Chronic exposure to nonylphenol induces oxidative stress and liver damage in male zebrafish (Danio rerio): Mechanistic insight into cellular energy sensors, lipid accumulation and immune modulation. (5th January 2022)

• Record Type: Journal Article
• Authors: Mukherjee, Urmi; Samanta, Anwesha; Biswas, Subhasri; Ghosh, Soumyajyoti; Das, Sriparna; Banerjee, Sambuddha; Maitra, Sudipta
• Is Part Of: Chemico-biological interactions. Volume 351(2022)
• Publication Date: 2022-01-05
• Subjects: Nonylphenol -- Danio rerio -- Oxidative stress -- Estrogen receptor (ER) -- Hepatotoxicity -- Inflammation; Biochemistry -- Periodicals; Toxicological chemistry -- Periodicals; Biochemistry -- Periodicals; Biologie moléculaire -- Périodiques; Biochimie -- Périodiques; Toxicologie biochimique -- Périodiques; 572
• DOI: 10.1016/j.cbi.2021.109762
• Languages: English
• ISSNs: 0009-2797

Abstract

Abstract: Nonylphenol (NP), an environmentally persistent and toxic endocrine-disrupting chemical with estrogenic properties, has severe implications on humans and wildlife. Accumulating evidence demonstrates the toxic response of NP on the developmental process, nervous system, and reproductive parameters. Although NP exposure has been implicated in chronic liver injury, the underlying events associated with hepatic pathophysiology remain less investigated. Using male zebrafish ( Danio rerio ) as the model, the present study investigates the impact of environmentally relevant concentrations of NP (50 and 100 μg/L, 21 days) on hepatic redox homeostasis vis-à-vis cellular energy sensors, inflammatory response, and cell death involving a mechanistic insight into estrogen receptor (ER) modulation. Our results demonstrate that congruent with significant alteration in transcript abundance of antioxidant enzymes ( SOD1, SOD2, Catalase, GPx1a, GSTα1 ), chronic exposure to NP promotes ROS synthesis, more specifically superoxide anions and H2 O2 levels, and lipid peroxidation potentially through elevated NOX4 expression. Importantly, NP perturbation of markers associated with fatty acid biosynthesis ( srebf1/fasn) and cellular energy-sensing network ( sirt1 / ampkα / pgc1α ) indicates dysregulated energy homeostasis, metabolic disruption, and macrovesicular steatosis, albeit with differential sensitivity at the dose level tested. Besides, elevated p38-MAPK phosphorylation (activation) together with loss of ER homeostasis at both mRNA ( esr1, esr2a, esr2b ) and protein (ERα, ERβ) levels suggest that NP modulation of ER abundance may have a significant influence on hepatic events. Elevated expression of inflammatory markers (TLR4, p-NF-κB, TNF-α, IL-6, IL-1β, and NOS2) and pro-apoptotic and necrotic regulators, e.g., Bax, caspase- 8, -9 and cleaved PARP1 (50 kDa), indicate chronic inflammation and hepatotoxicity in NP-exposed males. Collectively, elevated oxidative stress, metabolic dysregulation and immune modulation may lead to chronic liver injury in organisms exposed to metabolic disrupting chemicals. Graphical abstract: Image 1 Highlights: NP exposure induces NOX4 expression, ROS synthesis, H2 O2 and superoxide radicals. Induction of p38MAPK phosphorylation corresponds with loss of ER homeostasis. NP modulation of energy sensors and lipogenic markers indicates metabolic disruption. Dyslipidemia induces p-p65 NF-ĸB and its downstream pro-inflammatory markers. Increased caspase 8, 9, Bax/Bcl2, cleaved PARP1, DNA damage indicates liver injury.