The Reproductive Toxicity of Molinate and Metabolites to the Male Rat: Effects on Testosterone and Sperm Morphology

doi:10.1006/taap.1998.8371

Toxicology and Applied Pharmacology

Volume 151, Issue 1, July 1998, Pages 22-32

https://doi.org/10.1006/taap.1998.8371 Get rights and content

Abstract

Molinate causes an impairment in reproductive capability in the male rat. Administration of molinate to rats (40 mg/kg/day for 7 days) caused a distinctive sperm lesion. At higher doses of molinate (140 mg/kg for 7 days) this lesion was accompanied by morphological changes to the testis that were consistent with a delayed release of the late spermatids to the seminiferous tubular lumen, a process controlled by the release of testosterone. In accordance with this, molinate (≥40 mg/kg) caused a marked decrease in the concentration of circulating and testicular testosterone. The Leydig cells of the testis appear to be the primary target site in that radiolabel from [³H]molinate specifically localized within this cell type. In addition, esterase activity in the Leydig cells was inhibited following molinate administration.In vitro,molinate is a poor inhibitor of esterase activity, whereas molinate sulfoxide, a major metabolite of molinate in rats, and molinate sulfone were shown to be potent inhibitors of this process, suggesting that metabolic activation of molinate is requiredin vivo.Molinate sulfoxide (≥10 mg/kg) caused an identical sperm lesion to that of molinate and markedly decreased plasma and testicular testosterone concentration. These effects were not seen with the molinate metabolites 4-hydroxymolinate (10 mg/kg), molinate sulfone (10 mg/kg), and hexamethyleneimine (10 mg/kg). Since the sperm lesion is a secondary event caused by a disruption of spermatogenesis, this would imply that the testis lesion and the reproductive impairment are also a consequence of molinate sulfur oxidation.

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Thiocarbamate herbicides were found to be harmful to organisms. For example, the molinate was used in the rice industry, which has been found to produce male reproductive toxicity in rats and demonstrated to be severe hepatotoxicity to the common carp (Ellis et al., 1998; Sancho et al., 2000). As thiocarbamate herbicide, prosulfocarb (PSC, (C3H7)2NC(O)SCH2C6H5), S-benzyl dipropylcarbamothioate) is mainly used in winter cereals.
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Leydig cells are the testicular cells responsible for the biosynthesis and secretion of androgens, which are critical for the development of the reproductive tract and for reproductive function in the male. There are two distinct populations of Leydig cells: fetal Leydig cells (FLCs), which originate and function in the fetus but largely regress soon after birth, and adult Leydig cells (ALCs). FLCs produce high levels of testosterone (T) required for the stimulation of male sexual differentiation and testis descent. ALCs form from precursor cells during postnatal life. The adult cells produce high levels of T required for maintaining spermatogenesis and male secondary sexual characteristics in adult life. A number of environmental toxicants have been shown to disrupt FLC function, ALC development, and/or ALC function. Based on when in the life cycle cells are exposed, exposures to toxicants have been shown to have a variety of pathological consequences, including hypospadia and cryptorchidism, resulting from exposures of FLCs; delayed puberty, resulting from Leydig cell precursor cell postnatal exposures; or hypogonadism and infertility, resulting from ALC exposures.
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^☆: GreepKoblinsky

¹: To whom correspondence should be addressed.

²: Current address: Regulatory Affairs Department, Zeneca Agrochemicals, Fernhurst, Haslemere, Surrey, GU27 3JE, UK.

³: Current address: Diabetes and Endocrinology Research Group, Department of Medicine, University of Liverpool, Liverpool, L69 3BX, UK.

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Regular ArticleThe Reproductive Toxicity of Molinate and Metabolites to the Male Rat: Effects on Testosterone and Sperm Morphology☆

Abstract

Biochim. Biophys. Acta

Toxicol. Appl. Pharmacol.

Anal. Biochem.

Pestic. Biochem. Physiol.

Regul. Toxicol. Pharmacol.

Rec. Prog. Horm. Rsch.

Toxicol. Appl. Pharmacol.

Arch. Biochem. Biophys.

J. Lipid Res.

Toxicol. Appl. Pharmacol.

Rat testicular carboxylesterase: Cloning, cellular localization, and relationship to liver hydrolase A

Arch. Biochem. Biophys.

Metabolism of [ring-14

J. Agric. Food Chem.

Metabolism of [ring-14

J. Agric. Food Chem.

Species differences in the metabolism of the herbicide molinate

Drug Metab. Dispos.

The morphological effects of the thiocarbamate herbicide molinate on ovary, adrenal and testis of the Sprague Dawley rat

Fundam. Appl. Toxicol.

Dissociation of tissue uptake of cholesterol ester from that of apolipoprotein A-I of rat plasma high density lipoprotein: Selective delivery of cholesterol ester to liver, adrenal and gonad

Proc. Natl. Acad. Sci. USA

Adrenal cholesterol uptake from plasma lipoproteins: Regulation by corticotropin

Proc. Natl. Acad. Sci. USA

Regular Article
The Reproductive Toxicity of Molinate and Metabolites to the Male Rat: Effects on Testosterone and Sperm Morphology☆

Metabolism of [ring-¹⁴

Metabolism of [ring-¹⁴