I cannot have control over what I am unable to name.

Jorge Bucay.

Since the Industrial Revolution and especially after World War II, the environment has been heavily polluted with industrial waste and products, vehicle exhaust and numerous human-made chemicals used in agriculture, animal husbandry and aquaculture. Although the acute and chronic toxicity of various pollutants was known previously, a question arose in the late 1950s as whether certain compounds used in livestock farming could interact with the human endocrine system (Gassner et al., 1958). In 1960s and 1970s, ecologists observed several poorly understood phenomena. Egg hatching failure was reported in some bird populations inhabiting North American lakes, reproductive disorders were observed in domesticated minks, and premature births were reported in sea lions (Gilbertson and Reynolds, 1972; Aulerich et al., 1973; DeLong et al., 1973). Furthermore, endocrine disruption has been intensively studied since the early 1990s, revealing that these pollutants can have unpredictable and widespread effects on both human and animal health (Schug et al., 2016). Some pioneering studies set the stage for research into endocrine disruption and deserve mention. In 1992, Carlsen et al. (1992) reported a decline in semen quality in humans over the prior 50 years and connected these results with increased pollution in the period studied. One year later, Sharpe and Sakkbeak (1993) listed several compounds with oestrogenic activity and linked them to human reproductive and developmental disorders. In the same year, Colborn et al. (1993) reviewed studies that described endocrine-disrupting effects in several wildlife species and started to use the term endocrine-disrupting chemicals (EDCs) (even though “wildlife” refers to undomesticated animals and uncultivated plant species, in this article we use the term only for undomesticated animals). In addition, Guillette et al. (1994) reported a population decline and feminization of male alligators in a contaminated lake in Florida. Furthermore, an increased incidence of some developmental disorders such as hypospadias and cryptorchidism was observed in human newborns (Paulozzi, 1999). These studies raise questions about the broader effects of EDCs on wildlife and humans. In the following years, research focused on the identification of EDCs, their potency, and their interactions with the regulatory mechanisms in animal and human bodies. These aspects, with a particular focus on wild mammals, are also addressed in the present paper. The historical insight into the research of endocrine disruption is well documented in the review by Schug et al. (2016).

Building decades of research demonstrating the widespread and multi-level impacts of EDCs, recent studies have increasingly focused on epigenetic mechanisms by which these chemicals influence gene expression and developmental programming (Herráez et al., 2023). Attention has also shifted towards transgenerational effects, revealing that EDC exposure can affect not only directly exposed individuals but also subsequent generations (Dias et al., 2025). Beyond classical reproductive outcomes, current research investigates broader health impacts, including metabolic, neurological, and cancer-related effects (Ahn and Jeung, 2023). Methodologically, there is a move towards integrative approaches, addressing mixture effects, and long-term environmental monitoring (Boahen et al., 2025). There is also a growing emphasis on translating scientific findings into policy and mitigation strategies, highlighting the need to link mechanistic understanding with actionable interventions to reduce environmental and human exposure to EDCs (Hilz and Gore, 2023).

EDCs are defined by Endocrine Society as an exogenous chemical, or mixture of chemicals, that can interfere with any aspect of hormone action (Zoeller et al., 2012; Schug et al., 2016). These xenobiotics are mainly of anthropogenic origin and occur in various forms. Many substances, including pesticides and their metabolites, plasticizers, various industrial pollutants, pharmaceutical residues and cosmetic ingredients, are on the list of EDCs (The ED Lists, 2022). Owing to their widespread presence and strong persistence in the environment, EDCs can affect a wide range of organisms. For example, wild animals are exposed to a mixture of different EDCs, even if the ecosystem to which they belong is not directly contaminated by the nearest industrial plants, traffic, agricultural land or landfills. From the point of origin or deposition, EDCs can spread widely in the environment via the atmosphere and water. Importantly, EDCs, even when generated on land, not only have serious impacts on terrestrial ecosystems but also cause damage to the aquatic environment (Teng et al., 2012; Johnson et al., 2013; McKinney et al., 2015; Brown et al., 2018; Butnariu, 2022).

Wild mammals play vital roles in ecosystems and contribute not only to ecosystem stability and biodiversity but also to key ecological processes such as nutrient cycling, seed dispersal, and trophic regulation (Lacher et al., 2019). By controlling prey populations, influencing vegetation dynamics, and serving as prey for higher predators, wild mammals help maintain ecological balance and resilience (Sinclair, 2003). They are also linked to human nutrition: some species have served as ancestors of domesticated animals, while others have traditionally been hunted as game, highlighting their dual ecological and socio-economic importance (Bennett et al., 2007). Endocrine disruption in these species can affect metabolism, reproduction, behaviours, and development, including fetal growth, and may decrease fertility through reduced sperm counts or disrupted oestrous cycle (Colborn et al., 1993; Guillette et al., 1994; Tyler et al., 1998; Lister and Van Der Kraak, 2001; Snoj et al., 2013; Graceli et al., 2020) and thus affect population dynamics, food web and ecosystems. As many EDCs have a long half-life, they tend to accumulate in soil and subsequently in plants, thereby exposing herbivores, and even more carnivores and scavengers to these compounds through the food web. This process, where the contaminant concentration increases at progressively higher levels of the food web, is known as biomagnification and is characteristic of both terrestrial and aquatic environments (Figure 1).

In light of mention facts, this overview explores the multifaceted drivers of endocrine disruption in wild mammals, with a particular focus on key anthropogenic and environmental factors contributing to hormonal imbalances. By elucidating these dynamics, we aim to improve understanding of the long-term implications for the health of wild mammals, identify gaps in current knowledge, and support the development of effective strategies to mitigate the harmful effects of EDCs. Ultimately, these goals will contribute to environmental sustainability and the preservation of biodiversity in the long term.

In animals and humans, the endocrine system includes hormones acting as signalling molecules, hormone receptors in target cells and genes and enzymes involved in hormone synthesis and metabolism. Once released, hormones bind to specific receptors, triggering specific responses within target cells. Proper endocrine function relies on precise homeostatic regulation. However, endocrine homeostasis can be disrupted by both internal and external factors (Bartkowiak-Wieczorek et al., 2024). Among external factors, EDCs represent a major class of xenobiotics capable of interfering with hormonal signalling, synthesis, metabolism, and receptor binding, thereby leading to endocrine dysfunction.

EDCs can affect the endocrine system at every step of endocrine activity, as shown in Figure 2. For example, these substances can affect the transcription of genes encoding peptide and protein hormones or enzymes involved in the synthesis of thyroid, steroid or other hormones. EDCs can also bind to hormone receptors as agonists or antagonists, interfering with endocrine signalling and disrupting the proper activity of endocrine axes and feedback loops; induce conformational changes in the tertiary structure of receptors; or affect the recruitment of cofactors, which are critical for ligand‒receptor transcriptional regulation and the modulation of target gene expression (Djordjevic et al., 2020; Marlatt et al., 2022). Some EDCs can induce or suppress enzymatic activity involved in hormone metabolism by interacting with regulatory receptors or directly inhibiting metabolic enzymes including cytochrome P450 and key steroidogenic enzymes (Mikamo et al., 2003). These mechanisms can alter hormone degradation and the clearance rate thereby significantly affecting the half-life and bioavailability of endogenous hormones (Balaguer et al., 2019). In addition, some EDCs have pleiotropic effects and can interact with several steps of endocrine activity (hormone synthesis and distribution, receptor binding, and hormone metabolism) and influence several endocrine signalling pathways (Shanle and Xu, 2011). EDCs also have tissue-specific effects depending on tissue receptor expression and the expression of intracellular kinases (Guvvala et al., 2020). Kinases play a role in the endocrine system by mediating hormone signal transduction, regulating metabolism, controlling transcription, and influencing cellular growth and differentiation (Robinson-White and Stratakis, 2002). When EDCs bind to cell receptors, they either activate or block the receptor, leading to phosphorylation of intracellular kinases. Subsequently, transcription factors and metabolic enzymes are activated or inactivated, resulting in tissue-specific responses (Lee et al., 2013). The expression of kinases determines the cell’s response to EDCs; active kinases produce strong effects, while low kinase expression leads to weaker responses. These effects depend on the type and density of hormone receptors in the tissue as well as the expression and activity of intracellular kinases (Robinson-White and Stratakis, 2002).

In general, the impact of EDCs on the mammalian organism results from the following mechanisms.

Stimulation of endogenous hormone biosynthesis (e.g., EDC-induced upregulation of aromatase (CYP19) expression leading to increased oestrogen synthesis; atrazine indirectly enhancing aromatase activity).

These mechanisms are not mutually exclusive; many EDCs can act through multiple pathways simultaneously, and their effects can vary across tissues and species depending on receptor expression, kinase activity, and metabolic context (Combarnous and Nguyen, 2019).

There is extensive data on the acceptable daily intake of EDCs. Table 1 presents data on the prevention of chronic toxicity caused by certain xenobiotics as reported in some publications and documents from global organizations. Generally, to protect against chronic toxicity, levels below maximum residue limits (MRLs) are considered acceptable for public health. However, EDCs can disrupt endocrine homeostasis at concentrations much lower than the MRLs (Vandenberg et al., 2012). In addition, wildlife feed is uncontrolled, and other non-oral routes of exposure to EDCs can also occur. In some environments, many different xenobiotics may be present, causing unpredictable toxic and endocrine-disrupting effects.

Under physiological conditions, endocrine system homeostasis is maintained by very low concentrations (nmol or pmol) of hormones. Therefore, even a small amount of exogenous compounds can affect endocrine homeostasis. In addition, the dose-response effect of EDCs is not fully understood. It has been reported that low doses of EDCs can affect the endocrine system more than high doses. This is most likely because low doses up-regulate hormone receptors and thus provide a more intensive effect, while high doses cause receptor downregulation (Vandenberg et al., 2012).

However, we believe that exposure to high doses of EDCs can cause other subchronic, subacute, or acute toxic effects (such as cytotoxicity and oxidative stress resulting in nephrotoxic, hepatotoxic, haematotoxic, neurotoxic, etc .,… effects) which alter animals’ health, welfare, and behaviour and therefore mask or modify their impact on the endocrine system. Endocrine effects occur after a longer period and cannot be observed in animals with other, more evident health disturbances. In addition, developing foetuses appear to be more susceptible to the action of EDCs than adults (Marlatt et al., 2022), especially during hormonally regulated sexual differentiation and brain development (Ottinger and vom Saal, 2002), which is important from a conservation perspective.

Given the evolutionary conservation of the endocrine system, all vertebrates and even some invertebrates are susceptible to the effects of EDCs. Since EDCs are now found in nearly all ecosystems, the true scale and impact of endocrine disruption on wild mammals are probably much greater than current research has revealed or documented.

Most of the EDCs are persistent organic pollutants (POPs) and residues of pharmaceuticals. Although natural substances such as phytoestrogens, certain mycotoxins, and steroid metabolites in urine and faeces are not considered as EDCs, they might have endocrine-disrupting effects (Demaegdt et al., 2016; Darbre, 2022; Wojnarowski et al., 2021).

In this overview, we have described some EDCs found in the environment and their effects on organisms. Although endocrine disruption is a well-known phenomenon reported in many research articles, the subject is vast and somewhat mysterious and constantly raises new questions. Studies of endocrine disruption are carried out as retrospective, observational and epidemiological studies of the changes occurring in ecosystems, more in the context of pollution monitoring, and in laboratories under controlled conditions (Rier et al., 2001; Hallanger et al., 2012; Ishiniwa et al., 2013; Encarnação et al., 2019). Additionally, in vitro and in vivo laboratory dose‒response studies and mechanistic studies have revealed the effects of individual EDCs and mixtures of EDCs and explained the mechanisms of their action. However, wildlife is typically exposed to complex mixtures of EDCs, the compositions of which can vary over time and across locations. Therefore, exposure to EDCs and their effects are unpredictable, even if they are expected. The discrepancies between controlled laboratory conditions and uncontrolled environmental conditions highlight the importance of observational research in wildlife conservation and management. Here, we highlight some gaps in knowledge about EDCs and suggest research opportunities to elucidate some of the links between the presence of EDCs and changes in ecosystems (Table 5). This knowledge will enable action to reduce the impact of EDCs on the environment.

First, many observational and controlled laboratory studies have shown the effects of some EDCs on fish and reptiles (Guilette et al., 1994; Zhao et al., 2015; Shi et al., 2019; Shi et al., 2020; LaLone et al., 2012; Ankley et al., 2018), but there are few data on their effects in wild mammals (Tables 2 and 3). We would like to emphasize that this does not mean that there is no influence on wild mammals but rather that the effect on mammals has not yet been verified or confirmed. Many observational studies of aquatic ecosystems dedicate limited attention to mammals, largely because mammal populations are often too small to provide statistically meaningful data or because no clear signs of threat or decline are detected in those species.

Furthermore, wildlife is usually exposed to a mixture of EDCs in their natural environment and determining the harmful effects of each individual compound is difficult. In response to EDC exposure, differences between species have been observed (Jocsak et al., 2019). As already described, these differences result from the position of the species in the food web and thus from exposure to EDCs. However, there are also important differences in the toxicokinetic properties of EDCs and other xenobiotics between fish and mammals. The differences occur in the intensity of absorption, the distribution of individual EDCs in the body, and the intensity of xenobiotic metabolism and excretion. Additionally, the toxicodynamic properties should also be considered when different classes of vertebrates are compared. This also applies to the interaction between EDCs and receptors and the dose‒response relationship, where interspecies variations are to be expected.

Research on endocrine disruption is difficult to conduct for ethical reasons, as experiments on the effects of EDCs on target animals are not acceptable. Some nonmammalian animal models such as zebrafish and zebrafish embryos are generally used for laboratory testing of the disrupting effects of individual EDCs. Considering legislation and ethical reasons, experiments can be performed on laboratory rodents only if no other animal model is available, which is why researchers often do not use laboratory mice or rats. Therefore, basic information on the effects of EDCs on organisms under laboratory conditions can be obtained from embryos and adult zebrafish; however, for more detailed studies of the effects of EDCs on mammals, mammalian models should be included in research. We consider the lack of information on many EDCs that may affect the mammalian endocrine system to be an important gap in the knowledge of endocrine disorders. In silico methods and emerging digital technologies, such as artificial intelligence, can be used to assess the effects of multiple EDCs on individual animals and animal populations. These results may reflect real-world ecological conditions; however, observational studies should also be conducted continuously to validate and complement such findings.

Although EDCs can affect almost all endocrine signalling pathways, public attention has focused mainly on the disruption of oestrogen signalling. At the population level, disruption of reproductive homeostasis leads to a decline in reproduction and endangers the survival of the species. For this reason, understanding and good knowledge of EDC activities is an important prerequisite as part of the conservation strategy. As mentioned previously, many EDCs affect oestrogenic signalling. This raised the question of why several chemically different substances can bind the same receptor. Oestrogen receptors (a and b subtypes) do not seem to be highly specific. They belong to the family of nuclear receptors that contain a ligand-binding domain and a DNA-binding domain involved in the transcriptional activation of target genes (Gajadeera and Hanson, 2019). For the cellular effects of oestrogens, these receptors require several coregulatory proteins and peptides (Heldring et al., 2007), which can also be targets of EDCs. Since numerous compounds can interact with oestrogen receptors, it appears that oestrogen receptors, particularly their ligand-binding domain, are less specific for binding various ligands than other nuclear receptors (e.g., thyroid or glucocorticoid). We have not found an explanation for this statement in the literature, but interspecies variations in oestrogen receptors are well documented (Asnake et al., 2019). 17β-oestradiol, a physiological endogenous ligand with the same chemical structure in all vertebrates, can bind oestrogen receptors and thus provides physiological effects. However, the effects of different xenobiotics on the organism can vary between species and depend on the species-specific receptor expression and differences in receptor structure (Jocsak et al., 2019; Baker, 2022). This could explain why EDCs have more or less intense adverse effects in different species living in the same environment. This topic has not been sufficiently studied to draw conclusions and requires further investigation. Moreover, interspecies differences in the oestrogenic effects of EDCs are expected, as there are well-documented interspecies variations in the activation of PPARγ which is also a target of EDCs. PPARγ acts as a receptor regulating fatty acids, prostaglandins, and leukotrienes, and decreases the transcription of oestrogen-dependent genes (Garoche et al., 2021). To address this issue, the binding affinity of EDCs to oestrogen receptors across different species should be investigated using in silico modelling and receptor-based assays. At the ecosystem level, if endocrine-disruptive effects are observed in one species, a detailed examination of other species inhabiting the same environment should also be conducted.

Another little-known effect of EDCs on wildlife populations is their epigenetic effect. EDCs can directly influence oogenesis and spermatogenesis, and the germ cells themselves via DNA methylation and epimutation. Thus, many compounds can cause transgenerational epigenetic effects (Montjean et al., 2022; Dutta et al., 2023; Herráez et al., 2023), meaning that changes in gene expression induced by EDC exposure in one generation can persist for multiple subsequent generations, even when those descendants have not been directly exposed to the chemical.

For example, studies in rodents have demonstrated that prenatal exposure to the fungicide vinclozolin during the critical window of foetal gonadal development induces altered DNA methylation in the male germline, resulting in reproductive and health disorders that persist to at least the F3 generation (Skinner and Anway, 2007; Skinner et al., 2008). Moreover, ancestral vinclozolin exposure has been associated with changes in brain transcriptomes, stress responses, mate preference, and behaviour in descendants, highlighting the profound and heritable nature of these epigenetic changes (Crews et al., 2012). The long-term consequences of such epigenetic effects are difficult to predict, but they likely impact the ecological balance by reducing population fitness, altering developmental trajectories, and increasing heritable susceptibility to disease, with serious implications for wildlife conservation. Future studies should focus on explaining the persistence and reversibility of EDC-induced epigenetic changes across generations in wild populations using integrated genomic, endocrine, and ecological approaches. Long term monitoring combined with epigenetic markers should be established to evaluate how EDCs impacts the population structure and adaptation to certain contaminants.

Several endangered species face increasing threats from climate change, human activities, illegal hunting, habitat loss, and ecological imbalances. Some of these species inhabit environments contaminated with EDCs. To what extent, if at all, do EDCs contribute to their extinction? In some well-documented cases, population declines have been linked to EDCs, such as alligators in Lake Apopka, Florida (Guilette et al., 1994), but it is not entirely clear, for example, what is happening to the smallest harbour porpoise, the vaquita (Phocoena sinus), in the Gulf of California. The species is highly endangered because of illegal fishing with gillnets used to catch totoaba fish. The number of vaquita decreased from approximately 600 in 1997 to approximately 10 in 2024. (Jaramillo-Legorreta et al., 2019). Moreover, several EDCs have been reported to be present in the tissues of different species from the Gulf of California (Stack et al., 2022). The main reason for the extinction of the vaquita is known, but EDCs can severely affect the reproduction of marine animals (Reijnders, 1986; Murphy et al., 2010; Murphy et al., 2015; Hoydal, 2017), which may be an additional reason for the decline in the vaquita population. This is just one example from the list of endangered species. Using this example, we suggest that conservation strategies should consider the impact of EDCs, even if it appears that the problem lies elsewhere.

Wildlife is also exposed to natural hormones that are excreted from other animals via urine and faeces and contaminate the environment or are present in the environment as phytoestrogens and mycotoxins. Omnivores and carnivores in particular are also exposed to natural hormones present in the tissues of their prey. All animal tissues and excreta contain natural hormones (Snoj and Majdič, 2018; Palacios et al., 2020). Some wild omnivores and carnivores also forage in urban areas, near human dwellings, in garbage and dumps where they can find discarded meat and dairy products. The amounts of hormones in animal tissue vary greatly and depend on the animal’s sex, age, reproductive status, endocrine disorders, health status and stress responses. Since carnivores have been exposed to hormones from other animals throughout their evolution, the question arises as to whether these exogenous hormones play a physiological role in carnivorous species. This question remains largely unexplored in the current literature. Interestingly, some studies report that the levels of sex hormones and glucocorticoids are generally greater in carnivores than in herbivores, potentially reflecting specific physiological or ecological adaptations (Dixit et al., 1985; Seal et al., 1985; Felska-Blaszczyk et al., 2012; Karaer et al., 2023). We are aware that many environmental and endogenous factors influence blood hormone concentrations and that we cannot conclude that sex hormone and glucocorticoid levels are relatively high in carnivores in every comparable situation. Unfortunately, the proportion of exogenous hormones in the total concentration is not known. However, it is certainly greater in carnivores than in herbivores, which is why the possible physiological role of the exogenous hormones as mentioned above should be investigated in further studies. A study in carnivore species in which animal feed is supplemented with isotope-labelled exogenous hormones would partially elucidate this question.

Given the diverse effects of EDCs across species and their complex interactions within ecosystems, adopting a One Health perspective offers a crucial framework for understanding their broader implications. Future studies should aim to link EDC presence in wildlife not only to observable ecological changes but also to mechanistic outcomes that may affect domestic animals and human health. Integrating observational field studies, laboratory-based mechanistic research, and ecotoxicological monitoring will enable assessment of how EDCs propagate through trophic networks, influence reproductive and endocrine systems, and potentially increase disease susceptibility across species. By combining data from wildlife populations, livestock, and humans, researchers can elucidate shared pathways of endocrine disruption, including receptor-mediated and epigenetic mechanisms, and determine how these effects contribute to population-level outcomes. Such an integrative approach would support the development of evidence-based conservation strategies and public health policies to mitigate the environmental and health impacts of EDCs, highlighting the interconnectedness of ecosystems, wildlife, domestic animal, and human health.

Finally, we would like to emphasize that although is well known from historical experience that several synthetic compounds (or their metabolites) exhibit endocrine-disrupting effects–often recognized decades after their introduction to the market–there is currently no single, universal rule requiring all new chemicals to be screened for endocrine-disrupting activity before entering the market. Regulatory requirements vary depending on the type of substance and its intended use. In the European Union, regulations such as REACH (European Parliament and Council, 2006) and the EU Biocidal Products Regulation (European Parliament and Council, 2012) provide frameworks for the identification and control of substances with endocrine-disrupting properties, but the obligation to test a new compound depends on its classification, hazard profile, and product category. Similarly, other sectors such as cosmetics and pharmaceuticals follow separate directives, and not all new compounds are automatically subjected to EDC-specific testing. Considering the One Health approach, these facts highlight the need for implementation of global testing standards for chemicals in order to minimize environmental hazards.

In conclusion, this overview highlights key gaps in our understanding of endocrine disruption and suggests important topics for further investigation. While the disrupting effects of pesticides and industrial contaminants are well documented, the potential endocrine-disrupting role of pharmaceutical residues remains poorly understood. Similarly, natural compounds with endocrine activity (e.g., phytoestrogens, mycotoxins, cyanotoxins, and hormones excreted by animals) may also contribute to endocrine disruption, either independently or through interactions with other EDCs. Species-specific endocrine responses to EDC exposure are also a topic that requires a multidisciplinary research approach. Furthermore, the epigenetic role of different EDCs needs to be considered. The endocrine effects of mixtures of several EDCs are also important challenges for researchers, as the ratio of EDCs in the mixture is constantly changing.

Notably, if industrial and agricultural activities continue to release pollutants, ecosystems face increasing threats, underscoring the need for effective pollution control. Renewable energy may help reduce endocrine disruption in wild mammals by lowering reliance on fossil fuels and decreasing the release of harmful pollutants. This transition could lower the risk of endocrine-related health issues in ecosystems and promote the sustainable use of natural resources, preserving biodiversity. Similarly, adopting organic farming methods, reducing pesticide use, and promoting biological control can help protect ecosystems. Sustainable farming practices, efficient water management, and advanced technologies such as sensors can further reduce environmental contamination. Stricter regulations on toxic chemicals in agriculture may also help protect wildlife and improve overall ecosystem health. These strategies collectively contribute to reducing endocrine disruption and promoting environmental sustainability. Ultimately, every individual can contribute to the preservation of biodiversity by making small lifestyle changes. We urge everyone to focus on using renewable energy sources, using less plastic, buying food and other goods wisely and disposing of waste properly. In this way, with little effort, we can reduce—although, of course, not stop—the pollution of the environment with substances whose effects on ecosystems often remain unknown. From this point of view, it is necessary to disseminate knowledge about endocrine disruption, which can be achieved through publications on social media. In addition to political actions such as international environmental agreements, everyone can contribute to reducing the number of unknown negative effects on the environment, leading to fewer cases where, in the words of Jorge Bucay as quoted in our introduction ‘we cannot have control over that we are unable to name’.