Abstract
Breast cancer is the most common cancer in Western women and while its precise etiology is unknown, environmental factors are thought to play a role. The organochlorine pesticide dieldrin is a persistent environmental toxicant thought to increase the risk of breast cancer and reduce survival in the human population. The objective of this study was to define the effect of developmental exposure to environmentally relevant concentrations of dieldrin, on mammary tumor development in the offspring. Sexually mature FVB-MMTV/neu female mice were treated with vehicle (corn oil), or dieldrin (0.45, 2.25, and 4.5 µg/g body weight) daily by gavage for 5 days prior to mating and then once weekly throughout gestation and lactation until weaning. Dieldrin concentrations were selected to produce serum levels representative of human background body burdens, occupational exposure, and overt toxicity. Treatment had no effect on litter size, birth weight or the number of pups surviving to weaning. The highest dose of dieldrin significantly increased the total tumor burden and the volume and number of tumors found in the thoracic mammary glands. Increased mRNA and protein expression of the neurotrophin BDNF and its receptor TrkB was increased in tumors from the offspring of dieldrin treated dams. This study indicates that developmental exposure to the environmental contaminant dieldrin causes increased tumor burden in genetically predisposed mice. Dieldrin exposure also altered the expression of BNDF and TrkB, novel modulators of cancer pathogenesis.
Highlights
Breast cancer is the most prevalent cancer in women, and the incidence varies with age, geography, ethnicity and socioeconomic status, the lifetime risk of developing breast cancer is 1 in 9, with 1 in 28 women expected to die from breast cancer [1,2]
Body weight was affected by low dose dieldrin (0.45 mg/ g) with a modest increase in postnatal body weight from weeks 1–3 after which body weight did not differ from control for the remaining 19 weeks (Figure 1)
This study demonstrates that dieldrin increases the formation of mammary tumors and alters the expression profile of neurotrophins/neurotrophin receptors in resulting tumors
Summary
Breast cancer is the most prevalent cancer in women, and the incidence varies with age, geography, ethnicity and socioeconomic status, the lifetime risk of developing breast cancer is 1 in 9, with 1 in 28 women expected to die from breast cancer [1,2]. A large prospective study in a Danish population found a two-fold increased risk of developing breast cancer (adjusted odds ratio 2.05 [95% CI 1.17–3.57]) in women with the highest dieldrin exposure [10] with poorer overall survival and increased mortality in breast cancer patients (RR, 2.61 [95% CI 0.97–7.01]) [9] While this positive association was not observed in several smaller studies [12,13], the strong statistical correlation observed in the Danish studies taken together with results of animal studies demonstrating that dieldrin alters mammary gland development following developmental exposure [14], indicates the need to further investigate this association. Adequate study of toxicant exposures during critical windows of mammary gland development are necessary given the higher susceptibility to environmental toxicants in developing mammary structures and that dieldrin readily crosses the placental barrier and is excreted in breast milk leading to its accumulation in fetal and neonatal adipose tissues including the mammary glands [21,22,23]
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