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Seeing the implications of their study on the larger research community, Dey and his colleague Haibin Wang, Ph.D., assistant professor in his division, who led the study, presented their findings to the National Institute of Environmental Health Sciences (NIEHS) in an effort to convince feed companies to standardize their diets. But perhaps most significantly, the findings could be clinically important for women who consume diets containing significant sources of phytoestrogens, such as soybeans.

Another potential problem is exposure to chemicals in the environment that can act as estrogen mimics. Dey’s colleague, Sanjoy K. Das, Ph.D., has investigated whether some of these environmental estrogens – the pesticides kepone, methoxychlor and DDT – might still be harmful even though they exist only at very low levels in the environment.

“There is a controversy surrounding these compounds…because they have not been used in this country since the 1970s. But they are very stable compounds. They are not quickly degraded and still persist in the environment in the soil and in the water. Humans can be exposed to them through consumption of plant products and fish,” says Das, associate professor of Pediatrics and Cancer Biology.

The three compounds are known to have estrogen-like (estrogenic) effects – they increase uterine weight and uterine cell proliferation – but only at very high doses.

“We thought that even at lower concentrations, they might be potently estrogenic, and we have provided molecular evidence in this regard, particularly with kepone.”

Das and colleagues found that low levels of kepone – but not of the other two compounds – have potent estrogenic effects due to the amplifying actions of a natural protein in the body called Bip. By increasing the expression of Bip in the mouse uterus, Das found that low doses of kepone increased cellular proliferation, uterine weight and the expression of genes that control uterine growth – similar to the effect of high doses of natural estrogen. Such changes may make the uterus nonreceptive to embryo implantation and might even lead to uterine cancer.

Because Bip expression is induced by stress, Das proposes that stress might increase a person’s susceptibility to the estrogenic effects of these compounds. At least, this happens in mice.

“This strongly suggests that environmental factors can lead to the induction of this protein (Bip), which may amplify the harmfulness of these estrogenic compounds even at low doses.”

Dey’s group is also using mouse models to probe the actions of progesterone – the ovarian hormone known as the “hormone of pregnancy.” Progesterone plays a major role in implantation and pregnancy maintenance, but how it supports these events is not clearly understood.

Studies led by a graduate student in Dey’s lab, Susanne Tranguch, have shown that FKBP52, a co-chaperone molecule that optimizes progesterone receptor signaling, plays a role in female reproduction: mice lacking the Fkbp52 gene have complete implantation failure. Recently, the researchers reported that progesterone supplementation restores embryo implantation in Fkbp52 knockout mice on one genetic background, but not another, and that to maintain the pregnancy past implantation requires higher levels of daily progesterone, suggesting that progesterone signaling is a function of genetic makeup and pregnancy stage. The findings may have clinical relevance for women who are infertile and/or have endometriosis due to progesterone resistance.

Cannabinoids
Although the classic “female” hormones estrogen and progesterone may be the most obvious areas of implantation research, another class of molecules called cannabinoids also plays a key role.

Marijuana is perhaps the most “famous” source of cannabinoids, but cannabinoid-like chemicals (endocannabinoids) are also found naturally in our bodies where they act as neurotransmitters in the brain and are responsible for the cognitive effects of marijuana.

But they came to Dey’s attention when he saw a study showing abnormal breast development in some male Vietnam veterans who were chronic marijuana smokers – which, in a male, indicates excessive estrogen effect.

This sparked Dey’s interest in the compound’s possible role in the female reproductive cycle and fertility. Over the past 10 years, Dey has become an international leader in the field and has launched the only program of its kind in the country to study endogenous cannabinoid (endocannabinoid) signaling during early pregnancy.

Dey and colleagues presented the first evidence for the presence of cannabinoid receptors in the mouse blastocyst, which they found has 25-times more cannabinoid receptors than the brain. One particular type of endocannabinoid, called anandamide, is produced in the uterus and activates these receptors.

While levels of both anandamide and the receptors are high in nonreceptive uterus and dormant blastocysts, levels drop drastically in receptive uterus and activated blastocysts – showing that cannabinoid signaling must be optimally balanced to synchronize pre-implantation development of the embryo and preparation of the uterine lining.

“Endocannabinoid signaling is important for several aspects of female reproduction – embryogenesis, embryo transport through the oviduct, and embryo implantation,” says Dey.

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