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