BPA is a xenoestrogen endocrine disruptor that is thought to act as a weak estrogen by binding to the estrogen receptor with low affinity. It is a common ingredient in the manufacture of polycarbonate plastics and production has grown rapidly, from 16 million pounds in 1991 to 2.3 billion pounds in 2004 in the United States alone (34
). Several harmful health effects have been associated with BPA exposure including prostate cancer, breast cancer, obesity, early sexual maturation in females, and altered reproductive function (35
). The effects of BPA are dependent on time of exposure and dose. Low dose neonatal exposure to BPA in mice causes abnormalities in the female reproductive tract including early vaginal opening and ovarian and reproductive tract abnormalities in females (36
). Low levels of BPA exposure in-utero have also led to uterine disruption in rat offspring and altered vaginal morphology in postpubertal offspring (7
) BPA leads to epigenetic alterations and an increase in HOXA10 mRNA expression; an essential gene associated with uterine development and fertility (38
In humans there is an association between recurrent miscarriage and BPA exposure (12
). This correlation is interesting given that mice exposed to low doses of BPA have high rates of meiotic failure, specifically an increase in aneuploid eggs and embryos (40
). While the increased aneuploidy rates are expected contribute to adverse pregnancy outcomes and pregnancy loss, uterine effects of BPA are likely to have an impact on pregnancy as well.
Uterine proliferation and differentiation during the preimplantation period and in pregnancy have been well characterized and these processes are dependent on estrogen and progesterone. These two hormones are both necessary and sufficient to achieve endometrial development and to support pregnancy. Estrogen induces expression of progesterone receptor (PR). A balance between estrogen and progesterone is necessary for the normal and cyclic function of the endometrium, and disruption of this balance can lead to pathologies such as infertility, abnormal bleeding, endometriosis, pregnancy loss, and cancer (42
). Rhesus monkeys treated with CDR0I-85/287, a non-steroidal estrogen antagonist known for its anti-implantation effects, show markedly decreased progesterone receptor expression (43
). Similarly, in humans an inadequate response to progesterone or an insufficient serum progesterone concentration may lead to pregnancy loss and infertility (40
). The alteration of PR expression by BPA could provide an explanation for how BPA exerts its estrogenic endocrine disrupting effects in early pregnancy.
BPA exposure has also been associated with disorders characterized by unrestrained endometrial growth such as endometriosis and endometrial hyperplasia (14
). Estrogens typically cause endometrial growth and proliferation, while progestins cause endometrial differentiation. Estrogen exposure unopposed by progesterone leads to excessive endometrial growth hyperplasia and an increased risk of endometrial epithelial cancer. Similarly endometriosis is characterized by a loss of the usual inhibitory effects of progesterone and is considered progesterone resistant (13
,). Diminished PR expression and therefore diminished progesterone action would be expected to result in increased endometrial proliferation, seen in both of these conditions. The association of BPA with each of the previously described clinical conditions may be due to diminished PR expression, progesterone resistance, diminished opposition of estrogen and therefore, indirectly, a functional increase in estrogen action.
In summary BPA exposure results in antagonism of estradiol’s effect on PR. By decreasing PR expression BPA decreases the ability of progesterone to inhibit estradiol action. BPA exposure in women may affect the balance between estrogen and progesterone action and in turn lead to a heightened estrogen response. Therefore, BPA indirectly leads to increased estrogen action. The effect of BPA on PR may explain the association of BPA exposure with diseases associated with increased endometrial proliferation and diminished differentiation, including spontaneous abortion, endometriosis, endometrial hyperplasia and cancer.