Fetal mouse susceptibility to transplacental carcinogenesis: differential influence of Ah receptor phenotype on effects of 3-methylcholanthrene, 12-dimethylbenz[a]anthracene, and benzo[a]pyrene.
Genetic backcrosses of C57BL/6 and DBA/2 mice were used to examine the influence of maternal and fetal polymorphisms at the Ahr locus on susceptibility to transplacental carcinogenesis by 3-methylcholanthrene, 7,12-dimethylbenz[a]anthracene, and benzo[a]pyrene. (C57BL/6 x DBA/2) F1 mothers were backcrossed to DBA/2 males, and DBA/2 females to F1 males to produce both Ahr-responsive (Ah+) and nonresponsive (Ah-) fetuses carried by mothers that were themselves either Ah+ or Ah-. 3-Methylcholanthrene was given intragastrically on gestation days 13-18 and 7,12-dimethylbenz[a]anthracene or benzo[a]pyrene on day 17 as a single intraperitoneal dose. Ahr phenotype was determined by the zoxazolamine sleeping time test after beta-naphthoflavone pretreatment at 6 weeks of age. The offspring were examined for tumours at 1 year. Both 3-methylcholanthrene and 7,12-dimethylbenz[a]anthracene treatments resulted in a two- to five-fold greater incidence and multiplicity of lung and liver tumours in the Ah+ offspring compared with that in Ah- littermates. By contrast, there was no difference between Ah+ and Ah- offspring with regard to numbers of tumours caused by benzo[a]pyrene. Maternal Ahr phenotype appeared to play a role also, in that the offspring of the Ahr-responsive F1 mothers developed fewer tumours per unit dose than those of the nonresponsive DBA/2 mothers. The effect of maternal phenotype on risk was three- to five-fold. Fetal and maternal phenotype combined yielded a 10- to 20-fold risk differential for transplacental carcinogenesis by the methylated compounds, with greatest risk experienced by responsive fetuses in nonresponsive mothers, and least by nonresponsive progeny of responsive mothers.
Anderson
L M
LM
Laboratory of Comparative Carcinogenesis, Division of Cancer Etiology, National Cancer Institute, Frederick Cancer Research and Development Center (FCRDC), MD 21702, USA.
Ruskie
S
S
Carter
J
J
Pittinger
S
S
Kovatch
R M
RM
Riggs
C W
CW
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D001564:Benzo(a)pyrene / Q000378:metabolism / Q000633:toxicity; D002273:Carcinogens / Q000378:metabolism / Q000633:toxicity*; D003433:Crosses, Genetic; D005260:Female; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced; D008175:Lung Neoplasms / Q000139:chemically induced; D008297:Male; D008431:Maternal-Fetal Exchange; D008748:Methylcholanthrene / Q000378:metabolism / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D010597:Pharmacogenetics; D010641:Phenotype; D011247:Pregnancy; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics* / Q000378:metabolism; D012307:Risk Factors
D002273:Carcinogens; D018336:Receptors, Aryl Hydrocarbon; D001564:Benzo(a)pyrene; D008748:Methylcholanthrene; D015127:9,10-Dimethyl-1,2-benzanthracene