A novel effect of dioxin: exposure during pregnancy severely impairs mammary gland differentiation

Many ligands for the aryl hydrocarbon receptor (AhR) are considered endocrine disruptors and carcinogens, and assessment of adverse health effects in humans exposed to such chemicals has often focused on malignancies, including breast cancer. Mammary tissue contains the AhR, and inappropriate activation of the AhR during fetal development causes defects in mammary development that persist into adulthood. However, it is not known whether the extensive differentiation of mammary tissue that occurs during pregnancy is also sensitive to disruption by AhR activation. To examine this, we exposed pregnant C57Bl/6 mice to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on days 0, 7, and 14 of pregnancy. Examination of mammary glands on days 9, 12, and 17 of pregnancy and on the day of parturition showed severe defects in development, including stunted growth, decreased branching, and poor formation of lobular alveolar structures. This impaired differentiation was biologically significant, as expression of whey acidic protein in the gland was suppressed, and all pups born to TCDD-treated dams died within 24 h of birth. Analysis of circulating progesterone, prolactin, and estradiol suggest that hormone production was slightly impaired by inappropriate activation of the AhR. However, hormone levels were affected only very late in pregnancy. Given that the observed defects in gland development preceded these hormonal effects, altered hormone levels are an unlikely mechanistic explanation for impaired mammary development. This novel finding that AhR activation during pregnancy disrupts mammary gland differentiation raises questions about the susceptibility of mammary tissue to direct injury by endocrine disrupting agents and the potential for AhR-mediated signaling to adversely affect lactation and breast tissue development in human populations.