Lymphomas and leukemias are the most common cancer in children and young
adults and in utero exposure to carcinogens may contribute to the etiology of these
cancers. A polycyclic aromatic hydrocarbon (PAH), dibenzo[a,l]pyrene (DBP), was
administered to pregnant mice (15 mg/Kg b.w., gavage) on gestation day 17. Significant
mortalities in young offspring were observed due to T-cell lymphoma. Lung and liver
tumors also were observed in survivors at 10 months of age. To assess the role of the
Aryl Hydrocarbon Receptor (AHR), we utilized crosses of B6129SF1/J (responsive) mice
with strain 129S1/SvImJ (non-responsive). Offspring born to AHR non-responsive
mothers had greater susceptibility to lymphoma, irrespective of offspring genotype.
Responsive offspring displayed increased mortality if the mother was responsive. Lung
adenomas showed Ki-ras mutations and exhibited a 50% decrease and a 35-fold increase
in expression of Rb and p19/ARF mRNA, respectively.
To examine the risk/benefit of maternal dietary phytochemical treatment against
transplacental cancer, 2000 ppm indole-3-carbinol (I3C) was given to pregnant mice
through diet from gestation day 9 till weaning. I3C significantly lowered mortality
caused by lymphomas regardless of the maternal genotype, and also reduced lung tumor
multiplicity in offspring born to AHR [superscript b-l/d] dams. Distribution of I3C in most maternal
and fetal tissues was quantified following a single gavage of [¹⁴C]-I3C to the pregnant
mice. DBP-DNA adducts were observed in both maternal and fetal tissues by ³³P
postlabeling and HPLC analysis and were modulated by I3C and AHR genotype. I3C
also modulated phase I and phase II enzyme protein expression in dams and gene
expression in newborn thymus. I3C chemoprotection may involve modification of the
bioavailability of DBP to the fetus and/or modulation of gene expression in the fetus as
well.
This is the first demonstration that transplacental exposure to an environmental PAH
can induce a highly aggressive lymphoma in mice. These results raise the possibility that
PAH exposures to pregnant women could contribute to similar cancers in children and
young adults and, that the addition of chemoprotective agents to the maternal diet may
reduce cancer risk among offspring. / Graduation date: 2006
| Identifer | oai:union.ndltd.org:ORGSU/oai:ir.library.oregonstate.edu:1957/28600 |
| Date | 30 November 2005 |
| Creators | Yu, Zhen |
| Contributors | Williams, David E. |
| Source Sets | Oregon State University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis/Dissertation |
Page generated in 0.002 seconds