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.
Highlights
Simazine (6-chloro-N,N9-diethyl-1,3,5-triazine-2,4-diamine) is an herbicide of the triazine family, which includes atrazine and propazine, and has been applied worldwide in both agricultural and nonagricultural uses, including treatment on a diversity of deep-rooted crops to control broad-leaved and grassy weeds and on algae in farm ponds for pre-emergence purposes [1]
These results suggest that the doses of simazine used in the present study are low enough to not elicit maternal toxicity (Table 2)
The body weights of mothers exposed to simazine were not affected, the body weights of their male offspring exposed to 5 or 500 mg/kg/day simazine in utero and by lactation were significantly reduced, by approximately 7% on postnatal day (PND) 14, and there was a significant decrease in body weight for the offspring exposed to 500 mg/kg/day simazine on PND 21 (Table 3)
Summary
Simazine (6-chloro-N,N9-diethyl-1,3,5-triazine-2,4-diamine) is an herbicide of the triazine family, which includes atrazine and propazine, and has been applied worldwide in both agricultural and nonagricultural uses, including treatment on a diversity of deep-rooted crops to control broad-leaved and grassy weeds and on algae in farm ponds for pre-emergence purposes [1]. In the United States, an estimated 5 to 7 million pounds of simazine are applied to agricultural crops each year, and an additional 1.2 million pounds are applied for nonagricultural uses [1]. Simazine is one of most commonly detected pesticides in surface and ground water due to herbicide runoff [3]. Numerous recent in vivo and in vitro studies have reported an array of toxic responses to atrazine, a close homologue of simazine, affecting neuroendocrine systems, antioxidant mechanisms, behavior, and mammary gland development [5,6,7,8,9]
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