Xenoestrogens are potent activators of nongenomic estrogenic responses

Abstract

Studies of the nuclear transcriptional regulatory activities of nonphysiological estrogens have not explained their actions in mediating endocrine disruption in animals and humans at the low concentrations widespread in the environment. However, xenoestrogens have rarely been tested for their ability to participate in the plethora of nongenomic steroid signaling pathways elucidated over the last several years. Here we review what is known about such responses in comparison to our recent evidence that xenoestrogens can rapidly and potently elicit signaling through nongenomic pathways culminating in functional endpoints. Both estradiol (E 2 ) and compounds representing various classes of xenoestrogens (diethylstilbestrol, coumestrol, bisphenol A, DDE, nonylphenol, endosulfan, and dieldrin) act via a membrane version of the estrogen receptor-α on pituitary cells, and can provoke Ca ++ influx via L-type channels, leading to prolactin (PRL) secretion. These hormones and mimetics can also cause the oscillating activation of extracellular regulated kinases (ERKs). However, individual estrogen mimetics differ in their potency and temporal phasing of these activations compared to each other and to E 2 . It is perhaps in these ways that they disrupt some endocrine functions when acting in combination with physiological estrogens. Our quantitative assays allow comparison of these outcomes for each mimetic, and let us build a detailed picture of alternative signaling pathway usage. Such an understanding should allow us to determine the estrogenic or antiestrogenic potential of different types of xenoestrogens, and help us to develop strategies for preventing xenoestrogenic disruption of estrogen action in many tissues.

Expression of Concern: Laccase treatment impairs bisphenol A‐induced cancer cell proliferation affecting estrogen receptor α‐dependent rapid signals

“…Rapid modulation of ERK and AKT signaling in response to BPA has been observed in neurons, immune cells, and during brain development (14,(40)(41)(42). As far as we know, no information is available on the involvement of these BPA-induced rapid responses on cancer cell proliferation.…”

Bisphenol-A alters gene expression and functional parameters in molluscan hepatopancreas

“…With regards to the possible mechanisms of action of BPA, both genomic and non genomic modes of action involving ER-like receptors, as well as receptor-independent mechanisms may participate in mediating the effects (Quesada et al, 2002;Walsh et al, 2005;Ropero et al, 2006;Watson et al, 2007). In mussel immunocytes, BPA was shown to interfere with signaling components whose activation plays a key role in mediating the effect of E 2 .…”

“…However, estrogens can also act through rapid, 'non genomic' mechanisms of action that may be initiated at either membrane or cytosolic locations and can result in both direct local effects (such as changes in ion fluxes) and regulation of gene transcription secondary to activation of cytosolic kinase cascades (Levin, 2005;Vasudevan and Pfaff, 2007). Recent studies demonstrated that xenoestrogens can rapidly and potently elicit signaling through non genomic pathways culminating in functional endpoints (Walsh et al, 2005;Ropero et al, 2006;Tabb and Blumberg, 2006;Waring and Harris, 2005;Watson et al, 2007).…”

Selective estrogen receptor α activation disrupts sex organ differentiation and induces expression of vitellogenin II and very low-density apolipoprotein II in Japanese quail embryos

“…This does not exclude that similar effects can also be induced or modulated by other mechanisms, e.g., through membrane ERs and non-genomic signaling pathways (Watson et al 2007) or through ERb. Although ERa was the predominantly expressed ER subtype in gonads and MDs during early differentiation, small amounts of ERb mRNA were also found.…”