Chemical Effects on Breast Development, Function, and Cancer Risk: Existing Knowledge and New Opportunities

Abstract

Population studies show worrisome trends towards earlier breast development, difficulty in breastfeeding, and increasing rates of breast cancer in young women. Multiple epidemiological studies have linked these outcomes with chemical exposures, and experimental studies have shown that many of these chemicals generate similar effects in rodents, often by disrupting hormonal regulation. These endocrine-disrupting chemicals (EDCs) can alter the progression of mammary gland (MG) development, impair the ability to nourish offspring via lactation, increase mammary tissue density, and increase the propensity to develop cancer. However, current toxicological approaches to measuring the effects of chemical exposures on the MG are often inadequate to detect these effects, impairing our ability to identify exposures harmful to the breast and limiting opportunities for prevention. This paper describes key adverse outcomes for the MG, including impaired lactation, altered pubertal development, altered morphology (such as increased mammographic density), and cancer. It also summarizes evidence from humans and rodent models for exposures associated with these effects. We also review current toxicological practices for evaluating MG effects, highlight limitations of current methods, summarize debates related to how effects are interpreted in risk assessment, and make recommendations to strengthen assessment approaches. Increasing the rigor of MG assessment would improve our ability to identify chemicals of concern, regulate those chemicals based on their effects, and prevent exposures and associated adverse health effects.

Application of the Key Characteristics Framework to Identify Potential Breast Carcinogens Using Publicly Available in Vivo , in Vitro , and in Silico Data

“…Ninety-six putative non-MCs met our criteria for being genotoxic EDCs (see the “Methods” section). Note that based on our reviews of mammary tumors in cancer bioassays, as described in in the “Discussion” section in “Two-year cancer bioassay” and in Cardona and Rudel 58 and Kay et al., 83 we expect that some of these putative non-MCs may in fact be rodent MCs.…”

“…Of the 30 mammary developmental toxicants, 6 were in our list of MCs, and many of the others [benzyl butyl phthalate, dichlorodiphenyltrichloroethane (DDT), zearalenone, perfluorooctanoic acid (PFOA), 2,3,7,8-tetrachlorodibenzo- -dioxin (TCDD), and polybrominated diphenyl ethers] have been found to affect the breast in humans. 44 , 82 , 83 …”

“…Finally, some putative non-MCs may be false negatives (discussed below and by Kay et al. 83 ), so enrichment calculations may be over- or underestimates.…”

Environmental exposure and the role of AhR in the tumor microenvironment of breast cancer

“…Approximately 2 decades ago, AhR was found to be overexpressed in mammary cancer in rats ( Trombino et al, 2000 ) sparking curiosity as to its role in breast cancer progression. Several studies have since shown that chemical exposure and AhR activation affect processes of mammary gland differentiation, disrupting pregnancy-related differentiation and milk production, and increasing the risk of breast cancer ( Warner et al, 2002 ; Vorderstrasse et al, 2004 ; Lew et al, 2011 ; Belton et al, 2018 ; Kay et al, 2022 ). Further studies have elucidated AhR’s molecular contribution to carcinogenic progression and ratified the oncogenic role of AhR in breast cancer cells ( Wang et al, 2017 ; Wang et al, 2020 ).…”

Multiclass Determination of Endocrine-Disrupting Chemicals in Meconium: First Evidence of Perfluoroalkyl Substances in This Biological Compartment

“…Thus, in utero exposure to EDCs has been associated with anomalous neonatal weight and head circumference values [ 3 , 4 ], urogenital malformations [ 5 ], reproductive development abnormalities [ 6 , 7 ], and cognitive and neurodevelopmental disorders [ 8 , 9 ]. Early exposure to EDCs has also been associated with health problems later in life, including male infertility [ 10 ], endometriosis [ 11 ], and even cancer and cancer progression [ 12 , 13 , 14 ].…”