title: Resveratrol ameliorates benzo(a)pyrene-induced testicular dysfunction and apoptosis: involvement of p38 MAPK/ATF2/iNOS signaling.
abstract: Benzo(a)pyrene [B(a)P] is an environmental toxicant that alters the steroidogenic profile of testis and induces testicular dysfunction. In the present study, we have investigated the molecular signaling of B(a)P and the ameliorative potential of the natural aryl hydrocarbon receptor (AhR) antagonist and antioxidant, resveratrol, on B(a)P-induced male reproductive toxicity. Studies showed that B(a)P treatment resulted in p38 MAPK activation and increased inducible nitric oxide synthase (iNOS) production along with testicular apoptosis and steroidogenic dysfunction. Resveratrol cotreatment maintained testicular redox potential, increased serum testosterone level and enhanced expression of major testicular steroidogenic proteins (CYPIIA1, StAR, 3βHSD, 17βHSD) and prevented subsequent onset of apoptosis. Resveratrol cotreatment resulted inhibition of testicular cytochrome P4501A1 (CYP1A1) expression, which is the major B(a)P metabolizing agent for BPDE-DNA adduct formation. Resveratrol also significantly decreased the B(a)P-induced AhR protein level, its nuclear translocation and subsequent promoter activation, thereby decreased the expression of CYP1A1. Resveratrol also down-regulated B(a)P-induced testicular iNOS production through suppressing the activation of p38 MAPK and ATF2, thus improved the oxidative status of the testis and prevented apoptosis. Our findings cumulatively suggest that resveratrol inhibits conversion of B(a)P into BPDE by modulating the transcriptional regulation of CYP1A1 and acting as an antioxidant thus prevents B(a)P-induced oxidative stress and testicular apoptosis.
authors.affiliation: Division of Molecular Medicine, Bose Institute, Calcutta Improvement Trust Scheme VIIM, Kolkata, 700054, India.
authors.forename: Bhaswati
authors.initials: B
authors.lastname: Banerjee
authors.affiliation: Division of Molecular Medicine, Bose Institute, Calcutta Improvement Trust Scheme VIIM, Kolkata, 700054, India.
authors.forename: Pinki
authors.initials: P
authors.lastname: Nandi
authors.affiliation: Division of Molecular Medicine, Bose Institute, Calcutta Improvement Trust Scheme VIIM, Kolkata, 700054, India.
authors.forename: Supriya
authors.initials: S
authors.lastname: Chakraborty
authors.affiliation: Department of Biotechnology and Integrated Sciences, Visva Bharati, Shantiniketan, Birbhum, West Bengal, India.
authors.forename: Sanghamitra
authors.initials: S
authors.lastname: Raha
authors.affiliation: Division of Molecular Medicine, Bose Institute, Calcutta Improvement Trust Scheme VIIM, Kolkata, 700054, India.
authors.forename: Parimal C
authors.initials: PC
authors.lastname: Sen
authors.affiliation: Division of Molecular Medicine, Bose Institute, Calcutta Improvement Trust Scheme VIIM, Kolkata, 700054, India. Electronic address: kuladip@jcbose.ac.in.
authors.forename: Kuladip
authors.initials: K
authors.lastname: Jana
mesh_terms: D051698:Activating Transcription Factor 2 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D000975:Antioxidants / Q000009:adverse effects / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D051792:Basic Helix-Loop-Helix Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D001564:Benzo(a)pyrene / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000633:toxicity; D019363:Cytochrome P-450 CYP1A1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D019587:Dietary Supplements / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D004785:Environmental Pollutants / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000633:toxicity; D005786:Gene Expression Regulation / Q000187:drug effects; D007248:Infertility, Male / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000187:drug effects; D017208:Rats, Wistar; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000077185:Resveratrol; D013267:Stilbenes / Q000009:adverse effects / Q000627:therapeutic use*; D013737:Testis / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D013739:Testosterone / Q000819:agonists / Q000037:antagonists & inhibitors / Q000097:blood
chemical_list: D051698:Activating Transcription Factor 2; D000975:Antioxidants; D051792:Basic Helix-Loop-Helix Proteins; D001564:Benzo(a)pyrene; D019363:Cytochrome P-450 CYP1A1; D004785:Environmental Pollutants; D052247:Nitric Oxide Synthase Type II; D018336:Receptors, Aryl Hydrocarbon; D000077185:Resveratrol; D013267:Stilbenes; D013739:Testosterone; C000595703:Ahr protein, rat; C497107:Atf2 protein, rat; C496318:Nos2 protein, rat
keywords: ATF2; Apoptosis; B(a)P; ROS; Testis; iNOS; p38 MAPK