Extranuclear-initiated estrogenic actions of endocrine disrupting chemicals: Is there toxicology beyond paracelsus?
Endocrine Disrupting Chemicals (EDCs), including bisphenol-A (BPA) do not act as traditional toxic chemicals inducing massive cell damage or death in an unspecific manner. EDCs can work upon binding to hormone receptors, acting as agonists, antagonists or modulators. Bisphenol-A displays estrogenic activity and, for many years it has been classified as a weak estrogen, based on the classic transcriptional action of estrogen receptors serving as transcription factors. However, during the last two decades our knowledge about estrogen signaling has advanced considerably. It is now accepted that estrogen receptors ERα and ERβ activate signaling pathways outside the nucleus which may or may not involve transcription. In addition, a new membrane estrogen receptor, GPER, has been proposed. Pharmacological and molecular evidence, along with results obtained in genetically modified mice, demonstrated that BPA, and its substitute BPS, are potent estrogens acting at nanomolar concentrations via extranuclear ERα, ERβ, and GPER. The different signaling pathways activated by BPA and BPS explain the well-known estrogenic effects of low doses of EDCs as well as non-monotonic dose-response relationships. These signaling pathways may help to explain the actions of EDCs with estrogenic activity in the etiology of different pathologies, including type-2 diabetes and obesity.
CIBER de Diabetes y Enfermedades Metabólicas Asociadas, CIBERDEM, Universidad Miguel Hernández de Elche, Elche, Alicante, Spain; Instituto de Bioingeniería, Universidad Miguel Hernández de Elche, Alicante, Spain. Electronic address: nadal@umh.es.
Angel
A
Nadal
CIBER de Diabetes y Enfermedades Metabólicas Asociadas, CIBERDEM, Universidad Miguel Hernández de Elche, Elche, Alicante, Spain; Instituto de Bioingeniería, Universidad Miguel Hernández de Elche, Alicante, Spain; Departamento de Biología Aplicada, Universidad Miguel Hernández de Elche, Alicante, Spain.
Esther
E
Fuentes
CIBER de Diabetes y Enfermedades Metabólicas Asociadas, CIBERDEM, Universidad Miguel Hernández de Elche, Elche, Alicante, Spain; Instituto de Bioingeniería, Universidad Miguel Hernández de Elche, Alicante, Spain.
Cristina
C
Ripoll
CIBER de Diabetes y Enfermedades Metabólicas Asociadas, CIBERDEM, Universidad Miguel Hernández de Elche, Elche, Alicante, Spain; Instituto de Bioingeniería, Universidad Miguel Hernández de Elche, Alicante, Spain.
Sabrina
S
Villar-Pazos
CIBER de Diabetes y Enfermedades Metabólicas Asociadas, CIBERDEM, Universidad Miguel Hernández de Elche, Elche, Alicante, Spain; Instituto de Bioingeniería, Universidad Miguel Hernández de Elche, Alicante, Spain.
Manuel
M
Castellano-Muñoz
Departamento de Fisiología, Genética y Microbiología, Universidad de Alicante, Alicante, Spain.
Sergi
S
Soriano
Departamento de Fisiología, Genética y Microbiología, Universidad de Alicante, Alicante, Spain.
Juan
J
Martinez-Pinna
CIBER de Diabetes y Enfermedades Metabólicas Asociadas, CIBERDEM, Universidad Miguel Hernández de Elche, Elche, Alicante, Spain; Instituto de Bioingeniería, Universidad Miguel Hernández de Elche, Alicante, Spain; Departamento de Biología Aplicada, Universidad Miguel Hernández de Elche, Alicante, Spain.
Ivan
I
Quesada
CIBER de Diabetes y Enfermedades Metabólicas Asociadas, CIBERDEM, Universidad Miguel Hernández de Elche, Elche, Alicante, Spain; Departamento de Biología Aplicada, Universidad Miguel Hernández de Elche, Alicante, Spain.
Paloma
P
Alonso-Magdalena
D000818:Animals; D002467:Cell Nucleus; D052244:Endocrine Disruptors / Q000494:pharmacology*; D004967:Estrogens / Q000494:pharmacology*; D005786:Gene Expression Regulation; D006801:Humans; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D014116:Toxicology / Q000639:trends*
D052244:Endocrine Disruptors; D004967:Estrogens; D018160:Receptors, Cytoplasmic and Nuclear; D011960:Receptors, Estrogen
Beta-cells; Bisphenol-A; Bisphenol-S; Endocrine disruptors; Estrogen receptors; Islet of Langerhans