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In utero treatment with the herbicide linuron produces male rat reproductive malformations similar to the phthalate esters but through a different mechanism of action.
Citation:
WILSON, V. S., C. R. LAMBRIGHT, K. HOWDESHELL, AND L. E. GRAY. In utero treatment with the herbicide linuron produces male rat reproductive malformations similar to the phthalate esters but through a different mechanism of action. Presented at 2009 SOT Annual Meeting, Baltimore, MD, March 15 - 19, 2009.
Impact/Purpose:
To present at SOT 2009 annual meeting
Description:
Although linuron has been reported to act as an androgen receptor (AR) antagonist, the suite of malformations observed in male rat offspring after in utero exposure differs from that of other AR antagonists and more closely resembles that produced by phthalate esters (PE) such as dibutyl phthalate and diethyl hexyl phthalate. However, only the PEs induce malformations of the gubernacular ligament. Many of the malformations in male rat offspring produced by PEs have been attributed to reduced fetal testosterone synthesis due to lowered steroidogenic gene expression and decreased insl3 gene expression from the fetal Leydig cell; insl3 being critical for proper gubernacular ligament development. The current study investigated the dose response effects of in utero linuron treatment on fetal testis gene expression and testosterone production. Pregnant Sprague Dawley rats were administered corn oil vehicle or 12.5, 25, 50 or 75 mg linuron /kg/day orally from gestation day (GD)13-18. Fetal testes were collected on GD18 for ex vivo testosterone (T) production and gene expression. Ex vivo T, but not progesterone production, was significantly decreased by 50 and 75 mg linuron/kg/day. Unlike the phthalate esters, linuron treatment did not affect insl3, cyp17α, cyp11α or StAR mRNA expression. In a second study, control GD18 fetal testes were incubated with increasing concentrations of linuron (1 to 300 μM) to evaluate if linuron inhibited T production in vitro. T production was significantly reduced at 30 μM and above whereas progesterone production was not reduced at any concentration indicating that linuron directly inhibited testosterone production in the absence of cytotoxicity. Taken together, these data demonstrate that even though the profile of malformations produced by linuron resembles, in part, that of phthalate esters, the mechanism of action of linuron clearly differs from the phthalate esters. Disclaimer: Does not necessarily reflect US EPA policy.