Latent carcinogenicity of early-life exposure to dichloroacetic acid in mice.
Environmental exposures occurring early in life may have an important influence on cancer risk later in life. Here, we investigated carryover effects of dichloroacetic acid (DCA), a small molecule analog of pyruvate with metabolic programming properties, on age-related incidence of liver cancer. The study followed a stop-exposure/promotion design in which 4-week-old male and female B6C3F1 mice received the following treatments: deionized water alone (dH2O, control); dH2O with 0.06% phenobarbital (PB), a mouse liver tumor promoter; or DCA (1.0, 2.0 or 3.5g/l) for 10 weeks followed by dH2O or PB (n = 20-30/group/sex). Pathology and molecular assessments were performed at 98 weeks of age. In the absence of PB, early-life exposure to DCA increased the incidence and number of hepatocellular tumors in male and female mice compared with controls. Significant dose trends were observed in both sexes. At the high dose level, 10 weeks of prior DCA treatment induced comparable effects (≥85% tumor incidence and number) to those seen after continuous lifetime exposure. Prior DCA treatment did not enhance or inhibit the carcinogenic effects of PB, induce persistent liver cytotoxicity or preneoplastic changes on histopathology or alter DNA sequence variant profiles within liver tumors compared with controls. Distinct changes in liver messenger RNA and micro RNA profiles associated with prior DCA treatment were not apparent at 98 weeks. Our findings demonstrate that early-life exposure to DCA may be as carcinogenic as life-long exposures, potentially via epigenetic-mediated effects related to cellular metabolism.
National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA, wood.charles@epa.gov.
Charles E
CE
Wood
National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA.
Susan D
SD
Hester
National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA.
Brian N
BN
Chorley
National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA.
Gleta
G
Carswell
National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA.
Michael H
MH
George
National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA.
William
W
Ward
National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA.
Beena
B
Vallanat
National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA.
Hongzu
H
Ren
National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA.
Anna
A
Fisher
April D
AD
Lake
Experimental Pathology Laboratories, Morrisville, NC 27560, USA Present address: Pfizer Worldwide Research and Development, Groton, CT 06340, USA.
Carlin V
CV
Okerberg
Experimental Pathology Laboratories, Morrisville, NC 27560, USA Present address: Boehringer Ingelheim Pharmaceuticals, Inc., Ridgeﬁeld, CT 06877, USA.
Elias T
ET
Gaillard
National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA.
Tanya M
TM
Moore
National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA.
Anthony B
AB
Deangelo
D000818:Animals; D019175:DNA Methylation / Q000187:drug effects; D003999:Dichloroacetic Acid / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004435:Eating; D004785:Environmental Pollutants / Q000633:toxicity; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D008113:Liver Neoplasms / Q000139:chemically induced* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D008297:Male; D008815:Mice, Inbred Strains; D035683:MicroRNAs; D010634:Phenobarbital / Q000633:toxicity; D012333:RNA, Messenger
D004785:Environmental Pollutants; D035683:MicroRNAs; D012333:RNA, Messenger; D003999:Dichloroacetic Acid; D010634:Phenobarbital