DES effects on the mammary gland: rodent models and epidemiological studies

EDC-2: The Endocrine Society’s Second Scientific Statement on Endocrine-Disrupting Chemicals, 2015

Abstract

In addition to the better-known effects of early-life DES exposure on reproductive tract development and vaginocervical cancer in humans, animal studies have also shown that DES exposure affects mammary glands. In utero and lactational exposure to high doses of DES increased mammary gland growth and decreased the number of TEBs. Neonatal high-dose exposure to DES triggered extensive ductal dilation at P33 and promoted precocious lactogenesis in postpubertal, nulliparous 12-week-old female mice. In contrast, low-dose DES reduced ductal branching at P6 and P33. Low-dose exposure to DES during pregnancy caused impaired lactation in rats.

Gestational exposure of DES in rats resulted in an increase in spontaneous mammary gland tumors. Furthermore, multiple studies in mice showed that prenatal exposure to DES increased the risk of mammary tumorigenesis in females exposed to a known carcinogen, as well as the numbers of TEBs. In mice treated prenatally with DES there was a significant increase in enhancer of Zeste homolog 2 (EZH2) protein and EZH2 activity (measured by increased mammary histone H3 trimethylation)—a histone methyltransferase that may be linked to breast cancer risk and epigenetic regulation of tumorigenesis, as well as an increase in adult mammary gland EZH2. However, two studies found that relatively high-dose exposure during neonatal development reduced TEB numbers and prevented spontaneous mammary gland tumors. The mechanism for effects of DES on reproductive tissues likely varies by tissue. Taken together, this highlights the likelihood that DES daughters may have increased risk of adverse breast outcomes, cancer, and developmental abnormalities of the vagina.

References

  • Full study (free access) : EDC-2: The Endocrine Society’s Second Scientific Statement on Endocrine-Disrupting Chemicals, Endocrine Reviews, Volume 36, Issue 6, Pages E1–E150, doi.org/10.1210/er.2015-1010, 1 December 2015.
  • Image credit Esther Wechsler.
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