|
 |
|
EDRI Federal Project Inventory:
05352-13 Metabolic and Pharmacological Determinants in Perinatal Carcinogenesis
- Sponsor Organization: NIH/CP
- Project Title: 05352-13 METABOLIC AND PHARMACOLOGICAL DETERMINANTS IN PERINATAL
CARCINOGENESIS
- Project Focus: HUMAN HEALTH EFFECTS
- Description: Recent increases in certain childhood cancers call for continued
research on perinatal carcinogenesis. We define thisterm broadly to
include preconception, transplacental, and neonatal effects, as well
as those of agents received in breastmilk, and carry out research to
characterize and understand the mechanisms of chemical carcinogenesis
during theseperiods. Preconception carcinogenesis is a potentially
important phenomenon, suggested particularly for men inepidemiological
studies. We have investigated this in mice, especially with regard to
effects of metals such as chromium(Cr). Characteristics of
preconception carcinogenesis in animals suggests operation of a novel
mechanism, and we havebeen pursuing, with some success, the hypothesis
of deranged control of expression of the insulin-like growth factor
II(IGFII) gene. Offspring of fathers exposed to either chromium or
urethane show increased expression of IGFII in lungs,as assayed by
Northern/slot blots with cDNA probes, ribonuclease protection assay,
or quantitative reverse transcriptase(RT)-polymerase chain reaction
(PCR). This important, ground-breaking new finding will be
emphasized. Studies intransplacental carcinogenesis have included the
drug, cisplatin, which initiated tumors of kidney, liver, and
nervoussystem in fetal rats. We also tested the role of Ah locus
phenotype on susceptibility of mouse fetuses to three
polycyclicaromatic hydrocarbons, and confirmed that Ah responsiveness
increased fetal tumorigenesis by 3-methylcholanthreneand 7,12-
dimethylbenz[a]- anthracene (DMBA), but not by benzo[a]pyrene.
Maternal responsiveness protected thefetuses uniformly. An important
transplacental/neonatal trial has been started with the anti-AIDS
drug, azidothymidine(AZT), a tissue-specific carcinogen in adult mice,
now being administered to HIV-positive pregnant women. Genotoxicand
oxygen stress effects of AZT will be studied. Chlorinated aromatic
hydrocarbons, including polychlorinatedbipenyls (PCBs), 2,3,7,8-
tetrachloro-dibenzo-p-dioxin (TCDD), and dichlorodiphenyl
trichloroethane (DDT) oftenoccur in breast milk, and have been
suspected in causation of human breast and lung cancers. We found,
for the firsttime, TCDD to be a promoter of nitrosamine-initiated lung
tumors in mice. For breast tumors in rats, TCDD at anontoxic dose
suppressed tumor development, but in an initiator-specific way: those
initiated by DMBA werecompletely suppressed for 6 months, whereas
those initiated by an aryl amine were unaffected.
- References:
- Category: MODELS
- Subcategory: HAZARD IDENTIFICATION
- Keywords for Experimental System/Species: HUMAN, MAMMALIAN, LABORATORY STUDY
- Keywords for Experimental Endpoints: CARCINOGENESIS, TISSUE RESIDUE, AH RECEPTOR
- Chemical Agents: PCBs, DDT, TCDD
- Performing Institution: NCI INTRAMURAL PROGRAM
- Contact: ELAINE C. LEE; BUILDING 31; 11A21, NATIONAL CANCER INSTITUTE,
NIH,BETHESDA, MD 20892-2590; 301- 496-5515; LEEE@OD.NCI.NIH.GOV
|
|
