Quercetin abrogates bisphenol A induced altered neurobehavioral response and oxidative stress in zebrafish by modulating brain antioxidant defence system

https://doi.org/10.1016/j.etap.2020.103483Get rights and content

Highlights

  • Chronic waterborne exposure to BPA elicit altered neurobehavioral response in zebrafish.

  • BPA induces augmented oxidative stress & pyknosis in PGZ region of zebrafish brain.

  • Quercetin abrogates BPA induced altered scototaxis and bottom dwelling behavior in zebrafish.

  • Quercetin reinstate the cytosolic redox balance by augmenting GSH and antioxidant enzymes.

  • Neuroprotective efficacy of quercetin against BPA was validated by decrease in pyknosis in zebrafish brain.

Abstract

Bisphenol A (BPA), a well-recognized anthropogenic xenoestrogen, has been identified as a causative agent responsible for inducing carcinogenicity, cognitive impairment, neurotoxicity, oxidative stress, etc. However, BPA-induced neurotoxicity and its possible amelioration through natural compound intervention remain elusive. The current study was performed to elucidate the neurotoxic potential of BPA in zebrafish (Danio rerio) by waterborne exposure and its possible amelioration by quercetin co-supplementation. Protective effect of quercetin against BPA-induced altered neurobehavioral response, oxidative stress and neuromorphological changes were evaluated in zebrafish brain. The present findings reveal that BPA-induced altered neurobehavioral response was ameliorated by quercetin. Biochemical studies advocate the potential therapeutic efficacy of quercetin against BPA-induced oxidative stress in zebrafish brain. Quercetin also shows neuroprotection against BPA-induced augmented neuronal pyknosis in periventricular grey zone (PGZ) of zebrafish brain. These basic findings indicate that quercetin may act as an effective intervention against BPA-induced neurotoxicity in zebrafish through down-regulation of oxidative stress.

Introduction

Modern manufacturing of high demand consumer products has stimulated the increasing use of synthetic polymers. Their indiscriminate disposal into ambient soil, air and water may pose a potential threat in terms of the development of serious health problems in humans, including neurodegenerative diseases (Chin-Chan et al., 2015). One such synthetic polymer called bisphenol A (BPA), as an analogue of bisphenols (BPs), has been used since its inception in the 1950s (Ben-Jonathan and Hugo, 2016). BPA is primarily utilized in the production of epoxy resins and polycarbonate plastics (Kang et al., 2006; Staples et al., 1998; Vandenberg et al., 2007; Murata and Kang, 2018). The reported source of BPA contamination in ambient water and soil is through the natural degradation of epoxy resins and plastics, release of effluents from sewage treatment plants and junkyard seepage (Crain et al., 2007; Kang et al., 2007). BPA is now ubiquitous and it has been detected in dust and even in human urine (Calafat et al., 2005; Vandenberg et al., 2010; Flint et al., 2012; Liu et al., 2013). BPA, as an anthropogenic xenoestrogen classified under endocrine-disrupting chemicals (EDCs), possesses marginal estrogenic potential (Inadera, 2015; Nagel and Bromfield, 2013). Being lipophilic in nature, BPA can cross placenta and blood-brain barrier and even be delivered to infants through breast milk (Zimmers et al., 2014; Negri-Cesi, 2015; Nishikawa et al., 2010; Sun et al., 2002).

However, several reports have suggested a cluster of adverse effects of BPA exposure such as oxidative stress, mood disturbances, cognitive impairment, carcinogenicity and inflammation (Kawato, 2004; Kajta and Wójtowicz, 2013; Rochester, 2013; Inadera, 2015; Seachrist et al., 2016; Gassman, 2017; Zhou et al., 2017). Moreover, heightened oxidative stress has been the root cause of several health concerns involving cardiovascular disease, aging, neurodegeneration and inflammation (Rahal et al., 2014). BPA-induced oxidative stress and its consequences are well addressed with respect to cell lines and several organ specific studies including liver, colon, pancreas and testes, but its pathological manifestation in the brain remains elusive (Bindhumol et al., 2003; Kabuto et al., 2003; Ooe et al., 2005; Eid et al., 2015; Leem et al., 2017; Wang et al., 2019). Several earlier findings also suggested that BPA-induced rise in reactive oxygen species (ROS) generation could underwrite its toxic potential (Rochester, 2013; Seachrist et al., 2016). Therefore, the potential impact of rising load of BPA in inducing oxidative stress-mediated neurotoxicity needs to be addressed.

Primary contamination by BPA disposal in water bodies near human inhabitant areas poses a potent threat in terms of development of serious health maladies. In this regard, aquatic ecosystem may be a fragile target for sewage disposal through garbage dump outflow, environmental degradation and effluent release from establishments. As zebrafish (Danio rerio) exhibits characteristic pattern of behavioural responses to several toxic chemicals and stress conditions including that of therapeutic interventions similar to mammals, it is presently considered an ideal animal model of aquatic ecosystem in various preclinical studies (Winston, 1991; Kelly et al., 1998; Rennekamp and Peterson, 2015; Cassar et al., 2020). To counteract BPA-persuaded neurotoxicity, intervention of natural compounds as prophylactic/therapeutic strategy may be a plausible alternative. One such natural compound is quercetin (3,3′,4′,5,7-pentahydroxyflavone), which is a flavonol commonly found in several plant products (Costa et al., 2016). Several reports address the potential neuroprotective properties of quercetin against chemical induced neurotoxicity and as treatment strategy against neurodegenerative diseases (Abdalla et al., 2013; Ahn and Jeon, 2015; Kuo and Tsao, 2017; Singh et al., 2017; Denny Joseph and Muralidhara, 2015; El-Horany et al., 2016; Ansari et al., 2009). Quercetin primarily provides neuroprotection against oxidative stress by augmenting antioxidant enzyme activity, antioxidant level and by reduction in lipid peroxidation (Unsal et al., 2015; Ansari et al., 2009; Heo and Lee, 2004). Reports also show the protective effect of quercetin against BPA-induced oxidative stress and toxicity in testes, kidney and liver (Sangai et al., 2014; Samova et al., 2018; Shirani et al., 2019). However, the neuroprotective efficacy of quercetin against BPA-induced altered neurobehavioral response and oxidative stress is limiting in the literature. Therefore, the current experiments were performed on zebrafish model to elucidate the neurotoxic potential of BPA in altering the brain antioxidant defence system and its possible amelioration through quercetin co-supplementation.

Section snippets

Chemicals and reagents

The requisite analytical chemicals and standard reagents used in the present experiments were acquired from Sigma-Aldrich, SRL, except as otherwise provided.

Experimental animals

All tests mentioned were commenced with in the applicable guiding principles and procedures of the institutional animal ethics committee (IAEC) of Siksha ‘O’ Anusandhan (Deemed to be University), Odisha, India. The zebrafish (5–7 months; both sexes in equal proportion) were obtained from CIFA, Odisha, India and were kept in a 50-L

Amelioration of BPA-induced altered scototaxis behaviour by quercetin co-supplementation

Chronic waterborne exposure to BPA significantly altered the usual scototaxis behaviour of zebrafish, and it was inferred through augmented transition to light zone and time spent in light zone in comparison to naïve and control (Fig. 2b & c). BPA exposure also showed a significant increase in latency to entry in dark zone in LDPT in comparison with naïve and control groups (Fig. 2d). However, quercetin significantly ameliorated the altered scototaxis behaviour of zebrafish in BPA + quercetin

Discussion

BPA is primarily an anthropogenic toxicant, and its omnipresence in the inhabiting environment poses a potential threat for human beings through development of serious health maladies, including neurodegenerative diseases. Therefore, our present study not only focuses on determining the neurotoxic potential of BPA but also on elucidating the neuroprotective efficacy of quercetin against BPA-induced toxicity. Our preliminary dose response study of BPA showed that the behavioural changes were

Conclusion

In a nutshell, this study proposes the possible neuroprotective efficacy of quercetin against BPA-induced oxidative stress-mediated neurotoxicity in zebrafish. The altered neurobehavioral response was found to be strongly correlated with the increased oxidative stress in zebrafish brain. However, as a therapeutic intervention, quercetin exhibit strong capacity for scavenging ROS and hydroxy radicals following chronic waterborne exposure to BPA. The potential neuroprotective efficacy of

Author’s contribution

SKD: Conceptualization, Supervision, Funding acquisition, Writing - Original draft. PKS and LKP: Formal analysis, Investigation, Writing - Review and editing. KA and AB: Formal analysis, Investigation. SA: Data curation, Writing - Review and editing.

Conflict of interest

The authors declare no conflict of interest.

Declaration of Competing Interest

The authors report no declarations of interest.

Acknowledgments

The authors acknowledge the Centre for Biotechnology, SOA University for providing the infrastructure facility and support. Dr. Saroj Kumar Das is the recipient of UGC start-up and Indian Council of Medical Research (ICMR), extramural research grants (Multi-Institutional). The authors also acknowledge the contribution of Dr. Ritendra Mishra, Mumbai, India who helped in the copy editing and proofreading of the manuscript.

References (74)

  • A. Ishisaka et al.

    Accumulation of orally administered quercetin in brain tissue and its antioxidative effects in rats

    Free Radic. Biol. Med.

    (2011)
  • H. Kabuto et al.

    Effects of bisphenol A on the metabolisms of active oxygen species in mouse tissues

    Environ. Res.

    (2003)
  • M. Kajta et al.

    Impact of endocrine-disrupting chemicals on neural development and the onset of neurological disorders

    Pharmacol. Rep.

    (2013)
  • J.H. Kang et al.

    Human exposure to bisphenol A

    Toxicology

    (2006)
  • D. Lalwani et al.

    Nationwide distribution and potential risk of bisphenol analogues in Indian waters

    Ecotoxicol. Environ. Saf.

    (2020)
  • M. Lorber et al.

    Exposure assessment of adult intake of bisphenol A (BPA) with emphasis on canned food dietary exposures

    Environ. Int.

    (2015)
  • L.D. Magno et al.

    Pharmacological study of the light/dark preference test in zebrafish (Danio rerio): waterborne administration

    Pharmacol. Biochem. Behav.

    (2015)
  • M. Murata et al.

    Bisphenol A (BPA) and cell signaling pathways

    Biotechnol. Adv.

    (2018)
  • A.J. Rennekamp et al.

    15 years of zebrafish chemical screening

    Curr. Opin. Chem. Biol.

    (2015)
  • J.R. Rochester

    Bisphenol A and human health: a review of the literature

    Reprod. Toxicol.

    (2013)
  • S. Sarkar et al.

    Low dose of arsenic trioxide triggers oxidative stress in zebrafish brain: expression of antioxidant genes

    Ecotoxicol. Environ. Saf.

    (2014)
  • D.D. Seachrist et al.

    A review of the carcinogenic potential of bisphenol A

    Reprod. Toxicol.

    (2016)
  • C.A. Staples et al.

    A review of the environmental fate, effects, and exposures of bisphenol A

    Chemosphere

    (1998)
  • F. Tietze

    Enzymic method for quantitative determination of nanogram amounts of total and oxidized glutathione: applications to mammalian blood and other tissues

    Anal. Biochem.

    (1969)
  • L.N. Vandenberg et al.

    Human exposure to bisphenol A (BPA)

    Reprod. Toxicol.

    (2007)
  • K. Wang et al.

    Bisphenol A induces apoptosis, oxidative stress and inflammatory response in colon and liver of mice in A mitochondria-dependent manner

    Biomed. Pharmacother.

    (2019)
  • X. Wei et al.

    Assessment of risk to humans of bisphenol A in marine and freshwater fish from Pearl River Delta, China

    Chemosphere

    (2011)
  • G.W. Winston

    Oxidants and antioxidants in aquatic animals

    Comp. Biochem. Physiol. C

    (1991)
  • Y.M. Wong et al.

    The measurement of bisphenol A and its analogues, perfluorinated compounds in twenty species of freshwater and marine fishes, a time-trend comparison and human health based assessment

    Mar. Pollut. Bull.

    (2017)
  • E. Yamazaki et al.

    Bisphenol A and other bisphenol analogues including BPS and BPF in surface water samples from Japan, China, Korea and India

    Ecotoxicol. Environ. Saf.

    (2015)
  • Y. Zhou et al.

    Neurotoxicity of low bisphenol A (BPA) exposure for young male mice: implications for children exposed to environmental levels of BPA

    Environ. Pollut.

    (2017)
  • S.M. Zimmers et al.

    Determination of free bisphenol A (BPA) concentrations in breast milk of U.S. women using a sensitive LC/MS/MS method

    Chemosphere

    (2014)
  • F.H. Abdalla et al.

    Neuroprotective effect of quercetin in ectoenzymes and acetylcholinesterase activities in cerebral cortex synaptosomes of cadmium-exposed rats

    Mol. Cell. Biochem.

    (2013)
  • T.B. Ahn et al.

    The role of quercetin on the survival of neuron-like PC12 cells and the expression of α-synuclein

    Neural Regen. Res.

    (2015)
  • N. Ben-Jonathan et al.

    Bisphenols come in different flavors: is “S” better than “A”?

    Endocrinology

    (2016)
  • A.M. Calafat et al.

    Urinary concentrations of bisphenol A and 4-nonylphenol in a human reference population

    Environ. Health Perspect.

    (2005)
  • L. Canesi et al.

    Environmental effects of BPA: focus on aquatic species

    Dose Response

    (2015)
  • Cited by (34)

    View all citing articles on Scopus
    1

    Authors contributed equally.

    View full text