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The herbicide linuron reduces testosterone production from the fetal rat testis both in utero and in vitro
Citation:
WILSON, V. S., C. R. LAMBRIGHT, J. R. FURR, K. HOWDESHELL, AND L. E. GRAY. The herbicide linuron reduces testosterone production from the fetal rat testis both in utero and in vitro . TOXICOLOGY LETTERS. Elsevier Science Ltd, New York, NY, 186(2):73-77, (2009).
Impact/Purpose:
Previous studies have shown that in utero exposure to linuron results in malformations of androgen dependent tissues in adult Sprague-Dawley (SD) and Long Evans rat offspring. Even though linuron was previously characterized and an androgen receptor (AR) antagonist, the pattern of malformations produced closely resembles the phthalate “syndrome” a class of chemicals that decreases fetal testosterone production and insl3 gene expression levels but does not bind to the AR. The present study investigated the impact of in utero linuron treatment on testosterone production and mRNA expression of key steroidogenic enzymes from the fetal testis. In this study, in utero linuron treatment reduced testosterone synthesis during a time when testosterone secretion is critical to proper development of the male reproductive tract and sex accessory tissues. Unlike the phthalates, however, expression of mRNA for steroidogenic enzymes tested was not affected by linuron treatment. In vitro dosing confirmed that linuron could directly inhibited testosterone production from the fetal testes. Taken together, these results indicate that the malformations produced by linuron and PE in male offspring are similar because both reduce fetal testosterone production during the critical period of gestational sex differentiation even though the apparent mechanisms differ.
Description:
In utero exposure to linuron, an urea-based herbicide, results in a pattern of malformations of androgen-dependent tissues in adult male rat offspring resembling that produced by some phthalate esters which are known to decrease fetal testosterone production. This study investigated the impact of in utero linuron treatment on fetal testis gene expression and testosterone production. Timed-pregnant Sprague Dawley rats were administered corn oil vehicle, 12.5, 25, 50 or 75mg linuron/day/kg orally from GD13 to 18. Ex vivo testosterone (T) production was significantly decreased at 50 and 75mg/kg when analyzed on a per litter basis. Unlike the phthalate esters, linuron treatment did not affect insl3, cyp17a, cyp11a or StAR mRNA expression. Control GD18 fetal testes were then incubated with increasing concentrations of linuron (1-300microM) to evaluate if linuron inhibited T production in vitro. T production was significantly reduced at 30microM and above. Progesterone production was not affected in any of the studies indicating that linuron directly inhibited testosterone production in the absence of cytotoxicity. These results indicate the malformations induced by linuron and phthalate esters in male offspring are similar because both reduce fetal T levels during the critical period of sex differentiation but suggest that the mechanisms differ.
