary for promoting energy expenditure and non-shivering thermogenesis (Pani and Bal, 2022). The thermogenic function of BAT is primarily influenced by its high density of mitochondria and the activation of uncoupling protein 1 (UCP1), which causes heat generation by facilitating the typical process of oxidative phosphorylation (Chen et al., 2023a). In addition to WAT and BAT, BeAT is another intermediate type that generates heat and is often found within WAT. Although the morphology of BeAT is similar to that of BAT, it is typically derived from a Myf5-negative cell lineage, such as WAT.

These metabolic and thermogenic actions are mainly driven by the mitochondrial pool’s unique characteristics. Mitochondrial dysfunction leads to a loss of metabolic flexibility in adipocytes, leading to metabolic diseases such as IR, obesity, and T2D mellitus (Colosimo et al., 2023). These metabolic events create a vicious cycle that adversely affects AT function and metabolic homeostasis. According to Kong et al. (2025), WAT browning was inhibited in HFD group mice and obese patients, inhibiting the local energy expenditure and complications of obesity (Kong et al., 2025).

The hormone-genetic axis regulates obesity

Adipocytes produce several cytokine factors: leptin, Visfatin, interleukin 6, adiponectin (AdipoQ), tumor necrosis factor alpha, resistin, angiotensinogen, aromatase, and adipsin. These bioactive factors are critical to the control of appetite, satiation, and body fat content (Liu et al., 2022). When their normal regulating mechanisms are disrupted, they can result in IR associated with obesity and obesity itself, as the primary factors regulating energy balance are leptin and insulin (Gjermeni et al., 2021).

1- leptin

Obesity is associated with the dysregulation of key hormones. Elevated leptin levels due to leptin resistance promote hyperphagia and consequent energy imbalance, and IR increases ectopic lipid accumulation and metabolic dysfunction across the body (Engin and Engin, 2024). Under low-energy states. Under normal physiological conditions, ghrelin production and circulating levels are high during low-energy states (such as fasting or before meals) to stimulate appetite and conserve energy (Mihalache et al., 2016; Shi et al., 2022). Normally, AdipoQ promotes lipid oxidation; however, when it is low in the body, some metabolic dysfunctions are not expected to be regulated normally. Glucagon-like peptide-1 (GLP-1) analogs may help provide some therapeutic effects by promoting satiety, and ovarian hormones change the hedonic and cognitive components of eating. Strategies that target leptin and insulin signaling, promote GLP-1 activity, and restore AdipoQ may prevent some obesity-related metabolic disorders to which individuals are susceptible.

Leptin is synthesized from the obese gene and exerts its biological effects through binding and activation of a specific leptin receptor (LepRb), following production and release from adipocytes within WAT (Martínez-Sánchez, 2020). This adipocyte-derived hormone is considered a signaling molecule that conveys the nutritional condition of the body during states of energy deficit. Therefore, states of physiological caloric restriction or through decreased adiposity exhibit decreased leptin circulating levels (Miller et al., 2017).

Leptin affects appetite and caloric consumption by binding to receptors expressing proopiomelanocortin (POMC) in the brain stem, hypothalamus, and arcuate nucleus (Baldini and Phelan, 2019). Mechanistically, leptin inhibits the activity of hypothalamic Arcuate nucleus (ARC) neurons that secrete neuropeptide Y (NPY), a strong orexigenic mediator that amplifies hunger signals and decreases the use of metabolic energy for adipose accumulation (Christoffersen et al., 2022). HFD can activate Nuclear Factor kappa B (NF-κB) and its upstream regulatory factor, inhibitor of NF-κB kinaseβ, in the hypothalamus through endoplasmic reticulum (ER) stress. This entire cascade of events could lead to leptin resistance (Gruzdeva et al., 2019).

Leptin resistance is associated with reduced satiety signaling, hyperphagia, and incremental gain in body mass, which is a pathological state that disrupts metabolic homeostasis. For individuals with obesity, 85% of the total leptin that circulates is in the active free form, which leads to chronic overstimulation of the long-forming LepRb (Kong et al., 2025). Although the actual amount of leptin in the cerebrospinal fluid (CSF) of obese individuals may be greater than equivalent levels in normal-weight individuals, the effectiveness of leptin transport across the blood–brain barrier (BBB), as measured by the CSF: plasma leptin ratio, is reduced by as much as 80% in the obese individuals. Similarly, a HFD rapidly activates astrocytes, causing inflammation and hyperleptinemia. A long-term HFD also stimulates astrocytes and promotes inflammation, reducing the amount of leptin that reaches the brain (Obara-Michlewska, 2022). Therefore, these results suggest that leptin transport across the BBB is impaired in obese subjects.

Leptin increases the release of gonadotropin-releasing hormone (GnRH) from the hypothalamus, and follicle-stimulating hormone (FSH) and luteinizing hormone (LH) are released from the anterior pituitary. These then increase the release of testosterone from the testes in males and estrogen from the ovaries in females. Leptin exerts its effect on the hypothalamic GnRH neurons indirectly, as the GnRH neurons are devoid of LepRb, presumably involving the kisspeptin neurons, pre-mammillary nucleus, agouti-related protein (AgRP), and NPY neurons in the hypothalamus, which are well endowed with LepRb (Almabhouh and Singh, 2023).

2- insulin

The body can efficiently manage the load of eating fat (in the form of triglycerides), protein, and carbohydrates as each meal elevates plasma insulin levels. To summarize the biological mechanisms involved, Brito et al. (2025) utilized three signaling pathways, including the mitogen-activated protein kinase (extracellular signal-regulated kinase) pathway, the metabolic (phosphatidylinositol 3-kinase protein kinase B) pathway, and the oxidative transport chain pathway (Verma et al., 2023). Insulin-mediated satiation occurs through receptor activation in the ARC nucleus, POMC, AgRP/NPY neural circuits, which regulate energy homeostasis while nutrient partitioning and glucose control. In addition, excessively prolonged overeating, temporary periods of inactivity, sedentary behavior, and sleep deprivation significantly increased whole-body IR according to numerous studies (Bourdier et al., 2023). Hyperinsulinemia (increased circulating insulin above basal fasting levels) leads to less AT development due to intensified lipolysis, while also facilitating lipolytic release of FFAs from triglyceride depots. The excessive concentration of FFAs in insulin-sensitive non-AT, particularly in the obese state, contributes to ectopic lipid deposition and lipotoxicity and is a major contributor to IR. The pathophysiological trajectory of IR is characterized by bidirectional interactive pathways with obesity, as a core underpinning pathophysiological mechanism contributing to obesity-related metabolic morbidity (Bourdier et al., 2023).

T2D4 is associated with low testosterone levels and often results in hypogonadotropic hypogonadism in men. Moreover, low testosterone levels can affect insulin sensitivity and increase the risk of developing diabetes. In contrast, testosterone treatment improves insulin sensitivity by changing the body composition of subjects with T2D-induced hypogonadism. However, in rodent models, excess androgen can increase oxidative stress and induce beta-cell failure. Furthermore, elevated leptin levels, presumably due to leptin resistance, inhibit basal and human chorionic gonadotropin-induced testosterone secretion in rat testes and males with obesity. In association with low testosterone levels, gonadal dysfunction contributes to abdominal obesity in men due to changes in LH and FSH levels. Although the involvement of reduced LH and FSH levels in testicular dysfunction in T2D is clear from these studies, there is also evidence that insulin regulates testosterone production in obese subjects and inhibits sex hormone-binding globulin levels in patients with T2D. Indeed, overexpression of insulin in Leydig cells reduces germ cells and causes infertility in mice, suggesting that the elevated insulin level characteristic of T2D may have detrimental effects on testicular Leydig cells (Shirneshan et al., 2008).

3- growth hormone

Originally known as a growth hormone-releasing peptide, ghrelin has now been established as a multifaceted regulator of energy balance, showing an inverse relationship with BMI and a direct role in appetite regulation (Deschaine and Leggio, 2022). Accordingly, ghrelin expression is decreased in positive energy balance settings, such as obesity, but increased during states of undernutrition, such as anorexia nervosa (Fricke and Voderholzer, 2023). Within the VMH, ghrelin facilitates the activation of the energy-sensing function of AMP-activated protein kinase (AMPK) by binding to the growth hormone secretagogue receptor (GHSR), activating the calcium/calmodulin-dependent protein kinase 2 AMPK axis and the hypothalamic sirtuin 1 p53 axis. Chronic activation of AMPK induces ghrelin-dependent hyperphagia and obesity in mice and humans (Yavari et al., 2016). Furthermore, obese mice demonstrate decreased GHSR expression and ghrelin transport across the BBB, leading to decreased ghrelin sensitivity and possibly contributing to the development of hypothalamic ghrelin resistance (Varra et al., 2024).

AdipoQ, an adipocyte-derived cytokine expressed by the AdipoQ gene on the chromosome, facilitates adipocyte cell development through its autocrine activity (Engin and Engin, 2024). AdipoQ promotes FA oxidation and energy expenditure by markedly increasing peroxisome proliferator-activated receptor expression and activity of peroxisome proliferator-activated receptor-α (PPARα), leading to the upregulated expression of acetyl CoA oxidase and UCPs (Engin, 2017). AdipoQ has a proportionate relationship with insulin sensitivity that is diminished in obesity, as shown in various clinical biomarker studies. In the setting of obesity, AT demonstrates decreased AdipoQ secretion as a result of impaired leptin signaling and increased caveolin 1 expression (Roy et al., 2025).

Growth hormone acts directly and indirectly to promote sperm production via hepatic Insulin-like growth factor-1 at the testicular level. The locally produced GH may act in a paracrine or autocrine manner to regulate local processes that are strategically regulated by GH in the pituitary gland. GH promotes the early development of spermatogonia and ensures complete maturation (Magon et al., 2011).

Aryl hydrocarbon receptor

The AhR is a ligand-activated transcription factor that was first identified in the early 1970s as a mediator of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD/dioxin) toxicity. When humans are exposed to dioxins, they develop a chronic inflammatory condition referred to as chloracne, which is associated with persistent painful skin lesions. During the Vietnam War, many herbicides, particularly Agent Orange, were sprayed to destroy the forest and ground cover. TCDD dioxin is an extremely toxic and inescapable contaminant found in the herbicide 2,4,5-T, which is part of Agent Orange (Olson and Morton, 2019). The receptor possesses a shared ligand-binding site that can interact with different classes of exogenous molecules, such as polycyclic PAHs and polychlorinated biphenyls (Prasad Singh et al., 2020). The transcription of a spectrum of drug-metabolizing enzymes, including cytochrome P450 enzymes 1A1, 1A2, and 1B1, is the prototypical signaling pathway for AhR-mediated transcriptional activity (Shivanna et al., 2022).

By increasing cytochrome P450 levels, causing biotransformation, and making foreign chemicals more soluble in water, AhR plays a crucial role in regulating the metabolism of foreign substances and ultimately causing their elimination (Al-Kinany and Enayah, 2021). AhR’s function in metabolism and toxicity has been well-established since the first investigations. However, research suggests that AhR may also be essential for controlling immunity and reproduction (Alhamad et al., 2022).

The AhR is an essential immunomodulator and a ligand-dependent transcriptional factor that is broadly expressed in T cells, B cells, macrophages, natural killer cells, and dendritic cells (Alghetaa et al., 2023a). The AhR can be activated by both endogenous and exogenous ligands. The consequences of AhR activation can differ depending on the type of ligand that activates the AhR and range from immune response activation to immune response suppression. TCDD is an exogenous potent ligand of AhR, and its activation can induce T regs and suppress the immune system. 6-Formylindolo[3,2-b] carbazole (FICZ), an endogenous AhR ligand, also activates AhR and worsens inflammation by inducing Th17 cells. Finally, several dietary AhR ligands induce canonical Tregs and suppress Th17 cells. (Abdulla et al., 2021).

Physiological significance of the AhR

The physiological impact of AhR activation is broad and includes roles in immune modulation, intestinal homeostasis maintenance, and carcinogenesis. Different pathways allow AhR integration in both arms of immunity (innate and adaptive); for example, it represses genes associated with acute phase responses, promotes Treg differentiation, and promotes B-cell differentiation (Alghetaa et al., 2018, 2021; Wajda et al., 2020). The AhR supports intestinal homeostasis by regulating and allowing the differentiation of intraepithelial lymphocytes and innate lymphoid cells, both of which maintain critical first-line defenses against pathogenic microbes infiltrating through and toward the basolateral surface of the intestinal epithelium (Burgueño and Abreu, 2020). It also plays physiological roles in the pathogenesis of osteoporosis and endometriosis in females (Al-Salamy and Alghetaa, 2025; Alabsawy and Alghetaa, 2025)

Given its involvement in inflammatory signaling and cell cycle progression, AhR may be relevant to different phases of tumorigenesis. This is substantiated by data indicating that the receptor has significant constitutive activity and nuclear localization in aggressive tumors and tumor cell lines (Burgueño and Abreu, 2020).

Studies using knockout and transgenic mice have shown that AhR is necessary for liver development (Fernandez-Salguero et al., 1995; Schmidt et al., 1996) and contributes to the regulation of reproductive (Fernandez-Salguero et al., 1995), cardiovascular (Vasquez et al., 2003), renal (Harrill et al., 2013), hematopoietic (Gasiewicz et al., 2010), immune (Stevens et al., 2009), and microbial homeostasis (Bock, 2020). Furthermore, AhR regulates genes associated with proliferation, apoptosis, cell growth and differentiation, and cellular stress responses (Nebert et al., 2000).

Regulation of the AhR

The gene coding for AhR comprises 11 exons and is located on chromosome 7p15 in humans and chromosome 12 A3 in mice. In both species, the AhR promoter encompasses many transcriptional activator sites within a GC-rich region lacking TATA and CCAAT boxes. The expression of AhR is constitutively regulated via zinc-finger transcription activators, such as specificity protein (Sp) 1 and Sp3, which have consensus binding sites within the GC-rich region of the AhR promoter. Other factors associated with AhR expression include transforming growth factor-β, nuclear factor erythroid2-related factor 2 (NRF2), β-catenin, and PPAR-α. Similar to other transcription factors, these regulatory proteins activate the AhR gene in a cell-specific manner. As a conversed example, histone deacetylase inhibitors antagonize the AhR promoter, whereas histone acetylase inhibitors agonize the AhR promoter activity, showing that histone acetylation greatly contributes to AhR expression. Similarly, DNA hypermethylation downregulates AhR expression (Gargaro et al., 2021; Shivanna et al., 2022; Zhang et al., 2022).

AhR ligands

A variety of structurally distinct compounds activate AhR. AhR ligands fall into two categories: exogenous (from diesel exhaust, commercial production, or industrial contamination, including PAHs, PCBs, TCDD, and others), presented in Table 1, or dietary, and endogenous (for example, FICZ, indole-carbazoles, indigoids, and others), presented in Table 2 (Avilla et al., 2020).

Table 1. Exogenous AhR-ligands and their physiological roles in reproduction.

Table 2. Endogenous AhR-ligands and their physiological roles in the reproduction of AT.

AhR antagonists

One strategy is to create drugs and chemicals that can modulate the AhR signaling pathway. The most common AhR antagonists are 30methoxy-40-nitroflavone (Dertinger et al., 2000) and resveratrol (Wang et al., 2019; Shaito et al., 2020; Khayoon and Al-Rekabi, 2020). PAH BP enhances dermatophagoides group (UNDer f1)-induced allergic lung inflammation by activating the AhR (Alghetaa et al., 2021; Alharris et al., 2022), which was inhibited by the AhR antagonist CH223191. For example, the AhR antagonist CH223191 not only prevented but also reversed the development of Sufleunger 5146-induced experimental pulmonary hypertension in rats (Dean et al., 2018). AhR antagonists are also being considered for human therapeutics in the area of healing and cancer (Murray and Perdew, 2020).

The negative effect of obesity on fertility via thermoregulation

Obesity greatly affects male fertility, which negatively affects reproductive health via hormonal, metabolic, and physiological pathways. Excess AT increases the activity of aromatase, which converts testosterone to estrogen and ultimately lowers circulating testosterone levels, disrupting spermatogenesis. This hormonal imbalance can result in reduced sperm production, decreased sperm motility, abnormal morphology changes, and increased sperm DNA fragmentation. Obesity is often associated with IR, oxidative stress, and chronic low-grade inflammation, which can further reduce testicular function and sperm quality. Obesity is also correlated with lower levels of gonadotropins, such as LH and FSH, greater incidence of ED, and decreased libido, which contribute to subfertility or infertility in men (Chaudhuri et al., 2022).

Impaired thermoregulation of the testes is another key mechanism by which obesity negatively affects male fertility. Optimal sperm production occurs at testicular temperatures of approximately 2°C–4°C below the core body temperature (Sciorio et al., 2024). Increased fat accumulation around the thighs, groin, and scrotal region creates an insulating layer of fat around the scrotum in men with obesity, increasing scrotal temperature and affecting normal spermatogenesis. Exposure to elevated testicular temperature is associated with lower sperm counts, changes in sperm morphology, and increased oxidative stress, all of which can damage sperm DNA and negatively affect sperm function (Maroto et al., 2025).

The role of AhR in inflammatory-mediated obesity

AhR is a cytosolic transcription factor historically known for sensing xenobiotics, such as dioxins, and regulating detoxification enzymes (e.g., CYP1A1, CYP1B1) (Rakateli et al., 2023). More recently, AhR has been recognized for its roles beyond xenobiotic metabolism: it is activated by endogenous ligands, such as tryptophan-derived metabolites like kynurenine, and dietary components (e.g., polyphenols) (Salminen and A, 2023).

Mice with AhR variants show varying susceptibility to obesity. Strains with high-affinity AhR gained more weight on Western diets than those with lower-affinity versions (Iriady and I, 2024). Emerging evidence suggests that a Western diet promotes LDL oxidation and TLR2/4-mediated signaling, which activates the tryptophan catabolizing enzyme IDO1 (Engin and Engin, 2024). This boosts the production of kynurenine, an endogenous AhR agonist, fostering a vicious feedback loop that perpetuates AhR activation and obesity.

Context-dependent AhR activation can promote the resolution of obesity-mediated inflammation, such as via the induction of lipoxin A4 and IL22, particularly when activated by phytochemicals or microbial ligands. Conversely, uncontrolled activation of AhR (e.g., via TCDD) can promote chronic inflammation via nongenomic pathways (Bock, 2021). The pharmacological or genetic inhibition of AhR reverses obesity and liver steatosis in mice and hepatotoxicity in rats (Dawood et al., 2023; Dawood and Alghetaa, 2023), with associated downregulation of lipid-associated genes such as CYP1B1, PPARα, SCD1, and osteopontin (Zheng et al., 2025). AhR has been shown to help maintain gut barrier integrity in human obesity, potentially mitigating systemic inflammation stemming from gut dysfunction (Chen et al., 2023b).

AhR contributes to glucose homeostasis and lipid metabolism, possibly by maintaining ILC3 populations that produce IL22, which suppresses inflammation linked to IR and T2DM (Helm and Zhou, 2023). AhR is at the crossroads of environmental/dietary exposures, immune regulation, and metabolic homeostasis. Its modulation can influence obesity outcomes by either worsening weight gain and metabolic dysfunction (when activated aberrantly) or providing protection by promoting immune balance and preventing lipid accumulation (Bock, 2020).

Role of AhR in obesity hormonal disorder

ER stress upregulated the expression of AhR, its partner ARNT, and the target gene CYP1B1 in granulosa cells from both patients with PCOS and mouse models (Shahin et al., 2020; Gargaro et al., 2021; Haque and Tischkau, 2022).

In liver-specific AhR activation models, mice were protected from obesity and IR despite pronounced fatty liver. This metabolic protection was mediated by fibroblast growth factor 21 (FGF21), which was identified as a direct AhR transcriptional target (King, 2022). Thus, the AhR–FGF21 pathway forms a hormonal axis with systemic metabolic implications. AhR knockout (AhR⁻/⁻) mice demonstrated enhanced insulin sensitivity, improved glucose tolerance, and reduced expression of PPARα and gluconeogenic genes, illustrating the role of AhR in glycemic control and hormonal metabolic regulation (Sayed et al., 2022).

AhR-deficient mice (AhR⁻/⁻ and AhR⁺/⁻) were resistant to diet-induced obesity, showing increased energy expenditure linked to higher Ucp1 expression in BAT and enhanced mitochondrial β-oxidation in muscle. Although not strictly hormonal, these shifts influence systemic factors such as leptin and insulin (Chang et al., 2021). The potent AhR ligand TCDD inhibited adipogenesis in preadipocyte models by downregulating PPARγ, with no adipocyte differentiation seen in AhR⁻/⁻ fibroblasts. Since AT modulates endocrine factors, such as leptin and AdipoQ, AhR-driven adipogenesis blockade may indirectly alter hormonal networks (Qiu et al., 2025).

The role of AhR in male infertility

AhR is a transcription factor whose activity is regulated via ligand binding in the context of supporting male reproductive health, which is distinct from its primary function in xenobiotic detoxification. The AhR is an important component of male reproduction given its role in regulating spermatogenesis, sperm health, hormonal homeostasis, and overall testicular structure (Bustani et al., 2024, 2025; Bustani and Alghetaa, 2025a,b). In particular, AhR activity in response to endogenous ligands or food-based compounds enhances antioxidant activity, reduces oxidative stress, and preserves sperm DNA quality and chromatin condensation, which are also necessary for the best male reproductive capacity. Studies in rats specifically using resveratrol (a dietary compound) demonstrated that AhR signaling was modulated, enhancing the intratesticular environment, ultimately leading to increases in sperm concentration, sperm motility, sperm viability, sperm acrosomal integrity, testosterone, LH, and total antioxidant capacity (Abdulla and Al-Okaily, 2022; Bustani and Alghetaa, 2025b).

Improvement in the intratesticular environment was also associated with increased Dnah1 expression, a gene linked with sperm flagellar motility and function. In contrast, pharmacological blockade of AhR with CH223191 in previous studies induced oxidative stress, reduced total antioxidant capacity, increased sperm DNA fragmentation, disrupted spermatogenesis, caused testicular degeneration, and significantly reduced Dnah1 expression (Bustani et al., 2024). These findings proved that AhR signaling is essential for maintaining homeostasis within the testis and that AhR signaling blockade induces negative reproductive health effects. In addition, the AhR maintains blood-testis barrier integrity and testicular cross-talk between the endocrine system.Collectively, these data support the idea that AhR has unique roles and functions in reproductive biology and physiology (Bidgoli et al., 2011; Bustani and Alghetaa, 2025a).

In conclusion, the studies collectively suggest that regulated modulation of AhR activity, especially with naturally occurring compounds, may be an avenue for treating the negative reproductive consequences of environmental toxicants and maximizing male fertility capacity. Other studies have shown that more research is needed to apply these findings to humans, specifically addressing the effects of a ligand and the dose dependency of AhR and the long-term effects of modulating AhR activity on reproductive health (Bustani and Alghetaa, 2025b).

WHO criteria and rates of infertility

In the United States, infertility affects over six million couples, with male factors contributing to nearly half of all cases. This condition is defined as the inability to achieve pregnancy after 1 year of regular, unprotected intercourse (Westhoff, 2019). However, diagnosing male infertility remains challenging because it is often based solely on abnormal semen analysis results without investigating the underlying causes (Oh et al., 2024). With the growing use of ART, men with any abnormal semen parameter are frequently referred to infertility clinics for further evaluation. This approach depends on reference values established by the WHO over the past three decades to interpret semen quality (Zhang et al., 2024). These values are not definitive indicators of fertility but instead classify results as “above” or “below” minimum thresholds (Lamb and Marinaro, 2023). Since 1987, the WHO has published five editions of its semen analysis manual, introducing lower reference values based on data from fertile men across 14 countries. Establishing these standardized reference ranges aims to reduce misdiagnosis and improve the clinical management of male infertility (Wang et al., 2022).

Male fertility

Fertility refers to the ability to have a clinical pregnancy (Vander Borght and Wyns, 2018). The associated term infertility is used interchangeably by some clinicians and researchers with subfertility, but formal definitions are critical for the appropriate management of reproductive issues (Munro et al., 2022).

An estimated 186 million people worldwide are affected by infertility, most of whom reside in developing countries (Obeagu et al., 2023). Although age is the strongest negative predictive characteristic of fertility, other characteristics, including lifestyle and environmental factors, are purported to play an increasing role. Characteristics related to fertility will be presented in a gender-specific manner and non-gender (Skakkebæk et al., 2022).

Fertility disorders

Approximately 50% of total global infertility is attributed to male factor infertility (Huang et al., 2023). Male factor infertility involves complex pathophysiological mechanisms, and as the precise regulation of reproductive hormones partially regulates male reproductive function, a greater understanding of male hormonal imbalance and the effects of interactions with metabolic hormones, neuropeptides, stress markers, and others will promote further investigation (Eisenberg et al., 2023).

Hormonal disorders

The hypothalamic-pituitary-gonadal (HPG) axis is integral to the regulation of testicular function and male fertility. GnRH is secreted from the hypothalamus in a pulsatile manner, stimulating LH and FSH secretions, triggering events in Leydig and Sertoli cells to regulate testosterone production, spermatogenesis, and other reproductive processes (Sharma et al., 2022; Wistuba et al., 2023). However, disruption to this tightly regulated hormonal network—induced by inflammation, infections, varicocele, metabolic syndromes, thyroid disorders, or lifestyle changes—can alter the normal hormonal function in the HPG axis, negatively affecting fertility (Dutta and Sengupta, 2025). Energy homeostasis is commonly associated with reproductive function. For example, obesity leads to elevated levels of adipokines, adipose-derived hormones, and other inflammatory factors that can impair the regulation of the HPG axis, leading to subfertility (Genchi et al., 2022). Neuropeptides and metabolic signals, which regulate appetite, energy use, and circadian rhythms, may also affect reproductive hormones and sperm quality. These interrelated hormonal and metabolic factors indicate the complicated interactions between the male endocrine system and aspects of metabolic health and overall well-being, further emphasizing the importance of maintaining physiological homeostasis for adequate reproductive function (Pizarroso et al., 2021).

Inflammatory disorders

Proper development of the male reproductive system, hormonal regulation, and coordination between testicular cells supporting spermatogenesis are crucial processes for male fertility (Das et al., 2023). Nonetheless, inflammation can significantly jeopardize these processes and cause infertility. Testicular inflammation may arise from several pathologies, such as varicocele, obesity, infections, leukocyte-spermic, local trauma, and chemical exposure (Fomichova et al., 2025). Failure to manage or resolve testicular inflammation can ultimately lead to oxidative stress, DNA damage, lipid and protein oxidation, and mitochondrial dysfunction within Sertoli and Leydig cells, resulting in impaired function and potentially abnormal spermatogenesis (Adamczewska et al., 2022). This damage is largely driven by the excessive release of proinflammatory mediators such as cytokines, chemokines, and ROS from immune and testicular cells. These mediators can affect various testis components depending on their intensity, nature, and duration of inflammation and contribute to overall reduced spermatogenesis and reproductive dysfunction (Fomichova et al., 2025).

The role of AhR in inflammatory infertility

Research shows that semen quality has decreased over the past 30 years, and male infertility has been increasingly observed in numerous countries (Auger et al., 2022). While the precise mechanisms are unclear, reports suggested that environmental exposure to toxic pollutants is one contributor to this, among others (Ali et al., 2019). Polycyclic PAHs and dioxins are ubiquitous environmental contaminants produced through the incomplete combustion of organic matter and chlorinated hydrocarbon production. Case-controlled and epidemiologic studies have reported the negative effects of PAHs and dioxins on the reproductive health (Kirkok et al., 2020).

The toxic effects of PAHs and dioxins appear to be mediated through AhR, a ligand-activated transcriptional factor that may be involved in human health and disease (Mandal et al., 2023). Following AhR binding to PAHs or dioxins, AhR translocates into the nucleus to interact with xenobiotic responsive elements, resulting in the upregulation of phase I and phase II enzymes, including cytochrome P450 and glutathione S-transferases, which also play a role in PAH and dioxin metabolism (Bahman et al., 2024). Investigations with AhR-deficient mice, which are resistant to the toxicity of PAHs and dioxins, indicate that AhR accounts for this toxicity (Grishanova and Perepechaeva, 2022). In the male reproductive system, testicular tissue predominantly expresses AhR mRNA and its nuclear translocator mRNA, and evidence exists that AhR is present in sperm, providing a mechanism in which environmental PAHs, dioxins, and polyhalogenated biphenyls may directly affect sperm function. AhR activation through PAH exposure lowers testicular function with a specific decrease in spermatogenesis and sperm motility.

Furthermore, resveratrol, a natural competitive antagonist at the AhR, inhibited DNA damage and apoptosis in sperm in the presence of benzo[a pyrene (BaP), suggesting that the AhR mediates the toxic effects of BaP (ElKhatib et al., 2023). In addition to mediating the toxicity of environmental chemicals, AhR has also been implicated in several physiological functions that were not associated with the ingestion of exogenous chemicals (Dawood et al., 2023; Dawood and Alghetaa, 2023; Al-Khaqani and Mohammed, 2024). For example, in a new study, the seminal vesicle regresses in aged AhR-deficient mice, which was attributed to decreased likelihood of testosterone production. Considering that AhR might be involved in the pathogenesis of male infertility, we hypothesized that changes in AhR protein activity due to genetic variation may alter the adverse effects of PAHs and confer individual susceptibility to male infertility (Huang et al., 2016).

The role of AhR in metabolic infertility, particularly in fat metabolism

In addition to mediating the toxicity of environmental chemicals, AhR has been implicated in a variety of physiological functions that are independent of external chemical exposure (Larigot et al., 2018). Studies have shown that the seminal vesicle regresses in aged AhR-deficient male mice and is presumably related to a testosterone level deficit (Huang et al., 2016). Based on the potential role of AhR in the pathogenesis of male infertility, Bustani et al. (2025) proposed that modifications of AhR protein function by genetic variation could modify the detrimental effects of PAHs and dictate the extent of the association of PAHs to male infertility.

Role of AhR in spermatogenesis xenobiotic metabolism

In xenobiotic metabolism, the AhR is a multipurpose sensor (Rakateli et al., 2023) cytosolic ligand-activated transcription factors known as the AhR was first identified as a sensor of environmental xenobiotics, including dioxin-like compounds and polycyclic PAHs (Mandal et al., 2023; Bustani et al., 2024). When it binds, it moves to the nucleus, dimerizes with ARNT, and triggers the expression of detoxifying enzymes, especially those belonging to the cytochrome P450 family (e.g., CYP1A1).

When AhR is activated, it increases the activity of enzymes involved in phase I xenobiotic metabolism, such as CYP1A1, which converts substrates such as benzo[a]pyrene into more polar intermediates (Kyoreva et al., 2021). Fascinatingly, CYP1A1 activity can shield DNA in vivo by blocking the systemic absorption of harmful substances, particularly in the gut mucosa (Kyoreva et al., 2021).

Research on AhR-knockout (AhR^–/–) mice shows significant abnormalities in the architecture of seminiferous tubules, including sloughing of elongated spermatids, multinucleated giant cells, and vacuolization. In addition, these mice show decreased fertilization ability, decreased expression of oxidative stress regulators (e.g., Nrf2, Sod2), and downregulated genes crucial to spermatogenesis (e.g., Testin, Magea4) (Hansen et al., 2014; Sahib et al., 2025).

Exposure to xenobiotic pollutants such as dioxin (TCDD) and PAHs (such as benzo[a]pyrene) can affect male fertility because AhR activation causes oxidative stress, hormonal abnormalities, and DNA damage in spermatozoa and germ cells.

In addition to external toxins, endogenous metabolites (such as tryptophan derivatives) and substances originating from the gut can also activate AhR. For example, in a mouse model of cholestasis, decreased levels of tryptophan metabolites (natural AhR ligands) were associated with impaired testosterone production (Wang et al., 2024). An AhR agonist (ITE) supplement increased spermatogenesis and restored testosterone production, demonstrating the physiological significance of the receptor in preserving male fertility. Natural antagonists of AhR activation, such as lycopene, curcumin, and resveratrol, may lessen the detrimental effects of environmental AhR agonists on reproductive health (Merisalu et al., 2007; Ghazi Eid et al., 2020; Abdulla and Al-Okaily, 2022; Bustani and Alghetaa, 2025a,b; Bustani et al., 2025).

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Conclusion

The AhR is a key mediator of environmental, metabolic, and reproductive health. It mediates xenobiotic metabolism, immune response, and endocrinological effects and can therefore affect both obesity and male fertility. Aberrant AhR activity can negatively influence metabolic functioning, endocrine balance, and reproductive status through the pathway of environmental toxins, inflammation, and/or genetic contributions. Dosage modulation of AhR activity can re-establish homeostasis, reduce disease risk, and enhance overall reproductive health. Understanding how AhR influences various functions will be crucial in the development of prevention and therapeutic options. The limitations of this manuscript presented by a lack of a sufficient number of studies that link AhR, obesity, and male infertility. From this limitation, this manuscript recommends that interested researchers conduct topical research on the physiological roles of AhR in obesity and male infertility pathogenicity.

Acknowledgments

The authors would like to thank Dr. Amira Mohammed for her help in editing the manuscript.

Conflict of interest

The authors declare no conflicts of interest related to the contents of this manuscript.

Funding

None.

Authors’ contribution

The HA designed the article outline. MK drafted the manuscript according to the outline. HA and MK have approved the current version of the manuscript.

Data availability

Not applicable.

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