The influence of phthalate esters on Leydig cell structure and function in vitro and in vivo.
Phthalate esters are widely used in the manufacture of plastics and have been shown to cause testicular toxicity, purportedly, by targeting the Sertoli cell alone. Recent evidence, however, indicates that a paracrine control exists between Sertoli and Leydig cells and the breakdown of one component of this relationship is therefore detrimental to normal function. However, no data that explore the influence of testicular toxins on Leydig cell structure and function have been published hitherto. The preliminary studies reported here were initiated to test the hypothesis that phthalate intoxication may adversely alter Leydig cell structural and functional integrity. Four phthalate esters, namely, di(2-ethylhexyl) phthalate (DEHP, di-n-pentyl phthalate (DPP)., di-n-octyl phthalate (DOP), and diethyl phthalate (DEP) were investigated in vivo and their monoesters (MEHP, MPP, MOP, and MEP, respectively) in vitro for indications of Leydig cell toxicity in the rat. Rats were dosed by oral gavage with 2 g phthalate diester/kg/day in corn oil vehicle for 2 days, while Leydig cell primary cultures were incubated with 1,000 microM monoester for 2 hr. Light and electron microscopy were undertaken to determine the type and degree of any changes. Phthalate esters exerted a direct effect on Leydig cell structure and function (as determined by testosterone output) with correlation of the in vitro and in vivo effects of MEHP (DEHP) and MOP (DOP). No effects on Leydig cell structure or function were seen with MPP (DPP), although Sertoli cell cytoplasmic rarefaction and vacuolation were observed in vivo. DEP produced Leydig cell ultrastructural alterations in vivo. We conclude that individual phthalate esters may exert effects on both Sertoli and Leydig cells or one cell type alone.
Safety of Medicines Department, Zeneca Pharmaceuticals, Alderley Park, Macclesfield, Cheshire, United Kingdom.
H B
HB
Jones
D A
DA
Garside
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R
Liu
J C
JC
Roberts
D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004051:Diethylhexyl Phthalate / Q000633:toxicity; D004952:Esters; D007700:Kinetics; D007985:Leydig Cells / Q000187:drug effects* / Q000473:pathology / Q000648:ultrastructure; D007986:Luteinizing Hormone / Q000494:pharmacology; D008297:Male; D008854:Microscopy, Electron; D010795:Phthalic Acids / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D013739:Testosterone / Q000378:metabolism; D013997:Time Factors
D004952:Esters; D010795:Phthalic Acids; D013739:Testosterone; D007986:Luteinizing Hormone; D004051:Diethylhexyl Phthalate