Effects of phthalate esters on the developing reproductive tract of male rats

Phthalate esters are a large group of chemical agents used predominantly as plasticizers and solvents. Certain members of this chemical class have bee n shown to cause reproductive and developmental toxicity. Recent attention has focused on the potential of these agents to interfere with male reprodu ctive development through a postulated antiandrogenic mechanism. Observatio ns have focused on di-n-butyl phthalate (DBP), di-(2-ethylhexyl) phthalate (DEHP) and butyl benzylphthalate, with most information relating to dose-re sponse relationships obtained for DBP. Neither DBP, DEHP nor their major me tabolites interacted with human or rodent androgen receptors (AR) in transc riptional activation assays. DBP was administered during the critical windo w of development of the male reproductive system, after which the resulting offspring were examined until adulthood. DBP elicited marked effects on th e developing male reproductive tract, including malformations of the epidid ymis and vas deferens, and hypospadias. Retention of thoracic nipples/areol ae and reductions in anogenital distance were also noted. Surprisingly, Ley dig cell adenomas were induced in some male offspring at 100 days of age. A ll these events occurred in the absence of any toxicity in the pregnant dam . Examination of testes from fetal rats indicated markedly reduced testoste rone levels and increased Leydig cell numbers after DBP administration to t he dams. Leydig cells were positive for AR and 3-betahydroxysteroid dehydro genase.