Prediction of endocrine disrupters based on a new structure-activity relationship for sex and environmental hormones using chemical hardness concept

Classification of the relationship between electronic structures and biolog ical activities of endocrine disrupters (so-called environmental hormones) was attempted using the parameters of absolute hardness (eta), absolute ele ctronegativity (chi), and global softness (S), approximately defined as eta =1/2(epsilon (LUMO)- E-HOMO), chi= - 1/2(E-HOMO+ epsilon (LUMO)), and S=1/ eta respectively, based on the hardness concept. The strength of binding af finity and toxicity of the chemicals were approximately proportional to the absolute hardness, and laterally toxic chlorinated PCDDs, PCBs, and DDTs a re classified as chemically soft. Here we found that the electronic structu res of environmental hormones can be classified into four main groups: 17 b eta -estradiol type (group I), testosterone type (group II), thyroxine type (group III), and HCH (hexachlorocyclohexane) type (group IV), Therefore, i f we can predict the coordinate (chi, eta) of the electronic structure of o ne chemical on the eta-chi activity diagram, we would be able to predict th e receptor with which the chemicals (environmental hormones) interact. For instance, 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD) is classified in group III, therefore, it would bind with the thyroid receptor more than the estrogen receptor (group I). It appears that dibutyl phthalate would no t interact with estrogen receptor because it does not belong to group I, In addition, the coordinates of these four groups do not complementarily over lap with the electronic structures of 20 natural amino acid residues. The e ta-chi activity diagram is a new tool for the prediction of the toxicity an d biological activity of environmental hormones.