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.
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.
Comments
Post a Comment