Liver histopathological alteration and dysfunction after bisphenol A administration in male rats and protective effects of naringin

Document Type : Original Research Article


1 Toxicology Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

2 Cellular and Molecular Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

3 Department of Pharmacology, School of Pharmacy, Student Research Committee, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

4 Department of Toxicology, School of Pharmacy, Student Research Committee, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran


Objective: Bisphenol A (BPA) is an organic synthetic compound, often used in manufacturing polycarbonate plastics. Researches have shown the role of BPA as an endocrine disruptor. The present study intended to evaluate the hepatoprotective properties of naringin, an active flavanone glycoside present in many citrus fruit, against hepatotoxicity induced by BPA.
Materials and Methods: Male Wistar rats were orally treated with 50 mg/kg BPA for 30 consecutive days for induction of toxicity and 40, 80 and 160 mg/kg naringin for the same period along with BPA or alone.
Results: This study demonstrated that BPA significantly increased serum levels of triglyceride, lactate dehydrogenase (LDH), alkaline phosphatase (ALP), lipid peroxidation, and aspartate aminotransferase (AST) and significantly reduced catalase, glutathione peroxidase (GPx) and superoxide dismutase (SOD) activity, glutathione (GSH) and caused periportal inflammation and microvesicular steatosis in rat tissue. However, BPA did not change serum levels of high-density lipoprotein-cholesterol (HDL-C), total cholesterol, alanine aminotransferase (ALT), or low-density lipoprotein-cholesterol (LDL-C). Furthermore, the results displayed that administration of 80 and 160 mg/kg naringin improved hepatotoxicity and altered lipid peroxidation level, serum values of triglyceride and liver enzymes, and oxidative stress factors that were induced by BPA. The effect of two doses of 80 and 160 mg/kg naringin was more noticeable than that of dose 40 mg/kg.
Conclusion: The findings suggested the protective effects of naringin against BPA-induced hepatotoxicity via ameliorating liver histopathological alteration, suppressing oxidative stress and lipid-lowering properties.


Badary OA, Abdel-Maksoud S, Ahmed WA,
Owieda GH. 2005. Naringenin attenuates
cisplatin nephrotoxicity in rats. Life Sci, 76:
Bindhumol V, Chitra K, Mathur P. 2003.
Bisphenol A induces reactive oxygen
species generation in the liver of male rats.
Toxicology, 188: 117-124.
Chen J, Guo R, Yan H, Tian L, You Q, Li S,
Wu K. 2014. Naringin inhibits ROS‐
activated MAPK pathway in high glucose‐
induced injuries in H9c2 cardiac cells. Basic
Clin Pharmacol Toxicol, 114: 293-304.
Elswefy SES, Abdallah FR, Atteia HH, Wahba
AS, Hasan RA. 2016. Inflammation,
oxidative stress and apoptosis cascade
implications in bisphenol A‐induced liver
fibrosis in male rats. Int J Exp Pathol, 97:
Geng S, Wang S, Zhu W, Xie C, Li X, Wu J, Li
Y. 2017. Curcumin attenuates BPA-induced
insulin resistance in HepG2 cells through
suppression of JNK/p38 pathways. Toxicol
Lett, 272: 75-83.
Giannini EG, Testa R, Savarino V. 2005. Liver
enzyme alteration: a guide for clinicians.
Canadian Med Associat J, 172: 367-379.
Gong Y, Han XD. 2006. Nonylphenol-induced
oxidative stress and cytotoxicity in testicular
Sertoli cells. Reproduct Toxicol, 22: 623-
Gopinath K, Prakash D, Sudhandiran G. 2011.
Neuroprotective effect of naringin, a dietary
flavonoid against 3-nitropropionic acidinduced neuronal apoptosis. Neurochem Int,
59: 1066-1073.
Haavisto TE, Adamsson NA, Myllymäki SA,
Toppari J, Paranko J. 2003. Effects of 4-tertoctylphenol, 4-tert-butylphenol, and
diethylstilbestrol on prenatal testosterone
surge in the rat. Reproduc Toxicol, 17: 593-
Mahdavinia et al.
AJP, Vol. 11, No. 4, Jul-Aug 2021 404
Harisa GI, Mariee AD, Abo-Salem OM, Attiaa
SM. 2014. Erythrocyte nitric oxide synthase
as a surrogate marker for mercury-induced
vascular damage: the modulatory effects of
naringin. Environ Toxicol, 29: 1314-1322.
Hassan ZK, Elobeid MA, Virk P, Omer SA,
ElAmin M, Daghestani MH, AlOlayan EM.
2012. Bisphenol A induces hepatotoxicity
through oxidative stress in rat model. Oxid
Med Cell Longev, 2012: 194829.
Hassani FV, Mehri S, Abnous K, BirnerGruenberger R, Hosseinzadeh H. 2017.
Protective effect of crocin on BPA-induced
liver toxicity in rats through inhibition of
oxidative stress and downregulation of
MAPK and MAPKAP signaling pathway
and miRNA-122 expression. Food Chem
Toxicol, 107: 395-405.
Huc L, Lemarié A, Guéraud F, HélièsToussaint C. 2012. Low concentrations of
bisphenol A induce lipid accumulation
mediated by the production of reactive
oxygen species in the mitochondria of
HepG2 cells. Toxicol in Vitro, 26: 709-717.
Hussein RM, Eid JI. 2013. Pathological
mechanisms of liver injury caused by oral
administration of bisphenol A. Life Sci J,
10: 1050-1059.
Iwahashi H, Ishii T, Sugata R, Kido R. 1990.
The effects of caffeic acid and its related
catechols on hydroxyl radical formation by
3-hydroxyanthranilic acid, ferric chloride,
and hydrogen peroxide. Arch Biochem
Biophys, 276: 242-247.
Jagetia GC, Reddy TK. 2011. Alleviation of
iron induced oxidative stress by the grape
fruit flavanone naringin in vitro. Chem Biol
Interact, 190: 121-128.
Jeon SM, Bok SH, Jang MK, Lee MK, Nam
KT, Park YB, Choi MS. 2001. Antioxidative
activity of naringin and lovastatin in high
cholesterol-fed rabbits. Life Sci, 69: 2855-
Jeon SM, Park YB, Choi MS. 2004.
Antihypercholesterolemic property of
naringin alters plasma and tissue lipids,
cholesterol-regulating enzymes, fecal sterol
and tissue morphology in rabbits. Clin Nutr,
23: 1025-1034.
Kandhare AD, Alam J, Patil MV, Sinha A,
Bodhankar SL. 2016. Wound healing
potential of naringin ointment formulation
via regulating the expression of
inflammatory, apoptotic and growth
mediators in experimental rats. Pharm Biol,
54: 419-432.
Kandhare AD, Ghosh P, Bodhankar SL. 2014.
Naringin, a flavanone glycoside, promotes
angiogenesis and inhibits endothelial
apoptosis through modulation of
inflammatory and growth factor expression
in diabetic foot ulcer in rats. Chem Biol
Interac, 219: 101-112.
Kwatra M, Kumar V, Jangra A, Mishra M,
Ahmed S, Ghosh P, Vohora D, Khanam R.
2016. Ameliorative effect of naringin
against doxorubicin-induced acute cardiac
toxicity in rats. Pharm Biol, 54: 637-647.
Khodayar MJ, Kalantari H, Mahdavinia M,
Khorsandi L, Alboghobeish S, Samimi A,
Alizadeh S and Zeidooni L. 2020. Protective
effect of naringin against BPA-induced
cardiotoxicity through prevention of
oxidative stress in male Wistar rats. Drug
Chem Toxicol, 43: 85-95.
Kovacic P. 2010. How safe is bisphenol A?
Fundamentals of toxicity: metabolism,
electron transfer and oxidative stress. Med
Hypothes, 75: 1-4.
Krüger T, Long M, Bonefeld-Jørgensen EC.
2008. Plastic components affect the
activation of the aryl hydrocarbon and the
androgen receptor. Toxicology, 246: 112-
Kwatra M, Kumar V, Jangra A, Mishra M,
Ahmed S, Ghosh P, Khanam R. 2016.
Ameliorative effect of naringin against
doxorubicin-induced acute cardiac toxicity
in rats. Pharm Biol, 54: 637-647.
Maffini MV, Rubin BS, Sonnenschein C, Soto
AM. 2006. Endocrine disruptors and
reproductive health: the case of bisphenolA. Mol Cell Endocrinol, 254: 179-186.
Marmugi A, Ducheix S, Lasserre F, Polizzi A,
Paris A, Priymenko N, Martin PG. 2012.
Low doses of bisphenol A induce gene
expression related to lipid synthesis and
trigger triglyceride accumulation in adult
mouse liver. Hepatology, 55: 395-407.
Martella A, Silvestri C, Maradonna F,
Gioacchini G, Allarà M, Radaelli G,
Carnevali O. 2016. Bisphenol A induces
fatty liver by an endocannabinoid-mediated
positive feedback loop. Endocrinology, 157:
Metwally FM, Mohamed MM, Sharaf N,
Ghazy MA, El Mishad A, Elfiky A. 2016.
The Impact of bisphenol A (BPA) as
environmental obesogen on lipids and lipids
metabolism. Int J Pharm Clin Res, 8: 1323-
Liver dysfunction by bisphenol A
AJP, Vol. 11, No. 4, Jul-Aug 2021 405
Mikołajewska K, Stragierowicz J,
Gromadzinska J. 2015. Bisphenol A–
Application, sources of exposure and
potential risks in infants, children and
pregnant women. Int J Occup Med Environ
Health, 28: 209-241.
Moghaddam, HS, Samarghandian S,
Farkhondeh T. 2015. Effect of bisphenol A
on blood glucose, lipid profile and oxidative
stress indices in adult male mice. Toxicol
Mech Method, 25: 507-513.
Moon MK, Kim MJ, Jung IK, Koo YD, Ann
HY, Lee KJ, Park KS. 2012. Bisphenol A
impairs mitochondrial function in the liver
at doses below the no observed adverse
effect level. J Korean Med Sci, 27: 644-652.
Nakamura D, Yanagiba Y, Duan Z, Ito Y,
Okamura A, Asaeda N, Zhang SY. 2010.
Bisphenol A may cause testosterone
reduction by adversely affecting both testis
and pituitary systems similar to estradiol.
Toxicol Lett, 194: 16-25.
Niwa T, Fujimoto M, Kishimoto K, Yabusaki
Y, Ishibashi F, Katagiri M. 2001.
Metabolism and interaction of bisphenol A
in human hepatic cytochrome P450 and
steroidogenic CYP17. Biol Pharm Bulle, 24:
Pari L and Amudha K. 2011. Hepatoprotective
role of naringin on nickel-induced toxicity
in male Wistar rats. Eur J Pharmacol, 650:
Ptak A and Gregoraszczuk EL. 2012.
Bisphenol A induces leptin receptor
expression, creating more binding sites for
leptin, and activates the JAK/Stat,
MAPK/ERK and PI3K/Akt signalling
pathways in human ovarian cancer cell.
Toxicol Lett, 210: 332-337.
Ptak A, Hoffmann M, Gruca I, Barć J. 2014.
Bisphenol A induce ovarian cancer cell
migration via the MAPK and PI3K/Akt
signalling pathways. Toxicol Lett, 229: 357-
Ribeiro IA, Rocha J, Sepodes B, Mota-Filipe
H, Ribeiro MH. 2008. Effect of naringin
enzymatic hydrolysis towards naringenin on
the anti-inflammatory activity of both
compounds. J Mol Catal B Enzym, 52: 13-
Santangeli S, Maradonna F, Olivotto I,
Piccinetti CC, Gioacchini G, Carnevali
O. 2017. Effects of BPA on female
reproductive function: The involvement
of epigenetic mechanism. Gen Comp
Endocrinol, 245: 122-126.
Snyder RW, Maness SC, Gaido K, Welsch F,
Sumner SC, Fennell TR. 2000. Metabolism
and disposition of bisphenol A in female
rats. Toxicol Appl Pharmacol, 168: 225-
So FV, Guthrie N, Chambers AF, Moussa M,
Carroll KK. 2009. Inhibition of human
breast cancer cell proliferation and delay of
mammary tumorigenesis by flavonoids and
citrus juices. Nuter Cancer. 26: 167-181.
Soares A, Guieysse B, Jefferson B, Cartmell E,
Lester J. 2008. Nonylphenol in the
environment: a critical review on
occurrence, fate, toxicity and treatment in
wastewaters. Environ Int, 34: 1033-1049.
Sokolovic D, Djindjic B, Nikolic J, Bjelakovic
G, Pavlovic D, Kocic G, Pavlovic V. 2008.
Melatonin reduces oxidative stress induced
by chronic exposure of microwave radiation
from mobile phones in rat brain. J Rad Res,
49: 579-586.
Sun Y, Wang X, Zhou Y, Zhang J, Cui W,
Wang E, Du J, Wei B, Xu X. 2020.
Protective effect of metformin on BPAinduced liver toxicity in rats through
upregulation of cystathionine β synthase
and cystathionine γ lyase expression. Sci
Total Environ, 750: 141685.
Takayanagi S, Tokunaga T, Liu X, Okada H,
Matsushima A, Shimohigashi Y. 2006.
Endocrine disruptor bisphenol A strongly
binds to human estrogen-related receptor γ
(ERRγ) with high constitutive activity.
Toxicol Lett, 167: 95-105.
Thomas P and Dong J. 2006. Binding and
activation of the seven-transmembrane
estrogen receptor GPR30 by environmental
estrogens: a potential novel mechanism of
endocrine disruption. The J Steroid
Biochem Mol Biol, 102: 175-179.
Thorpe C, Hoober K L, Raje S, Glynn N M,
Burnside J, Turi GK, Coppock DL. 2002.
Sulfhydryl oxidases: emerging catalysts of
protein disulfide bond formation in
eukaryotes. Arch Biochem Biophys, 405: 1-
Vandenberg LN, Maffini MV, Sonnenschein C,
Rubin BS, Soto AM. 2009. Bisphenol-A and
the great divide: a review of controversies in
the field of endocrine disruption. Endocrine
Rev, 30: 75-95.
Mahdavinia et al.
AJP, Vol. 11, No. 4, Jul-Aug 2021 406
Weinhouse C, Anderson OS, Bergin IL,
Vandenbergh DJ, Gyekis JP, Dingman MA,
Dolinoy DC. 2014. Dose-dependent
incidence of hepatic tumors in adult mice
following perinatal exposure to bisphenol A.
Environ Health Perspect, 122: 485-491.
Xianchu L, Lan Z, Qiufang L, Yi L,
Xiangcheng R, Wenqi H, Yang D. 2016.
Naringin protects against
lipopolysaccharide-induced cardiac injury
in mice. Environ Toxicol Pharmacol, 48: 1-