A Novel Effect of Dioxin: Exposure during Pregnancy Severely Impairs Mammary Gland Differentiation

Abstract

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.

Regulation of Constitutive Mouse Hepatic Cytochromes P450 and Growth Hormone Signaling Components by 3-Methylcholanthrene

“…The STAT5 target gene product, whey acidic protein (WAP), was also reported to be down-regulated at the mRNA level by MC in mouse liver in an AHR-dependent manner (Nukaya et al, 2004). Using two primer sets for RT-PCR analysis, we could not detect WAP mRNA in mouse liver, consistent with the selective expression of WAP mRNA in mammary tissue (Vorderstrasse et al, 2004). We suggest that some mouse hepatic genes that are regulated by the GHR-JAK2-STAT5b pathway (e.g., Cyp2d9 and Mup2), but not others (e.g., Cis), are targeted for suppression by PAHs.…”

An enhanced postnatal autoimmune profile in 24 week-old C57BL/6 mice developmentally exposed to TCDD

“…This dose produced no overt toxicity in previous studies that utilized gd 18 data collection (Holladay et al, 1991) or in pups cross-fostered to naïve dams (Blaylock et al, 1992), suggesting sufficient postnatal TCDD exposure occurred by lactation to induce the wasting syndrome. Alternately, the higher dose of TCDD may have diminished lactation due to impaired mammary gland differentiation (Vorderstrasse et al, 2004). The other treatment groups did not show any significant mortality.…”

The Ligand Status of the Aromatic Hydrocarbon Receptor Modulates Transcriptional Activation of BRCA-1 Promoter by Estrogen

“…Prototypical environmental pollutants found in industrial pollution, tobacco smoke, and cooked foods include the polycyclic polyhalogenated 2,3,7,8-tetrachlorodibenzo-pdioxin (TCDD), which has been shown to alter mammary gland development (7,8), disrupt endocrine functions (9,10), and promote tumor growth (11,12). Population studies detected the accumulation of TCDD in breast milk (13,14), suggesting that this agent may reach breast tissue and be a risk factor in mammary neoplasia.…”