Implications of Adenogenesis

Endocrine-disrupting chemicals are defined by the US Environmental Protection Agency as a group of substances that “interfere with biosynthesis, secretion, transport, elimination and function of naturally existing hormones in the human body”. Exposure to endocrine disruptors during crucial developmental time windows increases an individual’s risk of developing a variety of diseases, including inborn errors, infertility, obesity and cancer. One of the most well-known EDCs is diethylstilbestrol, a synthetic estrogen that was widely prescribed to prevent miscarriage. During that time period, millions of women and their offspring were exposed to this compound, which was later shown to have teratogenic and oncogenic effects on many organ systems especially the reproductive tract. Since then, the mechanisms underpinning DES-related pathogenesis have been intensively studied and several animal models have been established. The most widely used model for DES research is the neonatal-DES model, which was first described by McLachlan and co-workers. 

This model is nonetheless valuable for understanding how EDCs impact reproductive organ function in general. Notably, most of these DES effects are mediated through the estrogen receptor, as shown by the finding that Esr1-null mice are largely resistant to DES-induced phenotypes. The effect of DES on the uterus is of particular interest because uterine metaplasia is one of the most common health problems for women exposed to DES before birth, which could lead to infertility. The neonatal uterus is composed of a simple columnar luminal epithelium, a fibroblast mesenchymal layer and smooth muscles. It is well known that stromal cells play an inductive role in the differentiation of the uterine epithelium during reproductive tract patterning. We and others have shown that the neonatal uterus is prone to DESmediated teratogenic effects, exhibiting marked morphological and gene expression changes shortly after DES exposure. A recent study demonstrated that the uterine epithelial ESR1 is dispensible for the proliferative response but is required for suppressing UE apoptosis as well as lactoferrin induction, indicating both cellautonomous and non-cell-autonomous mechanisms in estrogen signaling. This work implicates the adipogenic program as a downstream target of DES in the UE, which leads to the hypothesis that DES and possibly other EDCs might activate similar genetic pathways in other estrogen-responsive tissues, especially the adipocytes, to cause adulthood obesity.

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