Maternal dioxin exposure combined with a diet high in fat increases mammary cancer incidence in mice.
BACKGROUND
RESULTS from previous studies have suggested that breast cancer risk correlates with total lifetime exposure to estrogens and that early-life 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure or diets high in fat can also increase cancer risk.


OBJECTIVE
Because both TCDD and diet affect the estrogen pathway, we examined how TCDD and a high-fat diet (HFD) interact to alter breast cancer susceptibility.


METHODS
We exposed pregnant female FVB/NJ mice (12.5 days postcoitus) to 1 microg/kg TCDD or vehicle; at parturition, the dams were randomly assigned to a low-fat diet (LFD) or a high-fat diet (HFD). Female offspring were maintained on the same diets after weaning and were exposed to 7,12-dimethylbenz[a]anthracene on postnatal days (PNDs) 35, 49, and 63 to initiate mammary tumors. A second cohort of females was treated identically until PND35 or PND49, when mammary gland morphology was examined, or PND50, when mammary gland mRNA was analyzed.


RESULTS
We found that maternal TCDD exposure doubled mammary tumor incidence only in mice fed the HFD. Among HFD-fed mice, maternal TCDD exposure caused rapid mammary development with increased Cyp1b1 (cytochrome P450 1B1) expression and decreased Comt (catechol-O-methyltransferase) expression in mammary tissue. Maternal TCDD exposure also increased mammary tumor Cyp1b1 expression.


CONCLUSIONS
Our data suggest that the HFD increases sensitivity to maternal TCDD exposure, resulting in increased breast cancer incidence, by changing metabolism capability. These results provide a mechanism to explain epidemiological data linking early-life TCDD exposure and diets high in fat to increased risk for breast cancer in humans.
La Merrill
Michele
M
Department of Genetics, Center for Environmental and Health Susceptibility, Lineberger Cancer Center, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina, USA.
Harper
Rachel
R
Birnbaum
Linda S
LS
Cardiff
Robert D
RD
Threadgill
David W
DW
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D002394:Catechol O-Methyltransferase / Q000235:genetics; D003043:Cocarcinogenesis; D065633:Cytochrome P-450 CYP1B1; D004041:Dietary Fats / Q000008:administration & dosage / Q000009:adverse effects*; D004785:Environmental Pollutants / Q000008:administration & dosage / Q000633:toxicity; D004968:Estrogens, Non-Steroidal / Q000008:administration & dosage / Q000633:toxicity; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D051379:Mice; D000072317:Polychlorinated Dibenzodioxins / Q000008:administration & dosage / Q000633:toxicity*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000209:etiology*; D012307:Risk Factors
D004041:Dietary Fats; D004785:Environmental Pollutants; D004968:Estrogens, Non-Steroidal; D000072317:Polychlorinated Dibenzodioxins; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; C585498:Cyp1b1 protein, mouse; D065633:Cytochrome P-450 CYP1B1; D002394:Catechol O-Methyltransferase