Maternal Dioxin Exposure Combined with a Diet High in Fat Increases Mammary Cancer Incidence in Mice

BackgroundRESULTS 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.ObjectivesBecause both TCDD and diet affect the estrogen pathway, we examined how TCDD and a high-fat diet (HFD) interact to alter breast cancer susceptibility.MethodsWe 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.ResultsWe 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.ConclusionsOur 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

Dual effects of phytoestrogens result in u-shaped dose-response curves.

Endocrine disruptors can affect the endocrine system without directly interacting with receptors, for example, by interfering with the synthesis or metabolism of steroid hormones. The aromatase that converts testosterone to 17beta-estradiol is a possible target. In this paper we describe an assay that simultaneously detects aromatase inhibition and estrogenicity. The principle is similar to that of other MCF-7 estrogenicity assays, but with a fixed amount of testosterone added. The endogenous aromatase activity in MCF-7 cells converts some of the testosterone to 17beta-estradiol, which is assayed by quantifying differences in the expression level of the estrogen-induced pS2 mRNA. Potential aromatase inhibitors can be identified by a dose-dependent reduction in the pS2 mRNA expression level after exposure to testosterone and the test compound. Using this assay, we have investigated several compounds, including synthetic chemicals and phytoestrogens, for aromatase inhibition. The phytoestrogens, except genistein, were aromatase inhibitors at low concentrations (< 1 micro M) but estrogenic at higher concentrations (greater than or equal to 1 micro M), resulting in U-shaped dose-response curves. None of the tested synthetic chemicals were aromatase inhibitors. The low-dose aromatase inhibition distinguished phytoestrogens from other estrogenic compounds and may partly explain reports about antiestrogenic properties of phytoestrogens. Aromatase inhibition may play an important role in the protective effects of phytoestrogens against breast cancer

Reversal of increased mammary tumorigenesis by valproic acid and hydralazine in offspring of dams fed high fat diet during pregnancy

Maternal or paternal high fat (HF) diet can modify the epigenome in germ cells and fetal somatic cells leading to an increased susceptibility among female offspring of multiple generations to develop breast cancer. We determined if combined treatment with broad spectrum DNA methyltransferase (DNMT) inhibitor hydralazine and histone deacetylase (HDAC) inhibitor valproic acid (VPA) will reverse this increased risk. C57BL/6 mouse dams were fed either a corn oil-based HF or control diet during pregnancy. Starting at age 7 weeks, female offspring were administered 3 doses of 7,12-dimethylbenz[a]anthracene (DMBA) to initiate mammary cancer. After last dose, offspring started receiving VPA/hydralazine administered via drinking water: no adverse health effects were detected. VPA/hydralazine reduced mammary tumor multiplicity and lengthened tumor latency in HF offspring when compared with non-treated HF offspring. The drug combination inhibited DNMT3a protein levels and increased expression of the tumor suppressor gene Cdkn2a/p16 in mammary tumors of HF offspring. In control mice not exposed to HF diet in utero, VPA/hydralazine increased mammary tumor incidence and burden, and elevated expression of the unfolded protein response and autophagy genes, including HIF-1α, NFkB, PERK, and SQSTM1/p62. Expression of these genes was already upregulated in HF offspring prior to VPA/hydralazine treatment. These findings suggest that breast cancer prevention strategies with HDAC/DNMT inhibitors need to be individually tailored.</p

Body fatness during childhood and adolescence and incidence of breast cancer in premenopausal women: a prospective cohort study

INTRODUCTION: Body mass index (BMI) during adulthood is inversely related to the incidence of premenopausal breast cancer, but the role of body fatness earlier in life is less clear. We examined prospectively the relation between body fatness during childhood and adolescence and the incidence of breast cancer in premenopausal women. METHODS: Participants were 109,267 premenopausal women in the Nurses' Health Study II who recalled their body fatness at ages 5, 10 and 20 years using a validated 9-level figure drawing. Over 12 years of follow up, 1318 incident cases of breast cancer were identified. Cox proportional hazards regression was used to compute relative risks (RRs) and 95% confidence intervals (CIs) for body fatness at each age and for average childhood (ages 5–10 years) and adolescent (ages 10–20 years) fatness. RESULTS: Body fatness at each age was inversely associated with premenopausal breast cancer incidence; the multivariate RRs were 0.48 (95% CI 0.35–0.55) and 0.57 (95% CI 0.39–0.83) for the most overweight compared with the most lean in childhood and adolescence, respectively (P for trend < 0.0001). The association for childhood body fatness was only slightly attenuated after adjustment for later BMI, with a multivariate RR of 0.52 (95% CI 0.38–0.71) for the most overweight compared with the most lean (P for trend = 0.001). Adjustment for menstrual cycle characteristics had little impact on the association. CONCLUSION: Greater body fatness during childhood and adolescence is associated with reduced incidence of premenopausal breast cancer, independent of adult BMI and menstrual cycle characteristics

Role of dietary fatty acids in mammary gland development and breast cancer

Breast cancer is the most common cancer among women worldwide. Estimates suggest up to 35% of cases may be preventable through diet and lifestyle modification. Growing research on the role of fats in human health suggests that early exposure in life to specific fatty acids, when tissues are particularly sensitive to their environment, can have long-term health impacts. The present review examines the role of dietary fat in mammary gland development and breast cancer throughout the lifecycle. Overall, n-3 polyunsaturated fatty acids have promising cancer-preventive effects when introduced early in life, and warrant further research to elucidate the mechanisms of action

Effect of dietary intervention on serum lignan levels in pregnant women - a controlled trial

<p>Abstract</p> <p>Background</p> <p>Mother's diet during pregnancy is important, since plant lignans and their metabolites, converted by the intestinal microflora to enterolignans, are proposed to possess multiple health benefits. Aim of our study was to investigate whether a dietary intervention affects lignan concentrations in the serum of pregnant women.</p> <p>Methods</p> <p>A controlled dietary intervention trial including 105 first-time pregnant women was conducted in three intervention and three control maternity health clinics. The intervention included individual counseling on diet and on physical activity, while the controls received conventional care. Blood samples were collected on gestation weeks 8-9 (baseline) and 36-37 (end of intervention). The serum levels of the plant lignans 7-hydroxymatairesinol, secoisolariciresinol, matairesinol, lariciresinol, cyclolariciresinol, and pinoresinol, and of the enterolignans 7-hydroxyenterolactone, enterodiol, and enterolactone, were measured using a validated method.</p> <p>Results</p> <p>The baseline levels of enterolactone, enterodiol and the sum of lignans were higher in the control group, whereas at the end of the trial their levels were higher in the intervention group. The adjusted mean differences between the baseline and end of the intervention for enterolactone and the total lignan intake were 1.6 ng/ml (p = 0.018, 95% CI 1.1-2.3) and 1.4 ng/mg (p = 0.08, 95% CI 1.0-1.9) higher in the intervention group than in the controls. Further adjustment for dietary components did not change these associations.</p> <p>Conclusion</p> <p>The dietary intervention was successful in increasing the intake of lignan-rich food products, the fiber consumption and consequently the plasma levels of lignans in pregnant women.</p> <p>Trial registration</p> <p><b>ISRCTN21512277, <url>http://www.isrctn.org</url></b></p