Insights from the structure of estrogen receptor into the evolution of estrogens: Implications for endocrine disruption

Inherited human sex reversal due to impaired nucleocytoplasmic trafficking of SRY defines a male transcriptional threshold

“…Metazoans exhibit an extraordinary diversity of sex-determining genes and signals, including temperature and social cues (47,48). Intersexual phenotypes, readily obtained in model organisms (49), abound in the wild, especially in the presence of environmental endocrine disruptors (50). Further, the ubiquity of bisexual and homosexual behaviors among social mammals (including in…”

Expanding the structural footprint of xenoestrogens

“…Examination of the pathway for the synthesis of physiological estrogens indicates that the synthesis 27-hydroxy-cholesterol 33 and D 5 -androstenediol 54,55 is more parsimonious than E2, which is the basis for proposing that 27-hydroxy-cholesterol and D 5 -androstenediol may have been transcriptional activators of the ancestral ER. 33,54,55 From an evolutionary perspective, some estrogenic activities in mammals of D 5 -androstenediol and 27hydroxy-cholesterol may be vestiges of their activities in ancestral vertebrates.…”

“…5] and 5a-androstanediol [ Fig. 6] indicate that there is conformational flexibility in the ER so that 3b-hydroxyl on D 5androstenediol and 5a-androstanediol has stabilizing contacts with ERa and ERb: 33,49 Both D 5 -androstenediol and 5a-androstanediol form hydrogen bonds with Glu-353 and Arg-394 in ERa and with Glu-305 and Arg-346 on ERb. Their A ring contacts Leu-387 on ERa and Leu-339 on ERb, and C19 contacts Ala-350 on ERa and Ala-302 on ERb.…”

“…Although genistein has a different D ring than E2, [ Fig. 1C [31][32][33][34] have an A ring that mimics that of E2 and second ring with a hydroxyl that mimics the 17b-hydroxyl on E2 [ Fig. 4].…”

The microbiome as a target for endocrine disruptors: Novel chemicals may disrupt androgen and microbiome-mediated autoimmunity

“…[1][2][3][4][5][6] Some of these endocrine disruptors [EDCs] contain aromatic and cyclic structures that mimic part or all of structures on steroids, 2,[7][8][9][10][11][12] providing the EDC with sufficient affinity for the ligand-binding domain on steroid receptors 2,5,10,11,[13][14][15] or for enzymes involved in synthesis or inactivation of steroids, 3,14,[16][17][18][19] so as to interfere with the normal functioning of these proteins.…”