Role of the endocannabinoid system in teleostei fish physiology: implications for reproduction and environmental interactions

Papel do sistema endocanabinoide na fisiologia dos peixes teleostei: implicações para a reprodução e interações ambientais

Abstract

The endocannabinoid system (ECS) represents a vital neurotransmitter network in vertebrates, regulating neurogenesis, cognition, lipid metabolism, and immune activity. One of the vertebrates used for studying the endocannabinoid system is fish, specifically the species Danio rerio, known as zebrafish, due to its similarities with vertebrate development. This review explores the ECS in teleost fishes, emphasising its role in reproductive physiology and its interaction with environmental pollutants. Although extensive research has elucidated the ECS in mammals, limited data exist for teleosts. The literature revealed that endocannabinoids in Teleostei have an essential role in lipid metabolism, with effects revealed mainly in the brain and liver involving gene expression processes that regulate these metabolic pathways. Another key role of the endocannabinoid system in fish is in reproduction, as lipid metabolism directly influences gonadal function. Environmental pollutants, such as bisphenol A and phthalates, also disrupt ECS function, impairing reproductive performance and metabolic stability. These findings underscore the need for further studies on teleost-specific ECS mechanisms and their implications for aquatic ecosystems.

Keywords:
endocannabinoid system; lipid metabolism; neurotransmitters; teleostei fishes; reproduction; environmental pollutants

Resumo

O sistema endocanabinoide (SEC) representa uma rede vital de neurotransmissores nos vertebrados, regulando a neurogênese, a cognição, o metabolismo lipídico e a atividade imunitária. Um dos vertebrados utilizados para estudar o sistema endocanabinoide são os peixes, especificamente a espécie Danio rerio, conhecido como peixe-zebra devido às suas semelhanças com o desenvolvimento dos vertebrados. Esta revisão explora o SEC em peixes teleósteos, enfatizando o seu papel na fisiologia reprodutiva e a sua interação com os poluentes ambientais. Embora extensas pesquisas tenham elucidado o SEC em mamíferos, existem dados limitados para os teleósteos. A literatura revelou que os endocanabinoides em Teleostei têm um papel essencial no metabolismo lipídico, com efeitos revelados principalmente no cérebro e no fígado envolvendo processos de expressão genética que regulam essas vias metabólicas. Outro papel importante do sistema endocanabinoide nos peixes é na atividade reprodutiva porque sua atividade no metabolismo lipídico afeta a atividade das gônadas. Os poluentes ambientais, como o bisfenol A e os ftalatos, também perturbam a função do SEC, prejudicando o desempenho reprodutivo e a estabilidade metabólica. Essas descobertas sublinham a necessidade de mais estudos sobre os mecanismos SEC específicos dos teleósteos e as suas implicações para os ecossistemas aquáticos.

Palavras-chave:
sistema endocanabinóide; metabolismo lipídico; neurotransmissores; peixes teleostei; reprodução; poluentes ambientais

1. Introduction

In the early 1990s, molecular cloning and characterisation of two G protein-coupled cannabinoid receptors, CB1 and CB2, led to the discovery in animal tissues of an essential endogenous signalling system known as the endocannabinoid system (Wang and Ueda, 2009). The endocannabinoid system is made up of its endogenous ligands (the endocannabinoids), their molecular targets (cannabinoid receptors), synthesis and degradation enzymes proteins, as well as transporter proteins (Cottone et al. 2013b; Amoako et al. 2014), that support and control the manifold actions of endocannabinoids, both in the central nervous system and at the periphery (Maccarrone et al. 2010; Maccarrone et al., 2015). Endocannabinoids are endogenous bioactive lipids synthesised from phospholipids capable of binding to cannabinoid receptors. The most extensively investigated are those derived from arachidonic acid, arachidonoyl ethanolamine (anandamide-AEA), and 2-arachidonoyl glycerol (2-AG) (Lewis et al., 2012), which are degraded by specific enzymes and control various biological processes by attaching to specific G protein-coupled receptors, for example, CB1 and CB2 cannabinoid receptors. AEA and 2-AG can also interact with other receptors, such as proliferator-activated receptors (PPAR- α and γ). Moreover, AEA interacts with GPR55 and the Transient Receptor Potential Vanilloid Type 1 (TRPV1) (Ambrosini et al., 2010; Campos et al., 2017).

The endocannabinoids best characterised (eCBs) are Anandamide (AEA) and 2-arachidonoylglycerol (2-AG) (Lewis et al., 2012). Both are endowed with distinct biological activities in the central nervous system (CNS) and in the periphery, where they mimic several actions of THC. The eCBs act principally through cannabinoid receptors, which are members of the rhodopsin family of G protein-coupled seven-transmembrane spanning receptors and include type-1 and type-2 cannabinoid receptors (CB1 and CB2) as the best-characterised targets of eCBs (Lewis et al., 2012). CB1 has been found mainly in the central nervous system, the ovary, testis, vas deferens, and other peripheral endocrine and neurological tissues. CB2 has been found mainly in peripheral and immune cells but also neuronal cells, reproductive cells, and tissues

For example, endocannabinoid substances are known to play a key role in human sperm viability, wherein the activity of different elements of the endocannabinoid system (SEC) can be useful to assess sperm function and, therefore, to monitor sperm quality potentially (Maccarrone, 2013). Others include the effect of the cannabinoid receptor type 1 (CB1) in regulating energy metabolism and motility in human spermatozoa and that of transient potential receptor vanilloid type 1 (TRPV1) channels in controlling its fertilising capacity. Surprisingly, both receptors share a common natural agonist, which is the endocannabinoid (eCB) N-arachidonoylethanolamine (anandamide, AEA); in contrast, another important eCB such as 2-arachidonoylglycerol (2-AG) can activate the CB1 receptor but is ineffective at TRPV1 receptors (Maccarrone, 2013).

Du Plessis et al. (2015) state that both CB1 and CB2 receptors are present in sperm. CB1 has been localised to the plasma membrane of the acrosomal region, midpiece, and tail of the sperm. At the same time, CB2 receptors are located mainly in the postacrosomal post-acrosomal region and the midpiece and tail. Transporters and enzymes responsible for endocannabinoid synthesis and hydrolysis have also been identified in the male gametes of various species, including humans.

Several reports have pointed to these lipid mediators as critical signals, along with sex hormones and cytokines, in various aspects of animal reproduction (Battista et al., 2012b). Endocannabinoids (ECS) have been identified in cells and reproductive organs of non-mammalian vertebrates, such as teleosts and amphibians (Ricci et al., 2007; Battista et al., 2012a).

The identification of endocannabinoids, such as anandamide (AEA) and 2-arachidonoylglycerol (2-AG) (Krug 2nd and Clark 2015) in the tissues of reproductive cells of invertebrates, vertebrates and mammals, the key role played by these endogenous compounds along the evolutionary axis stands out (Battista et al., 2012b). In humans, AEA affects motility, sperm mitochondrial activity, capacitation, and acrosomal exocytosis (Rossato, 2008; Cacciola et al., 2010). Endocannabinoid concentrations such as oleoylethanolamide (OEA) and palmitoylethanolamide (PEA) present in human seminal plasma are crucial for the maintenance of sperm motility, its viability, and its mitochondrial activity under in vitro conditions (Amoako et al., 2014). While there is a large quantity of information on the mammalian endocannabinoid system, little data has been reported on bony fish (Cottone et al., 2013a).

In bony fish, the essential components of the cannabinergic system, that is, the CB1 receptors, the fatty acid amide hydrolase (FAAH) (Krug 2nd et al., 2018), and the degrading enzyme of the AEA, were found and characterised in the gonads. CB1 mRNA expression was indeed detected in the gonads of Pelvicachromis pulcher, Carassius auratus, Sparus aurata and Solea solea (Cardinaletti et al., 2010). Furthermore, in the forebrain of Pelvicachromis pulcher, close contiguity and co-distribution of immunoreactive innervations to CB1-LI and GnRH-LI- were observed, supporting a possible relationship between the endocannabinoid system and GnRH morphofunctional type (Meccariello et al., 2008), the key molecule in Gonadotropic regulation of all vertebrates. These results suggest that there may be a CB1-mediated interaction between endogenous cannabinoids and gonadotrophin-releasing hormone-producing neurons in the forebrain of bony fish (Cardinaletti et al., 2010).

This review aims to elucidate the endocannabinoid system's role in teleost fish, especially in the reproductive system.

The overall conceptual framework summarising the interaction between environmental stressors, the endocannabinoid system, metabolic regulation, and reproductive outcomes in teleost fish is presented in Figure 1.

Figure 1
Conceptual framework of the role of the endocannabinoid system in linking environmental stressors to reproductive effects in teleost fish.

2. Material and Methods

A literature search was conducted for studies published between 1980 and the present, from scientific databases (Scopus; Google Scholar). The on-line bibliographic database of the Universidad de la Frontera and Universidad Católica de Temuco, Chile, mainly Wiley, Springerlink, Nature Publishing group, Science Direct and Scielo, were used. Keywords included “endocannabinoid system”, “teleost fish”, “reproduction”, and “environmental pollutants”. Studies were selected based on their relevance to the topic and on the inclusion of experimental or review data related to teleost physiology.

3. Results and Discussion

3.1. The endocannabinoid system in Teleost fish

The endocannabinoid system (ECS) consists of several components, among which are specific seven transmembranedomain receptors (e.g., CB1 and CB2 cannabinoid receptors), their exogenous (e.g., Δ9-THC) and endogenous ligands (i.e., anandamide (AEA) and 2-arachidonoylglycerol (2-AG)), and several biosynthetic and degradative enzymes (Cottone et al., 2013a, b). CB1 and CB2 receptors are present not only in mammals but also in almost all classes of vertebrates and urochordates and cephalochordates, but not in the nonchordate invertebrate phyla (Elphick, 2007, 2012). Nevertheless, enzymes involved in the biosynthesis/inactivation of the endocannabinoids occur throughout the animal kingdom. The fact that the ECS has a rather widespread phylogenetic allocation points to a fundamental modulatory role of endocannabinoids in managing central and peripheral activities, such as neural development, neurotransmission, and appetite regulation. Hormone release and action, immunomodulation, cardiovascular and respiratory functions, bony formation, and, notably, reproduction (Cottone et al., 2013b).

Although a significant amount of data on the mammalian endocannabinoid system does exist, little information has been reported on bony fish. Due to its similarities with vertebrate development, the existing data is related to the fact that bony fish are used as models to carry out studies on the endocannabinoid system, specifically the specie D. rerio known as zebrafish. The endocannabinoid system is a crucial component of the neurotransmitter system in vertebrates and involves many physiological responses such as neurogenesis, cognition, and immune activity (Krug 2nd et al., 2018).

The endocannabinoid system has an essential role as a neurotransmitter, and it regulates behaviour and physiological processes such as drug abuse, anxiety, pain, cognition, neurogenesis and immune activity because these involve organs of the nervous system (Demin et al., 2018; Forner-Piquer et al., 2018a, b). One of the main effects of the endocannabinoid system is related to sensitivity to temperature, anxiolysis, rewarding properties, hypoactivity and analgesia (Demin et al., 2018). For the study of the endocannabinoid systems in vertebrates, the first study was done with pufferfish Fugu rucripres that described its effects on neuroreceptor morphology, remarking on its similarity with human neuroreceptors (Yamaguchi et al., 1996). Other detailed studies were done with C. auratus (Cottone et al., 2005, 2008; Valenti et al., 2005), which denoted effects on brain activity that finally affect reproductive activity (Cottone et al., 2005; 2008) food intake (Valenti et al., 2005). The recent studies are based on zebrafish D. rerio (Cottone et al., 2008, 2013b; Forner-Piquer et al., 2017, 2018a, b) because this species has similarities with humans for studies in biological psychiatry and neurobiology (Demin et al., 2018).

The studies about the endocannabinoid system in fishes began in the last decade and described the presence of these in zebrafish, and one of the recent studies in this species revealed its role in behaviour (Demin et al., 2018; Forner-Piquer et al., 2017). Also, the comparative studies based on experiments among embryonic development, juveniles and adults in zebrafish revealed that the cannabinoid system has 60.7% similarity with Mus musculus and 60.9% with Homo sapiens (Demin et al., 2018).

Based on experimental evidence among zebrafish life cycle revealed that the endocannabinoid system is the main regulator of physiological responses in zebrafish, in neurobiological topics, that is expressed in reproduction activity, feeding preferences, and hypoactivity, which was similar to the results observed for mammalians such as M. musculus and H. sapiens (Demin et al., 2018). One crucial topic related to the endocannabinoid system in zebrafish is associated with its relation with environmental pollution derived from plastic debris (Martella et al., 2016), which generates alterations in the endocannabinoid system, specifically, an inverse relation between di-isononylphthalate (derived from plastics) with endocannabinoids system, that affect the composition of liver and brain (Forner-Piquer et al., 2017). The ingestion of these tiny plastic particles can cause different metabolic abnormalities in the fish body, like oxidative and physiological stress, reduced enzymatic activities, false hunger satisfaction, low growth rate, and reproductive complications (Mallik et al., 2021).

Moreover, Hatef et al. (2013) report that environmental contaminants (EC) such as bisphenol A interfere with neuroendocrine and endocrine functions of the hypothalamus, pituitary, and testes in fish captured from polluted areas or following in vivo exposure to endocrine-disrupting chemicals can lead to diminished reproductive parameters including sperm production and spermatozoa motility kinetics and fertilising ability. However, the mechanisms by which ECs, including endocrine-disrupting chemicals, decrease sperm production and impact spermatozoa motility kinetics and fertilising ability are mainly unknown.

Similar results have been reported for bisphenol A with the endocannabinoid system, which generates lipid vacuoles in the liver and brain that affect food intake (Martella et al., 2016; Forner-Piquer et al., 2018c) and reproductive activity (Ruggeri et al., 2007; Forner-Piquer et al., 2018a). Remarkably, the results obtained for Forner-Piquer et al. (2017) and Forner-Piquer et al. (2018a) are based on experiments done with one-year adult specimens exposed to different treatments for determining endocannabinoid activity. In contrast, the results of Demin et al. (2018) are based on studies of embryonic development, juveniles, and adult specimens.

One important fish species used to study the endocannabinoid system is gilthead sea bream (S. aurata), an important resource for fisheries and intensive European aquaculture (Forner-Piquer et al., 2019a). The published studies revealed the association between environmental pollution due to plastics that affect the endocannabinoid system and their consequences in physiological responses (Maradonna et al., 2014; Forner-Piquer et al., 2018b, 2019a, b). The results reported for S. aurata about the inverse association between di-isononylphthalate (derived from plastics) with endocannabinoids system are similar to results observed for zebrafish (Martella et al., 2016; Forner-Piquer et al., 2017, 2018a, 2018b).

In detailed studies, it was reported that the presence of di-isononylphthalate affects the endocannabinoid system inversely, which, in consequence, affects the lipid metabolism, which in consequence affects the physiological responses such as growth and reproduction (Forner-Piquer et al., 2018b). Another significant result remarked is the effect of the di-isononylphthalate effect, which generates a domino effect generating decreasing activity of the endocannabinoid system, with a consequence in the lipid metabolism, affecting the endocrine activity in males that finally would generate decreasing in sperm motility (Forner-Piquer et al., 2019a) these alterations in males, are specific changes in sexual hormone receptors (Forner-Piquer et al., 2019b). Similar results were reported for S. aurata females, where the endocrine alterations would generate specific gene expression changes and sexual hormone receptors that finally affect ovule generation (Maradonna et al., 2014; Forner-Piquer et al., 2019a).

The results obtained for this scenario suggest the design of management procedures to decrease the effect of plastic pollutant exposure in fish, specifically S. aurata, due to their importance as an aquaculture resource in Europe (Forner-Piquer et al., 2018b). Based on the results of Forner-Piquer et al. (2019a, b) about the role of plastic pollution in the endocannabinoid system and its final consequences in reproductive activity.

3.2. the endocannabinoid system in the reproduction of Teleost fish

The ECS is a lipid-based signalling system that regulates many physiological functions, including reproduction, in mammalian and non-mammalian species (Maccarrone, 2009; Meccariello et al., 2014a). Among bony fish, the ECS has been described in the gonads of D. rerio (Forner-Piquer et al., 2018a), S. aurata (Ruggeri et al., 2007) and C. auratus (Cottone et al., 2013b), among other species. The ECS has a key role in the control of reproduction. Centrally, at the hypothalamic level, the ECS negatively modulates the GnRH release, whereas, in the pituitary, ECS is related to the levels of pituitary hormones (i.e., LH), and a cross-talk among these hormones and the endocannabinoids exists. Locally, in the gonads, a balanced endocannabinoid tone is necessary for the correct progression of spermatogenesis and a successful reproductive outcome. However, some reproductive dysfunctionalities are reported when the ECS is not correctly acting (Battista et al., 2012a; Meccariello et al., 2014b).

The ECS is formed by the receptors (CB1 and CB2), the endocannabinoids N-arachidonoylethanolamide (anandamide or AEA) and 2-arachidonoyglycerol (2-AG), and the endocannabinoid-like mediators (or AEA-related compounds) such as N-palmitoyl-ethanolamide (PEA) and N-oleoyl-ethanolamide (OEA). In addition to the receptors and ligands, the ECS includes a list of enzymes that regulate endocannabinoid levels (Rapino et al., 2014).

The gametogenesis is regulated by the hypothalamus-pituitary-gonadal axis corresponding to the hormonal axis, gonadotropin-releasing hormone (GnRH)-gonadotropins-steroids, in both males and females. The main target of GnRH is the gonadotrope cells located in the adenohypophysis. These, in turn, release two gonadotropin hormones, the follicle-stimulating hormone (FSH) and the luteinising hormone (LH), that, through the central circulation, reach gonads to regulate gametogenesis via the synthesis of steroid hormones. It is now accepted that further than non-steroid factors support germ cell progression via intragonadal action (Meccariello et al., 2014b). Shahjahan et al. (2014) reported that the endocannabinoid system in mammalian and non-mammalian vertebrates regulates hypothalamic GnRH neurons and pituitary LH cells directly and indirectly.

The relation between sex steroids and endocannabinoids is well-established. For instance, the FAAH promoter possesses imperfect estrogen response elements (EREs). Thus, FAAH activity and faith mRNA expression can be modulated by E2, in agreement with the increased FAAH activity reported as concomitant with E2 levels but not with faith gene expression. FAAH is one of the main enzymes for AEA catabolism. Yet, the levels of AEA were not decreased by the DiNP LOW treatment as expected due to the up-regulation of FAAH activity. The N-acylethanolamines PEA and OEA, having similar metabolic pathways as AEA, may act as alternative substrates for FAAH and this probably may explain their down-regulation. Regarding 2-AG, the reduced levels found following the treatments do not match the transcriptional concentrations of the biosynthetic enzyme dagla and the catabolic abdh12 (Forner-Piquer et al., 2018c). However, FAAH can also inactivate 2-AG and possibly affect the final levels of 2-AG in testes (Forner-Piquer et al., 2019b).

The regulation of endocannabinoid tone during the different phases of reproduction is crucial in numerous species. However, little information is available regarding the role of AEA tone during oocyte maturation. It is tempting to hypothesise that the AEA produced from the granulosa cells of growing follicles play a role in controlling oocyte maturation in mammals. In the aquatic model, Xenopus laevis, AEA is associated with K+ current suppression in oocytes (stages V or VI) and, consequently, with the inhibition of oocyte responsiveness to gonadotropin and progesterone required for final meiotic maturation. Forner-Piquer et al. (2020) assumed that the augmented AEA levels (10 μg BPA/L) may contribute to the signals inducing vitellogenesis but impair final oocyte maturation. However, little information is available on the functional role of AEA in the teleost ovary, although Forner-Piquer et al. (2020) demonstrate that 10 μg BPA/L is associated with the down-regulation of oocyte maturation signals in female zebrafish. Furthermore, in rodents and humans, the hormonal environment regulates the endocannabinoid production in the gonads. Forner-Piquer et al. (2020) observed a decrease in ovarian OEA in the BPA-exposed groups of zebrafish. OEA, an AEA-related compound, may be involved in mammalian follicular maturation. OEA also plays a role as an anti-inflammatory signal molecule, suggesting an inflammatory process in the BPA ovaries. BPA-induced inflammatory responses have already been reported in other species.

About male ECS, a reduction in AEA and 2-AG levels was observed following exposure to 20 μg BPA/L in the testis. In male mouse germ cell cultures, the highest levels of 2-AG were observed in spermatogonia, and such levels progressively decreased in spermatocytes and spermatids. The latter study is consistent with our findings where the lowest levels of 2-AG were found in the BPA group associated with the reduced area of spermatogonia, and CB2 signalling through 2-AG contributes to the normal progression of the spermatogenesis (Forner-Piquer et al., 2020).

Forner-Piquer et al. (2020) found a decrease in testicular AEA following BPA exposure, while Grimaldi et al. (2009) demonstrated a constant AEA concentration during spermatogenesis (spermatogonia, spermatocyte and spermatids).

Forner-Piquer et al. (2020) said that two factors may explain this finding: 1) the observed reduction in AEA was the result of reduced spermatogonia induced by BPA, and/or 2) an increased activity of FAAH (AEA catabolic enzyme) induced by the estrogen-like activity of BPA, reduced the AEA levels, even if based on the results, they cannot distinguish between these two possibilities. Similar results were obtained following E2 treatment in mouse Sertoli cells. Very few studies have quantified testicular cell types, and to date, there are no published observations on the effects of environmental doses of BPA on testicular cell numbers. In zebrafish, higher doses of BPA exclusively reduced the proportion of spermatocytes. In male gonads, BPA can induce alterations in miRNAs and epigenetic markers, such as hyperacetylation of histones and DNA hypermethylation; these changes can also be inherited by the offspring and compromise early embryo development depending on the dose and the exposure window. The assessment obtained by Forner-Piquer et al. (2020) and others in different species suggested that exposure to BPA might be associated with low fertility in male zebrafish and reduced numbers of spermatogonia and spermatogenesis.

4. Conclusions and Perspectives

In the case of teleosts fish, it has been reported how the endocannabinoid system would play a role in reproduction. Still, it has not been specifically reported if it is present in seminal plasma or if endocannabinoid substances play a role in activating or inactivating fish sperm motility. The expression and distribution of the endocannabinoid receptors CB1 and CB2 in the sperm cell have not been studied as it has been done in mammals, especially in humans (Agirregoitia et al., 2010; Zufferey et al., 2020).

Acknowledgements

The authors acknowledge funding from FONDECYT REGULAR 1240197 and the doctoral scholarship ANID 21191555 for funding this study. Thanks to S.T. and M.I. for your comments.

Data Availability Statement

Not applicable.

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Edited by

• Editor:
  Takako Matsumura Tundisi

Publication Dates

• Publication in this collection
  01 June 2026
• Date of issue
  2026

History

• Received
  18 Jan 2025
• Accepted
  09 Mar 2026