Maternal dioxin exposure combined with a diet high in fat increases mammary cancer incidence in mice

Michele la Merril, Rachel Harper, Linda S. Birnbaum, Robert Cardiff, David W. Threadgill

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

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. Objectives: 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 μg/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.

Original languageEnglish (US)
Pages (from-to)596-601
Number of pages6
JournalEnvironmental Health Perspectives
Volume118
Issue number5
DOIs
StatePublished - May 1 2010

Fingerprint

Maternal Exposure
Dioxins
High Fat Diet
Breast Neoplasms
Incidence
Mothers
Human Mammary Glands
Cytochrome P-450 Enzyme System
Estrogens
Breast
Diet
Polychlorinated Dibenzodioxins
Catechol O-Methyltransferase
Fat-Restricted Diet
Weaning
Parturition
Messenger RNA

Keywords

  • COMT
  • CYP1B1
  • Dioxin
  • High-fat diet
  • Mammary cancer
  • Puberty. Environ health perspect

ASJC Scopus subject areas

  • Public Health, Environmental and Occupational Health
  • Health, Toxicology and Mutagenesis

Cite this

Maternal dioxin exposure combined with a diet high in fat increases mammary cancer incidence in mice. / la Merril, Michele; Harper, Rachel; Birnbaum, Linda S.; Cardiff, Robert; Threadgill, David W.

In: Environmental Health Perspectives, Vol. 118, No. 5, 01.05.2010, p. 596-601.

Research output: Contribution to journalArticle

la Merril, Michele ; Harper, Rachel ; Birnbaum, Linda S. ; Cardiff, Robert ; Threadgill, David W. / Maternal dioxin exposure combined with a diet high in fat increases mammary cancer incidence in mice. In: Environmental Health Perspectives. 2010 ; Vol. 118, No. 5. pp. 596-601.
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abstract = "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. Objectives: 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 μg/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.",
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