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Do ambient noise exposure levels predict hearing loss in a modern industrial cohort?

Authors
Rabinowitz-PM; Galusha-D; Dixon-Ernst-C; Slade-MD; Cullen-MR
Source
Occup Environ Med 2007 Jan; 64(1):53-59
NIOSHTIC No.
20031507
Abstract
Recent studies have demonstrated the potential of pesticides to either inhibit or induce xenobiotic metabolizing enzymes in humans. Exposure of human hepatocytes to doses of fipronil (5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-[(trifluoromethyl) sulfinyl]-1H-pyrazole-3-carbonitrile) ranging from 0.1 to 25 M resulted in a dose dependent increase in CYP1A1 mRNA expression (3.5 to approximately 55-fold) as measured by the branched DNA assay. In a similar manner, CYP3A4 mRNA expression was also induced (10-30-fold), although at the higher doses induction returned to near control levels. CYP2B6 and 3A5 were also induced by fipronil, although at lower levels (2-3-fold). Confirmation of bDNA results were sought through western blotting and/or enzyme activity assays. Western blots using CYP3A4 antibody demonstrated a dose responsive increase from 0.5 to 1 M followed by decreasing responses at higher concentrations. Similar increases and decreases were observed in CYP3A4-specific activity levels as measured using 6-hydroxytestosterone formation following incubation with testosterone. Likewise, activity levels for a CYP1A1-specific substrate, luciferin CEE, demonstrated that CYP1A1 enzyme activities were maximally induced by 1 M fipronil followed by dramatically declining activity measurements at 10 and 25 M. Cytotoxic effects of fipronil and fipronil sulfone were examined using the adenylate kinase and the trypan blue exclusion assays in HepG2 cells and human hepatocytes. The results indicate both that HepG2 cells and primary human hepatocytes are sensitive to the cytotoxic effects of fipronil. The maximum induction of adenylate kinase was ca. 3-fold greater than the respective controls in HepG2 and 6-10-fold in the case of primary hepatocytes. A significant time- and dose-dependent induction of adenylate kinase activity in HepG2 cells was noted from 0.1 to 12.5 M fipronil followed by decreasing activities at 25 and 50 M. For fipronil sulfone, cytotoxic effects increased throughout the dose range. The trypan blue assay indicated that cytotoxic effects contributing to an increase of greater than 10% of control values was indicated at doses above 12.5 M. However, fipronil sulfone induced cytotoxic effects at lower doses. The possibility that cytotoxic effects were due to apoptosis was indicated by significant time- and dose-dependent induction of caspase-3/7 activity in both HepG2 cells and human hepatocytes. Fipronil mediated activation of caspase-3/7 in concurrence with compromised ATP production and viability are attributed to apoptotic cell death.
Keywords
Pesticides; Pesticides-and-agricultural-chemicals; Insecticides; Hepatotoxicity; Hepatotoxins; Hepatocytes; Humans
Contact
Assistant Professor P. M. Rabinowitz, Yale University School of Medicine, Occupational and Environmental Medicine Program, 135 College Street, 3rd Floor, New Haven, CT 06510, USA
CODEN
OEMEEM
Publication Date
20070101
Document Type
Journal Article
Email Address
Peter.rabinowitz@yale.edu
Funding Type
Grant
Fiscal Year
2007
NTIS Accession No.
NTIS Price
Identifying No.
Grant-Number-R01-OH-007724
Issue of Publication
1
ISSN
1351-0711
Source Name
Occupational and Environmental Medicine
State
CT; PA
Performing Organization
Yale University
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