Assessing the health risks of environmentally relevant concentrations of fluoride and phenanthrene: Neurobehavioral toxicity induced in zebrafish through disruption of the microbiome-gut-brain axis and suppression of Wnt/B-catenin signalling.

Abstract

Full-text study online at
https://www.sciencedirect.com/science/article/pii/S2590182625002371

Highlights

Combined exposure of fluoride or/and phenanthrene induces neurobehavioral toxicity in zebrafish.
This toxicity may be due to the disruption of the steady state of the 5-HT system in the microbiota-gut-brain axis.
Fluoride or/and phenanthrene inhibits Wnt/B-catenin signalling, causing inflammation and apoptosis.Fluoride d phenanthrene inhibits Wnt/B-catenin signaling, causing inflammation and apoptosis.
Combined exposure to ecotoxicological risks for zebrafish is greater than the exposure to a single poison.

Chronic exposure to fluoride and phenanthrene is recognized as a significant risk factor for neurobehavioral toxicity, and the gut-brain axis has been identified as a key mechanism in the development of anxiety behaviors following prolonged toxic insult. Nevertheless, the connections between gut microbiota disruption, serotonin (5-HT) production, and neurobehavioral toxicity induced by long-term co-exposure to fluoride and phenanthrene remain unclear. In this study, co-exposure model of phenanthrene and fluoride at environmentally relevant concentrations was established in zebrafish. Through comparative database analysis, anxiety behavior tests, 16S rRNA sequencing, metabolomics, qPCR, Western blotting, ELISA, flow cytometry, comet assay, histological analysis, and immunohistochemistry, the neurotoxic effects of fluoride or/and phenanthrene were investigated. In this study, neurobehavioral toxicity was observed in zebrafish following co-exposure to environmentally relevant concentrations of fluoride and phenanthrene, characterized by diminished swimming capacity and heightened anxiety behavior. The toxic mechanism was mediated through disruption of the microbiome–gut–brain axis homeostasis and suppression of the Wnt/B-catenin signalling pathway. Specifically, co-exposure decreased intestinal synthesis of 5-HT and impaired the blood–brain barrier. As the intestine serves as the primary source of 5-HT, its impairment (histopathological alterations, gut microbiota dysbiosis and metabolomics) led to dysregulation of the 5-HT system. Histopathological analysis of brain tissue revealed synaptic loss, nuclear pyknosis, and the presence of apoptotic bodies. Investigations into the molecular mechanisms indicated that fluoride or/and phenanthrene inhibited Wnt signalling, promoted B-catenin degradation, and induced neurological dysfunction, as evidenced by reductions in SYP and MAP2, which subsequently activated pro-apoptotic genes (Bax, Caspase9, and Caspase3) and inflammatory responses (decreased IL-10, elevated NF-_kB, IL-6, TNF-a, and cleaved IL-1B). These alterations ultimately contributed to neurobehavioral deficits. Collectively, these findings indicate that fluoride and phenanthrene induce anxiety behavior and neurotoxicity, associated with perturbations in 5-HT metabolism, gut microbiota composition, oxidative stress, apoptosis, and neuroinflammation.

Graphical abstract

Keywords

Fluoride; Phenanthrene; Zebrafish neurotoxicity; Microbial-gut-brain axis; 5-Hydroxytryptamine

EXCERPTS

1. Introduction

The extensive use of fluoride has led to its accumulation in groundwater and ecosystems [1]. Fluorosis is known to cause more severe damage to the nervous system [2]. Research has demonstrated that increased urinary fluoride levels in women during early and mid-pregnancy—when fluoride concentrations in drinking water exceed 2 mg/L—are significantly associated with lower intelligence scores in children [3]. Xu et al. tracked the distribution of fluoride in human brain tissue and observed its tendency to accumulate preferentially in regions involved in learning and memory. They found that it tends to accumulate in areas of the brain associated with learning and memory [4]. The researchers found that in the brain tissues of pregnant mice and their offspring exposed to fluoride, neuronal processes shrank and broke, and the hippocampal neuronal structure was damaged, resulting in abnormal neurological function and a significant decline in learning and memory abilities [3]. Studies on fish subjected to lifelong fluoride exposure have demonstrated that fluoride adversely affects neurodevelopment, causing cognitive and behavioral abnormalities [5]. Mukhopadhyay et al. observed that zebrafish exposed to 15 ppm fluoride exhibited behavioral alterations, including restlessness, sporadic vertical swimming, frequent tail fin movements, and elevated reactive oxygen species production [6]. Nevertheless, research on the toxicity and underlying mechanisms of fluoride at environmentally relevant concentrations remains limited.

Environmental monitoring has confirmed the presence of polycyclic aromatic hydrocarbons (PAHs) in the atmosphere, aquatic systems, and human tissues. Phenanthrene, a tricyclic polycyclic aromatic hydrocarbon, is one of the most frequently detected and abundant PAHs in aquatic environments. Reported concentrations of phenanthrene include 435 ng/L in the subsurface water of Daya Bay, in China [7], 101.82 ng/L in the surface water of Macao [8], and 24.4 ng/L in the surface water of Maluan Bay [9]. Phenanthrene has been shown to significantly affect reproductive-related morphology, behavior, and physiological functions in fish. Studies indicate that phenanthrene can accumulate in fish tissues and trigger the activation of antioxidant enzymes [10]. In recent years, the neurotoxicity of phenanthrene has drawn increasing attention [11]. Similar to most lipophilic compounds, phenanthrene and its metabolites can cross the blood-brain barrier and exert toxic effects on the central nervous system, thereby impairing brain development and function. Animal experiments have revealed that phenanthrene can induce various neurological impairments, including reduced locomotor activity, neuromuscular dysfunction, physiological and autonomic abnormalities, as well as diminished responsiveness to sensory stimuli, ultimately leading to nervous system damage [12]. However, the precise mechanism through which PAHs cause neurotoxicity remains unclear. The contamination of aquatic ecosystems by fluoride and phenanthrene is becoming increasingly severe. There is an urgent need to assess the ecological risks posed by fluoride and phenanthrene in aquatic environments, as well as their ecotoxicological effects on aquatic organisms.

Zebrafish (Danio rerio) is widely regarded as a standard biological model in neurobehavioral toxicity assessment [13]. It is endorsed by both the International Organization for Standardization (ISO) and the Organization for Economic Co-operation and Development (OECD) as a key model organism, frequently utilized for evaluating the toxicity of pollutants and chemicals in aquatic environments [13]. The gut–brain axis is characterized as a bidirectional communication network connecting the intestine and the brain [14]. Gut microbiota can modulate pituitary adrenal (HPA) axis activity through various pathways. Elevated levels of glucocorticoid receptors (GR) and corticotropin-releasing hormone (CRH) may induce excessive stress responses, which directly impair brain function [15]. 5-Hydroxytryptamine (5-HT), also known as serotonin, is a neurotransmitter in animals. Over 90 % is produced in the gut, where it regulates intestinal motility, secretion, immunity, and maintains the intestinal barrier function [16]. As a core signalling molecule in the gut-brain axis, it transmits information through neural, endocrine, and immune systems, playing a crucial role in maintaining neural and intestinal homeostasis and regulating disease [17]. 5-HT is one of the key components of the gut-brain axis. 5-HTP produced by gut microbiota or enterocytes can cross the blood-brain barrier into the brain, where it is converted into 5-HT to exert its effects [18]. Deficiencies in 5-HT are associated with symptoms such as anxiety and restlessness. Reduced 5-HT levels may also negatively impact cognitive and memory processes [18]. Research indicates that in adults with inflammatory bowel disease, early life experiences can disrupt postnatal development of the gut microbiota. This disruption may cause an imbalance in gut-brain communication, ultimately influencing brain development and behavio [19]. As functional and anatomical structures, the intestinal barrier and the blood-brain barrier serve as key interfaces between the gut and the brain. They restrict the passage of microorganisms and toxins while permitting nutrients to enter the circulatory system and reach the brain [20]. Impairment of the blood-brain barrier can result in neurological damage by interfering with metabolites derived from the gut microbiota [21]. Therefore, maintaining a balanced microbial community is essential for the homeostasis of the gut-brain axis [21]. However, the relationship between gut microbiota and 5-HT, along with the mechanisms through which it influences neural function, remains inadequately explored.

The Wnt/B-catenin signalling pathway plays a critical role in neural development and function [22]. Upon activation, this pathway promotes the repair and regeneration of nerve cells, facilitates functional recovery, and helps maintain nervous system stability [23]. Additionally, the Wnt/B-catenin signalling pathway is essential for blood-brain barrier integrity [24]. Research has demonstrated its close association with both the formation and maintenance of the blood-brain barrier [24]. As a barrier that protects the central nervous system from external harmful substances, the proper functioning of the blood-brain barrier is essential for neurological health. Inhibition of the Wnt/B-catenin signalling pathway has been shown to result in blood-brain barrier impairment and neurological dysfunction [23]. This signalling pathway is also strongly associated with inflammation and apoptosis [25]. Within the nervous system, apoptosis serves a critical function in preserving developmental balance and eliminating compromised cells [26]. Research indicates that both activation and inhibition of the Wnt/B-catenin signalling pathway can influence neuronal apoptosis by modulating cell cycle progression, survival mechanisms, and death pathways [25]. Under pathological conditions, including neurodegenerative diseases, dysregulation of this pathway may trigger excessive neuronal apoptosis and inflammation, thereby accelerating disease progression [25].

This study utilized zebrafish as a model organism to evaluate the combined toxicity of fluoride and phenanthrene using systems toxicology approaches. After 28 days of exposure, behavioral assessments were conducted to determine the influence of different treatments on neurobehavior. Comprehensive analyses were carried out on the expression level and functional roles of 5-HT in the gut-brain axis. Intestinal health status, compositional changes in the gut microbiota, and metabolic profile variations in zebrafish were also assessed. By examining oxidative stress, DNA damage, apoptosis, inflammatory responses, and related gene expression as key endpoints, this study offers an enhanced understanding of the mechanistic basis of combined toxicity. Advancing research in this field will facilitate a thorough understanding of the neurotoxic effects exerted by these substances in the environment and contribute to the formulation of effective mitigation strategies.

4. Discussion

Although extensive research has been conducted on the mechanisms underlying fluoride toxicity, studies addressing PAHs toxicity and its combined exposure with fluoride in aquatic organisms remain scarce. Analysis of existing data indicates that fluoride and PAHs co-occur geographically and both exhibit neurotoxic effects. It has been demonstrated that fluoride exposure leads to impairments in spatial learning and memory, induces anxiety behaviors, and decreases neuronal populations in the brain, confirming its neurotoxic impact in mice [37]. In zebrafish, Fluoride exposure was found to suppress locomotor activity, increase anxiety levels, and disrupt vascular innervated neuronal patterning [38]. Fluoride exposure significantly contributes to neurotoxicity in zebrafish [39]. Phenanthrene exposure was found to reduce neonatal neurons and increase apoptotic brain cells in zebrafish larvae, thereby impairing central nervous system development [40,41]. These studies collectively confirm the individual neurotoxic effects of fluoride and phenanthrene. However, research remains limited regarding the impacts of combined exposure to environmental levels of fluoride and phenanthrene on neurological function and behavior in aquatic organisms. Our findings demonstrate that prolonged exposure to environmentally relevant concentrations of fluoride and phenanthrene induces anxiety behaviors in zebrafish. These behavioral alterations are closely linked to disruption of the gut-brain axis, reduced 5-HT synthesis, and activation of the Wnt/B-catenin signalling pathway, ultimately triggering mechanisms involving inflammation, cell death, and neurotoxicity.

Neurobehavioral assessment is widely utilized for evaluating the toxic effects of various substances on the nervous systems of animals [42]. The open field test is commonly applied to measure anxiety behavior in zebrafish [43]. Changes in behavioral activity represent the most intuitive and sensitive indicators for assessing the influence of water pollutants on fish [44,45]. In the present study, exposure to phenanthrene or fluoride alone significantly impaired the locomotor performance of zebrafish. Moreover, zebrafish in the MIX group exhibited a more substantial reduction in locomotor capacity. They heightened anxiety behavior relative to the other three groups, which was reflected by prolonged duration in the bottom zone or immobility. This finding is consistent with earlier research, Vignet et al. demonstrated that zebrafish exposed to phenanthrene displayed depressive symptoms, reduced feeding frequency, and elevated surface respiration rates [46]. Comparable outcomes, such as diminished locomotor activity, heightened anxiety behavior, and deficits in learning and memory, were observed in fish treated with fluoride solutions [47]. In summary, combined exposure to fluoride and phenanthrene led to a more pronounced reduction in locomotor performance and more severe anxiety responses in zebrafish relative to single exposures to either compound alone.

Anxious behavior is critically governed by the regulation of neural functions and neurotransmission, a process that encompasses a variety of molecular components [48]. As a key signalling molecule, 5-HT acts within both the enteric and central nervous systems, modulating the development, maintenance, and function of the gut–brain axis across the life cycle [49]. Moreover, elevated concentrations of the monoamine neurotransmitter 5-HT in the brain are closely correlated with learning, memory, emotional regulation, and social behavio [50]. In the present study, fluoride and phenanthrene exposure led to a reduction in 5-HT levels in zebrafish. Concurrently, significant suppression was observed in the expression of tph1a, tph1b, and tph2 genes associated with TPH, the key rate-limiting enzyme for intestinal 5-HT synthesis. Among brain 5-HT receptors, htr1aa, htr1ab, and htr2c were activated, while htr1b and htr4 were inhibited. Previous studies have shown that blocking or knocking down Htr1a, Htr1b, or Htr2c enhances 5-HT release, which in turn improves behavioral outcomes such as locomotor activity, anxiety, and learning and memory in mice [51]. Additionally, activation of htr1b or htr4 has been found to reverse learning and memory deficits in neuroendocrine mouse models of anxiety or depression [52]. Therefore, the observed upregulation of Htr1a and Htr2c, along with the downregulation of Htr1b and Htr4, further confirms that anxiety behavior in zebrafish results from abnormal 5-HT levels.

5-HT is primarily synthesized through tryptophan metabolism, a key pathway involved in regulating intestinal function and neurotransmitter activity [53]. Gut microbiota and their metabolites can modulate 5-HT synthesis by influencing tryptophan metabolism [54]. It has been demonstrated that exposure to fluoride and phenanthrene leads to structural damage and dysbiosis of the gut microbiota in the intestine. Notably, diminished 5-HT levels were associated with a reduced Firmicutes population in the gut, along with increased abundances of Proteobacteria, Actinobacteria, Patescibacteria, and Chloroflexi. Metabolomic analyses further indicated that fluoride and phenanthrene exposure significantly lowered concentrations of key tryptophan metabolites involved in 5-HT synthesis, such as 5-hydroxy-L-tryptophan, 3-indolebutyric acid, serine tryptophan, and melatonin glucuronide, while substantially increasing kynurenine levels. These alterations indicate that fluoride and phenanthrene exposure increase the abundance of potentially pathogenic bacteria within the Proteobacteria, Patescibacteria, and Chloroflexi phylum. This shift redirects tryptophan metabolism toward the kynurenine pathway, while suppressing both the 5-HT and indole pathways. Such metabolic dysregulation may contribute to diminished 5-HT synthesis and associated neurobehavioral impairments, including anxiety behavior, cognitive deficits, and neurodevelopmental disorders [55].

Beyond metabolic alterations, this study investigated the role of the gut–brain axis in mediating the neurotoxicity induced by combined fluoride and phenanthrene exposure. As a bidirectional communication pathway between the gut and the brain, the gut–brain axis is essential for regulating mood, cognition, and immune responses [56]. The gut microbiota modulates brain neurofunction and behavior through the regulation of tryptophan metabolism and 5-HT synthesis [54]. This finding is consistent with our observation that impaired gut barrier function not only aggravates dysbiosis but also facilitates the translocation of harmful substances and pathogens to the brain, thereby exacerbating neurotoxicity. Oxidative stress is widely acknowledged as a key biomarker of such toxic effects and has been correlated with 5-HT levels and related alterations [57]. In this study, zebrafish exposed to environmentally relevant concentrations of fluoride or/and phenanthrene showed decreased synaptic and neuronal densities in the brain and significant oxidative stress. Suppressed AChE activity and DNA damage may contribute to neuronal injury [58]. Our results are consistent with these reports. Based on these findings, co-exposure to fluoride and phenanthrene may induce neurological impairment in zebrafish,

Decreased 5-HT levels may influence neurotoxicity by interfering with the Wnt/B-catenin signalling pathway [59]. The Wnt/B-catenin pathway, essential for neurodevelopment, neuroprotection, and blood-brain barrier (BBB) maintenance, is identified as a key target of fluoride and phenanthrene in the present study. Yu et al. reported that 5-HT activates Wnt/B-catenin signalling through the HTR7 receptor [60], while Zhu et al. demonstrated that 5-HT enhances this pathway to support cellular development [61]. Concurrently, studies on brain-related disorders have reported decreased or abnormal Wnt signalling (e.g., involving B-catenin and Wnt2) in models of stress and depression, which is accompanied by reduced 5-HT levels [62]. However, the underlying mechanism in the zebrafish brain remains unclear. We therefore propose that diminished 5-HT levels inhibit the Wnt/B-catenin signalling pathway. In this study, fluoride and phenanthrene exposure downregulated Wnt3a expression and promoted B-catenin degradation, thereby reducing B-catenin nuclear translocation and impairing synaptic plasticity. Decreased levels of SYP and MAP2 further supported these effects.

The Wnt/B-catenin signalling pathway is essential for blood-brain barrier development and regulates both its permeability and neurodevelopment [23]. The blood-brain barrier functions as a vital protective structure that controls substance transfer between the bloodstream and the central nervous system [63]. Fluoride is able to cross the blood-brain barrier via alterations in ion channels, leading to neurotoxicity [64]. Meanwhile, phenanthrene exposure modifies the expression and localization of tight junction proteins in brain endothelial cells, resulting in affected levels of tight junction proteins (Claudin-5, occludin, ZO-1, and ZO-2) and increased permeability of the blood-brain barrier [48]. The present study further demonstrated that exposure to environmental levels of fluoride or/and phenanthrene resulted in disruption of the blood-brain barrier in zebrafish brains. Meanwhile, inhibition of the Wnt/B-catenin signalling pathway is generally linked to apoptosis [49]. In contrast, inhibition of this pathway commonly promotes inflammation and apoptosis [50]. Suppression of B-catenin transcription and its downstream target genes results in decreased expression of Bcl-2 and IL-10, along with increased expression of pro-apoptotic proteins such as Caspase3 and Bax, as well as inflammatory mediators NF-_kB, IL-6, and TNF-a. These changes collectively lead to impaired cell proliferation, migration, and differentiation, endothelial dysfunction, and the promotion of both apoptosis and inflammation [50,65]. The findings of this study align with the aforementioned observations. It is suggested that fluoride or/and phenanthrene exposure suppresses the Wnt/B-catenin signalling pathway, thereby inducing inflammation, apoptosis, and neural injury.

5. Conclusion

This study reveals that fluoride and phenanthrene, at environmentally relevant concentrations, induce neurotoxicity and anxiety behaviors in zebrafish by disrupting the gut-brain axis homeostasis, reducing 5-HT synthesis, and inhibiting the Wnt/B-catenin signalling pathway. The findings indicate that combined contamination from fluoride and phenanthrene may cause severe neurotoxicity in aquatic organisms, compromising ecosystem health. It is recommended to strengthen environmental monitoring and management of fluoride and PAHs, develop practical ecological risk assessment and pollution control policies to protect aquatic ecosystems and human health.

Compliance with ethics requirements

All animal experiments were conducted in strict accordance with the ethical guidelines and regulations approved by the Institutional Animal Care and Use Committee of Northeast Forestry University, under protocol number 2024087. The study complied with the “Regulations on the Management of Laboratory Animals (2017) for the Care and Use of Laboratory Animals, and the ARRIVE guidelines.

CRediT authorship contribution statement

Hongmin Lu: Writing – review & editing, Writing – original draft, Visualization, Validation, Methodology, Investigation, Funding acquisition, Formal analysis, Conceptualization. Ruoqi Wang: Resources, Formal analysis, Conceptualization. Xin Zhang: Supervision, Formal analysis. Yuze Dong: Methodology, Formal analysis. Hao Liu: Visualization, Software. Yunfan Zhang: Methodology, Formal analysis. Chengxue Ma: Supervision, Project administration, Formal analysis, Data curation, Conceptualization. Mingwei Xing: Supervision, Resources, Project administration, Funding acquisition, Formal analysis, Data curation, Conceptualization.

Funding

This work was supported by the Fundamental Research Funds for the Central Universities (Grant No. 2572024AW11), and Science and Technology Research Capacity Enhancement Project for Hulun Lake Nature Reserve – Phase 2 Sub-project (HSZCS-C-F-220050).

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Appendix A. Supplementary data

Download: Download Word document (648KB)

References

[1]

L. Hou, H. Dong, E. Zhang, H. Lu, Y. Zhang, H. Zhao, M. Xing

A new insight into fluoride induces cardiotoxicity in chickens: involving the regulation of PERK/IRE1/ATF6 pathway and heat shock proteins

Toxicology, 501 (2024), Article 153688

View PDF View article View in Scopus Google Scholar
[2]

C. Ren, H.H. Li, C.Y. Zhang, X.C. Song

Effects of chronic fluorosis on the brain

Ecotoxicol. Environ. Saf., 244 (2022), Article 114021

View PDF View article View in Scopus Google Scholar
[3]

R. Green, B. Lanphear, R. Hornung, D. Flora, E.A. Martinez-Mier, R. Neufeld, P. Ayotte, G. Muckle, C. Till

Association between maternal fluoride exposure during pregnancy and IQ scores in offspring in Canada

JAMA Pediatr., 173 (10) (2019), pp. 940-948

Crossref View in Scopus Google Scholar
[4]

K. Xu, N. An, H. Huang, L. Duan, J. Ma, J. Ding, T. He, J. Zhu, Z. Li, X. Cheng, G. Zhou, Y. Ba

Fluoride exposure and intelligence in school-age children: evidence from different windows of exposure susceptibility

BMC Public Health, 20 (1) (2020), p. 1657

View in Scopus Google Scholar
[5]

Y. Zhang, P. Zhang, P. Yu, X. Shang, Y. Lu, Y. Li

Transcriptome analysis reveals the mechanism of fluorine exposure on memory loss of common carp

Environ. Pollut., 265 (Pt A) (2020), Article 114927

View PDF View article View in Scopus Google Scholar
[6]

S. Mukherjee, R. Bhattacharya, O. Sarkar, S. Islam, S.R. Biswas, A. Chattopadhyay

Gut microbiota perturbation and subsequent oxidative stress in gut and kidney tissues of zebrafish after individual and combined exposure to inorganic arsenic and fluoride

Sci. Total Environ., 957 (2024), Article 177519

View PDF View article View in Scopus Google Scholar
[7]

M.C. Deng, J. Li, F.R. Liang, M. Yi, X.M. Xu, J.P. Yuan, J. Peng, C.F. Wu, J.H. Wang

Isolation and characterization of a novel hydrocarbon-degrading bacterium Achromobacter sp. HZ01 from the crude oil-contaminated seawater at the Daya Bay, southern China

Mar Pollut Bull, vol. 83 (1) (2014), pp. 79-86

View PDF View article View in Scopus Google Scholar
[8]

Z. Huang, L. Jiang, W. Lu, C. Luo, M. Song

Elsholtzia splendens promotes phenanthrene and polychlorinated biphenyl degradation under cu stress through enrichment of microbial degraders

J. Hazard. Mater., 438 (2022), Article 129492

View PDF View article View in Scopus Google Scholar
[9]

D.W. Klump, H. Huasheng, C. Humphrey, W. Xinhong, S. Codi

Toxic contaminants and their biological effects in coastal waters of Xiamen, China. I. Organic pollutants in mussel and fish tissues

Mar. Pollut. Bull., 44 (8) (2002), pp. 752-760

Google Scholar
[10]

C. Lin, C. Cheng, S. Zhong, Q. Xie, Z. Lai, H. Li, Z. Guo, Y. Tan, G. Yang, C. Jing

Polycyclic aromatic hydrocarbons, biological aging, and antioxidant diet associations with cardiometabolic multimorbidity: mechanistic pathways and precision prevention strategies

Environ. Chem. Ecotoxicol., 7 (2025), pp. 1861-1870

View PDF View article View in Scopus Google Scholar
[11]

S. Zhao, C. Li, Z. Wang, S. Yu, Z. Shi

Industrial polycyclic aromatic hydrocarbons (PAHs) emissions embodied in domestic trade in China in 2012

J. Environ. Manag., 284 (2021), Article 111994

View PDF View article View in Scopus Google Scholar
[12]

Z. Liu, M. An, X. Geng, Z. Wu, W. Cai, J. Tang, K. Zhang, Z. Zhou

The scleractinian coral Pocillopora damicornis relies on neuroendocrine regulation to cope with polycyclic aromatic hydrocarbons under heat stress

Environ. Pollut., 316 (Pt 1) (2023), Article 120565

View PDF View article View in Scopus Google Scholar
[13]

X. Li, Q. Wang, C. Wang, Z. Yang, J. Wang, L. Zhu, D. Zhang, J. Wang

Ecotoxicological response of zebrafish liver (Danio rerio) induced by di-(2-ethylhexyl) phthalate

Ecol. Indic., 143 (2022), Article 109388

View PDF View article View in Scopus Google Scholar
[14]

J.W. Lee, K.A. Lee, I.H. Jang, K. Nam, S.H. Kim, M. Kyung, K.C. Cho, J.H. Lee, H. You, E.K. Kim, Y.H. Koh, H. Lee, J. Park, S.Y. Hwang, Y.W. Chung, C.M. Ryu, Y. Kwon, S.H. Roh, J.H. Ryu, W.J. Lee

Microbiome-emitted scents activate olfactory neuron-independent airway-gut-brain axis to promote host growth in Drosophila

Nat. Commun., 16 (1) (2025), p. 2199

View in Scopus Google Scholar
[15]

S. Lahiri, H. Kim, I. Garcia-Perez, M.M. Reza, K.A. Martin, P. Kundu, L.M. Cox, J. Selkrig, J.M. Posma, H. Zhang, P. Padmanabhan, C. Moret, B. Gulyás, M.J. Blaser, J. Auwerx, E. Holmes, J. Nicholson, W. Wahli, S. Pettersson

The gut microbiota influences skeletal muscle mass and function in mice

Sci. Transl. Med., 11 (502) (2019)

Google Scholar
[16]

G.J. Sanger

5-hydroxytryptamine and the gastrointestinal tract: where next?

Trends Pharmacol. Sci., 29 (9) (2008), pp. 465-471

View PDF View article View in Scopus Google Scholar
[17]

Y. Deng, M. Zhou, J. Wang, J. Yao, J. Yu, W. Liu, L. Wu, J. Wang, R. Gao

Involvement of the microbiota-gut-brain axis in chronic restraint stress: disturbances of the kynurenine metabolic pathway in both the gut and brain

Gut Microbes, 13 (1) (2021), pp. 1-16

View in Scopus Google Scholar
[18]

K.G. Margolis, J.F. Cryan, E.A. Mayer

The microbiota-gut-brain Axis: from motility to mood

Gastroenterology, 160 (5) (2021), pp. 1486-1501

View PDF View article View in Scopus Google Scholar
[19]

B. Barberio, M. Zamani, C.J. Black, E.V. Savarino, A.C. Ford

Prevalence of symptoms of anxiety and depression in patients with inflammatory bowel disease: a systematic review and meta-analysis

Lancet Gastroenterol. Hepatol., 6 (5) (2021), pp. 359-370

View PDF View article View in Scopus Google Scholar
[20]

E. Schneider, K.J. O’Riordan, G. Clarke, J.F. Cryan

Feeding gut microbes to nourish the brain: unravelling the diet-microbiota-gut-brain axis

Nat. Metab., 6 (8) (2024), pp. 1454-1478

Crossref View in Scopus Google Scholar
[21]

A. Parker, S. Fonseca, S.R. Carding

Gut microbes and metabolites as modulators of blood-brain barrier integrity and brain health

Gut Microbes, 11 (2) (2020), pp. 135-157

Crossref View in Scopus Google Scholar
[22]

X. Zhang, Y. Zhang, H. Lu, H. Zhen, Y. Zhang, Q. Wang, R. Wang, M. Liu, M. Xing

Dietary omega-3 alleviates copper-induced nephrotoxicity via suppression of NLRP3-mediated pyroptosis and lipid metabolism disorder in chickens

J. Nutr. Biochem., 147 (2025), Article 110086

View in Scopus Google Scholar
[23]

K. Boyé, L.H. Geraldo, J. Furtado, L. Pibouin-Fragner, M. Poulet, D. Kim, B. Nelson, Y. Xu, L. Jacob, N. Maissa, D. Agalliu, L. Claesson-Welsh, S.L. Ackerman, A. Eichmann

Endothelial Unc5B controls blood-brain barrier integrity

Nat. Commun., 13 (1) (2022), p. 1169

View in Scopus Google Scholar
[24]

Q. Wang, X. Huang, Y. Su, G. Yin, S. Wang, B. Yu, H. Li, J. Qi, H. Chen, W. Zeng, K. Zhang, A. Verkhratsky, J. Niu, C. Yi

Activation of Wnt/?-catenin pathway mitigates blood-brain barrier dysfunction in Alzheimer’s disease

Brain, 145 (12) (2022), pp. 4474-4488

Crossref View in Scopus Google Scholar
[25]

L. Chen, D. Tao, F. Yu, T. Wang, M. Qi, S. Xu

Cineole regulates Wnt/?-catenin pathway through Nrf2/keap1/ROS to inhibit bisphenol A-induced apoptosis, autophagy inhibition and immunosuppression of grass carp hepatocytes

Fish Shellfish Immunol., 131 (2022), pp. 30-41

View PDF View article Google Scholar
[26]

A. Xu, Y. Wang, D. Luo, Y. Xia, H. Xue, H. Yao, S. Li

By regulating the IP3R/GRP75/VDAC1 complex to restore mitochondrial dynamic balance, selenomethionine reduces lipopolysaccharide-induced neuronal apoptosis

J. Cell. Physiol., 239 (4) (2024), Article e31190

View in Scopus Google Scholar
[27]

X. Shi, T. Xu, M. Gao, Y. Bi, J. Wang, Y. Yin, S. Xu

Combined exposure of emamectin benzoate and microplastics induces tight junction disorder, immune disorder and inflammation in carp midgut via lysosome/ROS/ferroptosis pathway

Water Res., 257 (2024), Article 121660

View PDF View article View in Scopus Google Scholar
[28]

D. Araya, J. Podgorski, M. Kumi, P.A. Mainoo, M. Berg

Fluoride contamination of groundwater resources in Ghana: country-wide hazard modeling and estimated population at risk

Water Res., 212 (2022), Article 118083

View PDF View article View in Scopus Google Scholar
[29]

J. Podgorski, M. Berg

Global analysis and prediction of fluoride in groundwater

Nat. Commun., 13 (1) (2022), p. 4232

View in Scopus Google Scholar
[30]

Y. Wu, X. Zhang, J. Chen, J. Cao, C. Feng, Y. Luo, Y. Lin

Self-recovery study of fluoride-induced ferroptosis in the liver of zebrafish (Danio rerio)

Aquat. Toxicol., 251 (2022), Article 106275

View PDF View article Google Scholar
[31]

Y. Zhang, Y. Chen, K. Xu, L. Fang, J. Huang, S. Xia, Q. Zhou, L. Lv, C. Wang

Embryonic exposure to phenanthrene caused developmental defects of craniofacial cartilage in F1 larvae

Aquat. Toxicol., 243 (2022), Article 106080

View PDF View article View in Scopus Google Scholar
[32]

C. Zhang, Y. Li, H. Yu, T. Li, L. Ye, X. Zhang, C. Wang, P. Li, H. Ji, Q. Gao, S. Dong

Co-exposure of nanoplastics and arsenic causes neurotoxicity in zebrafish (Danio rerio) through disrupting homeostasis of microbiota-intestine-brain axis

Sci. Total Environ., 912 (2024), Article 169430

View PDF View article View in Scopus Google Scholar
[33]

B. Dong, Y. Jiang, B. Shi, Z. Zhang, Z. Zhang

Selenomethionine alleviates decabromodiphenyl ether-induced oxidative stress and ferroptosis via the NRF2/GPX4 pathway in the chicken brain

J. Hazard. Mater., 465 (2024), Article 133307

View PDF View article View in Scopus Google Scholar
[34]

H. Lu, Y. Zhang, X. Zhang, R. Wang, T. Guo, Q. Wang, H. Zhao, M. Xing

New insights into zinc alleviating renal toxicity of arsenic-exposed carp (Cyprinus carpio) through YAP-TFR/ROS signaling pathway

Pestic. Biochem. Physiol., 205 (2024), Article 106153

View PDF View article View in Scopus Google Scholar
[35]

D. Wang, K. Yin, Y. Zhang, H. Lu, L. Hou, H. Zhao, M. Xing

Novel pathways of fluoride-induced hepatotoxicity: P53-dependent ferroptosis induced by the SIRT1/FOXOs pathway and Nrf2/HO-1 pathway

Comp. Biochem. Physiol. C Toxicol. Pharmacol., 264 (2023), Article 109526

View PDF View article View in Scopus Google Scholar
[36]

P.F. Dong, T.B. Liu, K. Chen, D. Li, Y. Li, C.Y. Lian, Z.Y. Wang, L. Wang

Cadmium targeting transcription factor EB to inhibit autophagy-lysosome function contributes to acute kidney injury

J. Adv., 72 (6) (2024), pp. 653-669

Crossref View in Scopus Google Scholar
[37]

F.G. Siméon, J.H. Lee, C.L. Morse, I. Stukes, S.S. Zoghbi, L.S. Manly, J.S. Liow, R.L. Gladding, R.M. Dick, X. Yan, S. Taliani, B. Costa, C. Martini, F. Da Settimo, S. Castellano, R.B. Innis, V.W. Pike

Synthesis and screening in mice of fluorine-containing PET Radioligands for TSPO: discovery of a promising (18)F-labeled ligand

J. Med. Chem., 64 (22) (2021), pp. 16731-16745

View article Crossref View in Scopus Google Scholar
[38]

T.J. Hamilton, J. Krook, J. Szaszkiewicz, W. Burggren

Shoaling, boldness, anxiety-like behavior and locomotion in zebrafish (Danio rerio) are altered by acute benzo[a]pyrene exposure

Sci. Total Environ., 774 (2021), Article 145702

View PDF View article View in Scopus Google Scholar
[39]

L. Wu, J. Wang, H. Ye, Y. Yao, M. Hu, J. Cheng, L. Kong, W. Liu, F. Ge

Impacts of hexafluoropropylene oxide tetrameric acid (HFPO-TeA) on neurodevelopment and GABAergic signaling in zebrafish larvae

Ecotoxicol. Environ. Saf., 289 (2025), Article 117424

View PDF View article View in Scopus Google Scholar
[40]

W. Sun, M. Wang, J. Zhao, S. Zhao, W. Zhu, X. Wu, F. Li, W. Liu, Z. Wang, M. Gao, Y. Zhang, J. Xu, M. Zhang, Q. Wang, Z. Wen, J. Shen, W. Zhang, Z. Huang

Sulindac selectively induces autophagic apoptosis of GABAergic neurons and alters motor behaviour in zebrafish

Nat. Commun., 14 (1) (2023), p. 5351

View in Scopus Google Scholar
[41]

L.T. Watts, M.L. Rathinam, S. Schenker, G.I. Henderson

Astrocytes protect neurons from ethanol-induced oxidative stress and apoptotic death

J. Neurosci. Res., 80 (5) (2005), pp. 655-666

Crossref View in Scopus Google Scholar
[42]

L. Wang, F. Liu, Y. Fang, J. Ma, J. Wang, L. Qu, Q. Yang, W. Wu, L. Jin, D. Sun

Advances in zebrafish as a comprehensive model of mental disorders

Depress. Anxiety, 2023 (2023), p. 6663141

View in Scopus Google Scholar
[43]

G. Han, X. Li, G. Dong, L. Zhang, J. Gao, M. Li, L. Du

Phenotyping aquatic neurotoxicity induced by the artificial sweetener saccharin at sublethal concentration levels

J. Agric. Food Chem., 69 (7) (2021), pp. 2041-2050

Crossref Google Scholar
[44]

X. Li, G. Dong, G. Han, L. Du, M. Li

Zebrafish behavioral Phenomics links artificial sweetener aspartame to behavioral toxicity and neurotransmitter homeostasis

J. Agric. Food Chem., 69 (50) (2021), pp. 15393-15402

Crossref View in Scopus Google Scholar
[45]

J. Yi, Y. Ma, J. Ma, H. Yu, K. Zhang, L. Jin, Q. Yang, D. Sun, D. Wu

Rapid assessment of ocular toxicity from environmental contaminants based on visually mediated zebrafish behavior studies

Toxics, 11 (8) (2023)

Google Scholar
[46]

C. Vignet, V.M. Trenkel, A. Vouillarmet, G. Bricca, M.L. Bégout, X. Cousin

Changes in brain monoamines underlie Behavioural disruptions after zebrafish diet exposure to polycyclic aromatic hydrocarbons environmental mixtures

Int. J. Mol. Sci., 18 (3) (2017)

Google Scholar
[47]

H.M. Pickard, B.J. Ruyle, C.P. Thackray, A. Chovancova, C. Dassuncao, J. Becanova, S. Vojta, R. Lohmann, E.M. Sunderland

PFAS and precursor bioaccumulation in freshwater recreational fish: implications for fish advisories

Environ. Sci. Technol., 56 (22) (2022), pp. 15573-15583

Crossref View in Scopus Google Scholar
[48]

T. Teglas, A.C. Marcos, S. Torices, M. Toborek

Circadian control of polycyclic aromatic hydrocarbon-induced dysregulation of endothelial tight junctions and mitochondrial bioenergetics

Sci. Total Environ., 952 (2024), Article 175886

View PDF View article View in Scopus Google Scholar
[49]

R. An, X. Wang, L. Yang, J. Zhang, N. Wang, F. Xu, Y. Hou, H. Zhang, L. Zhang

Polystyrene microplastics cause granulosa cells apoptosis and fibrosis in ovary through oxidative stress in rats

Toxicology, 449 (2021), Article 152665

View PDF View article View in Scopus Google Scholar
[50]

Q. Ma, J. Yu, X. Zhang, X. Wu, G. Deng

Wnt/?-catenin signaling pathway-a versatile player in apoptosis and autophagy

Biochimie, 211 (2023), pp. 57-67

View PDF View article Crossref View in Scopus Google Scholar
[51]

J. Wallach, A.B. Cao, M.M. Calkins, A.J. Heim, J.K. Lanham, E.M. Bonniwell, J.J. Hennessey, H.A. Bock, E.I. Anderson, A.M. Sherwood, H. Morris, R. de Klein, A.K. Klein, B. Cuccurazzu, J. Gamrat, T. Fannana, R. Zauhar, A.L. Halberstadt, J.D. McCorvy

Identification of 5-HT(2A) receptor signaling pathways associated with psychedelic potential

Nat. Commun., 14 (1) (2023), p. 8221

View in Scopus Google Scholar
[52]

Q. Wang, H. Zhang, H. Xu, D. Guo, H. Shi, Y. Li, W. Zhang, Y. Gu

5-HTR3 and 5-HTR4 located on the mitochondrial membrane and functionally regulated mitochondrial functions

Sci. Rep., 6 (2016), p. 37336

View in Scopus Google Scholar
[53]

D. Liu, C.H. Liang, B. Huang, X. Zhuang, W. Cui, L. Yang, Y. Yang, Y. Zhang, X. Fu, X. Zhang, L. Du, W. Gu, X. Wang, C. Yin, R. Chai, B. Chu

Tryptophan metabolism acts as a new anti-Ferroptotic pathway to mediate tumor growth

Adv. Sci. (Weinh.), 10 (6) (2023), Article e2204006

Google Scholar
[54]

M. Zhou, Y. Fan, L. Xu, Z. Yu, S. Wang, H. Xu, J. Zhang, L. Zhang, W. Liu, L. Wu, J. Yu, H. Yao, J. Wang, R. Gao

Microbiome and tryptophan metabolomics analysis in adolescent depression: roles of the gut microbiota in the regulation of tryptophan-derived neurotransmitters and behaviors in human and mice

Microbiome, 11 (1) (2023), p. 145

View in Scopus Google Scholar
[55]

A. Agus, J. Planchais, H. Sokol

Gut microbiota regulation of tryptophan metabolism in health and disease

Cell Host Microbe, 23 (6) (2018), pp. 716-724

View PDF View article View in Scopus Google Scholar
[56]

M. Xu, D. Pan, J. Yi, Y. Zheng, G. Zeng, J. Lin, Y. Song, D. Sun, J. Chen

Gut-brain axis dysfunction mediates neurotoxicity of embryonic p-phenylenediamine exposure in zebrafish

J. Hazard. Mater., 497 (2025), Article 139650

View PDF View article View in Scopus Google Scholar
[57]

Q. He, J. Ma, P.K. Kalavagunta, L. Zhou, J. Zhu, J. Dong, O. Ahmad, Y. Du, L. Wei, J. Shang

HgS inhibits oxidative stress caused by hypoxia through regulation of 5-HT metabolism pathway

Int. J. Mol. Sci., 20 (6) (2019)

Google Scholar
[58]

A. Du, J. Xie, K. Guo, L. Yang, Y. Wan, Q. OuYang, X. Zhang, X. Niu, L. Lu, J. Wu, X. Zhang

A novel role for synaptic acetylcholinesterase as an apoptotic deoxyribonuclease

Cell Discov., 1 (1) (2015), p. 15002

View in Scopus Google Scholar
[59]

J. Pan, Y. Xu, H. Song, X. Zhou, Z. Yao, G. Ji

Extracts of Zuo Jin Wan, a traditional Chinese medicine, phenocopies 5-HTR1D antagonist in attenuating Wnt/?-catenin signaling in colorectal cancer cells

BMC Complement. Altern. Med., 17 (1) (2017), p. 506

View in Scopus Google Scholar
[60]

J. Yu, Z. Wang, Y. Chen, Y. Dong

Restraint stress disrupted intestinal homeostasis via 5-HT/HTR7/Wnt/?-catenin/NF-kB signaling

Int. J. Mol. Sci., 26 (9) (2025)

Google Scholar
[61]

P. Zhu, T. Lu, Z. Chen, B. Liu, D. Fan, C. Li, J. Wu, L. He, X. Zhu, Y. Du, Y. Tian, Z. Fan

5-hydroxytryptamine produced by enteric serotonergic neurons initiates colorectal cancer stem cell self-renewal and tumorigenesis

Neuron, 110 (14) (2022), pp. 2268-2282.e4

View PDF View article View in Scopus Google Scholar
[62]

T. Nied?wiedzki, J. Filipowska

Bone remodeling in the context of cellular and systemic regulation: the role of osteocytes and the nervous system

J. Mol. Endocrinol., 55 (2) (2015), pp. R23-R36

View in Scopus Google Scholar
[63]

L. Yang, W.-X. Wang

Deciphering size-dependent inter-organ translocation of nanoplastics in fish using metal-labeled proxies and physiologically based toxicokinetic modeling

Environ. Chem. Ecotoxicol., 7 (2025), pp. 2509-2518

View PDF View article Google Scholar
[64]

D. Wang, K. Yin, Y. Zhang, H. Lu, L. Hou, H. Zhao, M. Xing

Fluoride induces neutrophil extracellular traps and aggravates brain inflammation by disrupting neutrophil calcium homeostasis and causing ferroptosis

Environ. Pollut., 331 (Pt 1) (2023), Article 121847

View PDF View article View in Scopus Google Scholar
[65]

Y. Wang, D. Wang, K. Yin, Y. Liu, H. Lu, H. Zhao, M. Xing

Lycopene attenuates oxidative stress, inflammation, and apoptosis by modulating Nrf2/NF-?B balance in sulfamethoxazole-induced neurotoxicity in grass carp (Ctenopharyngodon Idella)

Fish Shellfish Immunol., 121 (2022), pp. 322-331

View PDF View article Google Scholar

Research Studies

Study Tracker

Assessing the health risks of environmentally relevant concentrations of fluoride and phenanthrene: Neurobehavioral toxicity induced in zebrafish through disruption of the microbiome-gut-brain axis and suppression of Wnt/B-catenin signalling.

Abstract

EXCERPTS