Exposure to endocrine disrupting chemicals and other hormone-related variables, DNA methylation, and breast cancer

Abstract

Introduction Breast cancer is the most common cancer in the world and environmental factors such as endocrine disrupting chemicals, as well as reproductive and hormone-related factors play a crucial role in the development of this disease. In order to assess causal pathways between these exposures and disease initiation, biomarkers based on DNA methylation measurements can be used.

Methods The potential association between global and locus-specific DNA methylation and breast cancer risk was investigated in two prospective European nested case-control studies. The HM450 array was used to generate epigenomic profiles of archived blood samples, collected from study participants before the onset of disease in 324 matched case-control pairs. The association between endocrine disrupting chemicals measured in blood samples (n=368), reproductive and hormone-related variables assessed by questionnaire (n=324), and hormone levels measured in blood(n=36), and DNA methylation was studied. The meet-in-the-middle approach was applied to identify DNA methylation markers related to both exposures and disease endpoint.

Results Global hypomethylation was observed among breast cancer cases compared with controls and locus-specific analyses identified 26 CpGs whose DNA methylation was associated with breast cancer. Cadmium exposure was associated with DNA methylation at 62 CpGs but most associations did not survive adjustment for smoking status. In addition, numerous reproductive and hormone-related variables, as well as the hormones D4 and testosterone were associated with DNA methylation, and three potential meet-in-the-middle candidates were observed.

Discussion Despite the relatively low power, results indicated that genome-wide hypomethylation among breast cancer cases may serve as a biomarker for disease risk. More research with bigger sample sizes is needed to disentangle the potential effect of cadmium and smoking on DNA methylation and to further explore possible effects of reproductive and hormone-related factors, as well as hormone levels, on DNA methylation. It is of interest to investigate what the biological consequences of these changes in methylation are.