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Fetal programming
Published in Hung N. Winn, Frank A. Chervenak, Roberto Romero, Clinical Maternal-Fetal Medicine Online, 2021
Katherine E. Pelch, Jana L. Allison, Susan C. Nagel
To date, the largest group of environmental chemicals with hormonal activity interferes with normal estrogen signaling. Those chemicals that bind directly to the estrogen receptor are termed xenoestrogens. They can have estrogenic, antiestrogenic, or mixed receptor activity. While hundreds of xenoestrogens have been described, a few selected ones are described below.
Chemopreventive Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
There has been concern for some time that xenoestrogens in food and water may enhance the growth of estrogen-driven cancers, and may also reduce the effectiveness of antiestrogen drugs such as letrozole. Researchers from the Scripps Research Institute (TSRI) in the US studied the effect of palbociclib/letrozole on breast cancer cells growing in vitro using advanced metabolomics technology to investigate how metabolite populations changed when exposed to zearalenone and genistein. By profiling cell metabolomes with and without drug treatment the researchers obtained useful information about the biological pathways perturbed by the agent. Interestingly, the study revealed that neither palbociclib nor letrozole alone had a strong effect on metabolites in an ER-positive breast cancer cell line, although the combination had a significant impact consistent with patient benefit observed in clinical trials. However, even at very low doses, similar to typical dietary exposures, both genistein and zearalenone affected many key metabolites, essentially reversing the metabolomic impact of the anticancer drug combination. Furthermore, under the influence of either xenoestrogen, the breast tumor cells resumed proliferating at a rate comparable to that seen in the absence of drug treatment. Importantly, it was shown that even a low, background-level exposure to the xenoestrogens was sufficient to impact the effect of the therapy.
Disruption of Nongenomic Steroid Actions on Gametes and Serotonergic Pathways Controlling Reproductive Neuroendocrine Function by Environmental Chemicals
Published in Rajesh K. Naz, Endocrine Disruptors, 2004
Disruption of a nongenomic steroid action by a xenobiotic chemical binding to a steroid membrane receptor was first demonstrated for the maturation-inducing steroid (MIS) receptor mediating OM in a teleost model, the spotted seatrout [73]. Several xenoestrogens that antagonize MIS (17,20β-trihydroxy-4-pregnen-3-one, 20β-S) stimulation of sperm motility in Atlantic croaker are also effective competitors for 20-S binding to the sperm membrane receptor [35]. Xenoestrogens have also been shown to mimic the rapid, nongenomic actions of estrogens by binding to estrogen membrane receptors. Several xenoestrogens display relatively high binding affinities for the membrane estrogen receptor in Atlantic croaker testes, similar to their binding affinities for the nuclear estrogen receptor in this species [54, 74], and also mimic the inhibitory actions of estrogens on testicular androgen production [54]. In rats, the nongenomic action of a xenoestrogen, bisphenol A, on insulin secretion was associated with its binding to the membrane estrogen receptor [66].
Estrogen receptors as potential therapeutic target in endometrial cancer
Published in Journal of Receptors and Signal Transduction, 2023
Payel Guha, Koushik Sen, Piyali Chowdhury, Dilip Mukherjee
Natural and synthetic chemicals termed as xenoestrogens along with many plant- and fungus-derived compounds (phyto- and myco-estrogens) such as coumestans and stilbenes flavones, lignans, and isoflavones (genistein) have estrogenic activity in human and other animals acting as GPER ligands [64]. Majority of phytoestrogens and xenoestrogens although are reported to exert their physiological effects through modulation of ERα and ERβ [65], many of them including genistein and daidzein also can bind and activate GPER [66,67]. Drugs such as tamoxifen and raloxifene, the selective estrogen receptor modulators (SERMs) and fulvestrant, the selective estrogen receptor downregulator (SERD) used for treatment of breast cancer and osteoporosis for their inhibitory effects on ERα function are also reported to bind and function as GPER agonists [23,68]. The complex pharmacological specificities of these various ligands thus complicated the interpretation of the mechanism of their action in both physiological and pathological conditions.
Environmental toxin exposure in polycystic ovary syndrome women and possible ovarian neoplastic repercussion
Published in Current Medical Research and Opinion, 2020
Ilaria Soave, Tommaso Occhiali, Chiara Assorgi, Roberto Marci, Donatella Caserta
EDCs can cause epigenetic modifications, especially during pre- and peri-natal exposition158. These subtle epigenetic alterations accompany the individual throughout their life and can lead to carcinogenesis. The data available on epigenetic changes and ovarian cancer mainly show that ERs are involved, particularly downregulating suppressor receptors (ERβ), through gene promoter hypermethylation, resulting in silencing gene activity109. In the context of PCOS and EDC exposure, the shift toward ERα-only expression may be included in a pro-estrogenic milieu granted by abundant adipose tissue (PCOS), xenoestrogens (EDCs) and a spontaneous receptor selection already undertaken by the ovarian neoplasm striving to grow. Many xenoestrogens can only exert a modest estrogenic effect, but they have greater bioavailability (almost complete) when compared to endogenous estrogens. Moreover, xenoestrogens of different kinds can work synergically with one another and with endogenous estrogens159–162.
The role of xenobiotic-metabolizing enzymes in the placenta: a growing research field
Published in Expert Review of Clinical Pharmacology, 2020
Ricardo Blanco-Castañeda, Carlos Galaviz-Hernández, Paula C. S. Souto, Victor Vitorino Lima, Fernanda R. Giachini, Carlos Escudero, Alicia E Damiano, L. Jazel Barragán-Zúñiga, Gerardo Martínez-Aguilar, Martha Sosa-Macías
The exposition to xenobiotics during pregnancy is not only related to drug consumption/prescription, there are a lot of substances taken from either diet or environment that may have repercussion on the fetal development and wellbeing. One of these is bisphenol A (BPA), a xenoestrogen used as a monomer in the manufacture of plastic products [199]. BPA has been detected in measurable levels in umbilical cord serum both in mid-gestation and close to delivery [147,148]. In these studies, BPA and sulfated BPA levels in cord serum were higher than glucuronided BPA ones [147,148]. This could reflect the metabolic activity of conjugation in placenta, since several studies have reported higher sulfotransferase activity and lower UGT activity in the human placenta compared with liver [200–202]. Further, Liu et al. (2017) detected higher concentrations of conjugated BPA metabolites in cord serum than in paired maternal one, which could be the result of the placental and fetal metabolism at least at the end of pregnancy [148]. It has been found a limited placental permeability of BPA-glucuronide in a human placenta perfusion study [203], and a slower clearance of conjugated BPA in feto-placental compartment in animal studies [204,205]. The BPA exposure in-utero may provoke fewer parenchymal tissue development in endocrine pancreas, kidney, and uterus; triggering diabetogenic and atherogenic effects [199]. Besides, BPA exposure increases the risk of developing either attention-deficit/hyperactivity and/or autism spectrum disorders [206] and may be associated with adverse reproductive outcomes [207,208].