Disturbed Relaxin Signaling Pathway and Testicular Dysfunction in Mouse Offspring upon Maternal Exposure to Simazine

Abstract

Simazine is a triazine herbicide that is being widely applied worldwide and commonly detected in surface and groundwater. Despite its popular use in controlling weeds and algae, very limited information is available regarding its toxicity. In the present study, pregnant mice were orally exposed to low doses (0, 5, 50, or 500 µg/kg body weight per day) of simazine during gestation and lactation, during which no overt maternal toxic response was detected, and their offspring was assessed. Simazine-exposed male offspring showed decreased body, testicular, and epididymis weight, increased testicular apoptosis, and decreased sperm concentrations. Differentially-expressed genes in the testes of male offspring exposed to simazine were identified by DNA microarray, revealing 775 upregulated and 791 downregulated genes; among these, the relaxin-family peptide receptor 1 (Rxfp1), which is the receptor for relaxin hormone, was significantly downregulated. In addition, the expression of target genes in the relaxin pathway, including nitric oxide synthase 2 (Nos2) and Nos3, was significantly decreased in simazine-exposed F1 testes. Moreover, simazine inhibited NO release, and knockdown of Rxfp1 blocked the inhibitory action of simazine on NO production in testicular Leydig cells. Therefore, the present study provides a better understanding of the toxicities associated with the widely used herbicide simazine at environmentally relevant doses by demonstrating that maternal exposure interferes with the pleotropic relaxin-NO signaling pathway, impairing normal development and reproductive activity of male offspring.

The Effects of Simazine, a Chlorotriazine Herbicide, on the Expression of Genes in Developing Male Xenopus laevis

“…Studies have shown that acps are involved in immune, reproductive, digestive systems and apoptotic process (Bozzo et al 2002;Yoneyama et al 2004). Downregulated acps may play an important role in the simazine-induced adverse effects on the reproductive system observed in our study and other studies (Zorrilla et al 2010) as well as other genes such as Rxfp1 (Park and Bae 2012). We also found genes involved in endocrine functions including ptgs2, stc1 and th were downregulated.…”

Impaired development of female mouse offspring maternally exposed to simazine

“…The shortened AGD observed in female neonates exposed maternally and lactationally to 5 g/kg/day (Table 2), suggests an estrogenic effect of simazine on female mice since AGD is a common and sensitive index of in utero exposure to EDs (McIntyre et al, 2001;Wolf et al, 2004). In a previous report, AGD was not significantly altered in male offspring by maternal exposure to simazine (Park and Bae, 2012), implying that female littermates are more susceptible to perinatal exposure of simazine at low doses at least as it relates to endocrine disruption. Zorrilla et al demonstrated that exposure to simazine (25-200 mg/kg/day) in female weaned littermates of Wistar rats delays vaginal opening (Tinfo et al, 2011), indicating an antiestrogenic effect of simazine.…”

“…1016/j.etap.2014.10.008 1382-6689/© 2014 Elsevier B.V. All rights reserved. disruption of the relaxin pathway (Park and Bae, 2012). Male rats exposed to simazine exhibited increased release of adrenocorticotropic hormone and corticosterone (Laws et al, 2009).…”

Prenatal exposure to rutile-type alumina-coated titanium dioxide nanoparticles impairs mouse spermatogenesis

“…This was demonstrated to increase testicular oxidative stress, which leads to an increase in germ cell apoptosis and subsequent hypospermatogenesis (Turner and Lysiak, 2008). Regarding herbicide and heavy metal exposure during gestation and lactation, cadmium and simazine were found to interfere with the function of male reproductive system in offspring (Ji et al, 2011;Park and Bae, 2012).…”