Human Sex Hormone-Binding Globulin Binding Affinities of 125 Structurally Diverse Chemicals and Comparison with Their Binding to Androgen Receptor, Estrogen Receptor, and α-Fetoprotein

Abstract

One endocrine disruption mechanism is through binding to nuclear receptors such as the androgen receptor (AR) and estrogen receptor (ER) in target cells. The concentration of a chemical in serum is important for its entry into the target cells to bind the receptors, which is regulated by the serum proteins. Human sex hormone-binding globulin (SHBG) is the major transport protein in serum that can bind androgens and estrogens and thus change a chemical's availability to enter the target cells. Sequestration of an androgen or estrogen in the serum can alter the chemical elicited AR- and ER-mediated responses. To better understand the chemical-induced endocrine activity, we developed a competitive binding assay using human pregnancy plasma and measured the binding to the human SHBG for 125 structurally diverse chemicals, most of which were known to bind AR and ER. Eighty seven chemicals were able to bind the human SHBG in the assay, whereas 38 chemicals were nonbinders. Binding data for human SHBG are compared with that for rat α-fetoprotein, ER and AR. Knowing the binding profiles between serum and nuclear receptors will improve assessment of a chemical's potential for endocrine disruption. The SHBG binding data reported here represent the largest data set of structurally diverse chemicals tested for human SHBG binding. Utilization of the SHBG binding data with AR and ER binding data could enable better evaluation of endocrine disrupting potential of chemicals through AR- and ER-mediated responses since sequestration in serum could be considered.

Hazard assessment through hybrid in vitro / in silico approach: The case of zearalenone

“…In addition, the ranking observed in vitro is fully in line with the ranking of estrogenic potencies measured in animals in vivo (Everett et al, 1987). It should be kept in mind, however, that the complexity of the molecular events triggering the estrogenic response is high (Kocanova et al, 2010;Lee et al, 2012) and involves a number of cofactors beyond the estrogen receptors, including, for instance, the interaction with serum binding proteins (Hong et al, 2012(Hong et al, , 2015 -which may actually reduce the bioavailability of compounds. Nevertheless, the highly robust potency ranking observed with biological assays in vitro and in vivo as well as binding tests supports the role of the ligand-receptor interaction as the MIE in the estrogenic-mediated toxic effects induced by the members of this class of compounds.…”

Free and total plasma concentrations of elvitegravir/cobicistat during pregnancy and postpartum: a case report

“…Binding to a carrier protein that increases during pregnancy might be considered as a possible explanation for this finding. In this respect, we have investigated the adsorption of EVG on human sex hormone‐binding globulin, which is known to bind to a variety of chemicals ; however, our in vitro exploration did not reveal a specific affinity for this carrier (results not detailed).…”

sNebula, a network-based algorithm to predict binding between human leukocyte antigens and peptides

“…Prediction confidence has been proposed as one of the metrics to measure performance of predictive models developed in the FDA’s endocrine disruptors knowledge based project6465666768697071 using variety of machine learning methods such as decision tree72, Decision Forest models737475767778 based on molecular descriptors79 that are calculated using the algorithm developed for the expert systems of structure elucidation808182838485, support vector machine8687 and principal component analysis based algorithm8889. The continuous value output from sNebula for prediction of binding between an HLA and a peptide is the measure of likelihood of the peptide is a binder or non-binder of the HLA and indicates the confidence for the prediction.…”