Mechanism of metolachlor action due to alterations in cell cycle progression

Lowry, Dana M.; Greiner, Donovan; Fretheim, Michelle; Ubben, Macy; Dhanwada, Kavita R.

doi:10.1007/s10565-013-9256-z

Cited by 11 publications

(9 citation statements)

References 26 publications

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“…At present, studies have shown that environmental pollutions could induce cell cycle alteration. For example, organochlorine compounds significantly increased the number of MCF‐7 cells entering the S phase, herbicide butachlor‐treated human peripheral blood mononuclear PBMN cells exhibited an increase in sub‐G1 peak with concomitant reduction in G1 phase, and metolachlor decreased HepG2 cell number due to cell cycle arrest through alterations in Rb phosphorylation (Aube et al, ; Dwivedi et al, ; Lowry et al, ). However, the effect of endosulfan on endothelial cell cycle is not known.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of cell growth and induction of inflammation by endosulfan in HUVEC-C cells

Guo

et al. 2015

Environ. Toxicol.

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Endosulfan is one of the organochlorine pesticides. It has been associated with a wide range of adverse health effects. However, it is unknown whether endosulfan causes endothelial dysfunction. In the present study, we investigated the effects of endosulfan on human vascular endothelial cells. We exposed human umbilical vein endothelial cells (HUVEC-C) to varying concentrations of endosulfan for 48 h. The results showed that endosulfan lowered cell viability and inhibited cell proliferation in a dose-dependent manner. Flow cytometric analysis showed that endosulfan at 60 μM induced G1 cell cycle arrest, a response attributed to down-regulation of CDK6 and pRb dephosphorylation. We observed that endosulfan at 40 and 60 μM induced a considerable percentage of cells to undergo apoptosis, as detected by Annexin-V binding assays. Endosulfan reduced mitochondrial transmembrane potential, leading to the release of cytochrome c into the cytoplasm; meanwhile, endosulfan also inhibited the mRNA expression level of survivin, which resulted in the activation of caspase-3. These results indicated that the intrinsic mitochondria-mediated pathway was involved in apoptotic process. Exposure to endosulfan increased the secretion and mRNA expression levels of inflammation factors interleukin (IL)-6 and IL-8, suggesting that endosulfan could cause inflammation. Overall, these findings suggested that endosulfan is toxic to HUVEC-C cells, resulting in endothelial dysfunction. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1785-1795, 2016.

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Section: Discussionmentioning

confidence: 99%

Inhibition of cell growth and induction of inflammation by endosulfan in HUVEC-C cells

Guo

et al. 2015

Environ. Toxicol.

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“…A study with human liver (HepG2) cells suggests that metolachlor inhibits cell proliferation, affecting progression through the S phase of the cell cycle and entrance into the G2 phase (Lowry, Greiner, Fretheim, Ubben, & Dhanwada, 2013).…”

Section: Discussionmentioning

confidence: 99%

<b>Maternal and fetal toxicity of Wistar rats exposed to herbicide metolachlor

Vieira

Couto

Zanetti

et al. 2016

Acta Sci. Biol. Sci.

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ABSTRACT. Metolachlor is a selective pre-emergent herbicide widely used in agriculture to control weeds. The aim of this study was to evaluate the possible effects of metolachlor on reproductive performance of adult rats, as well as its teratogenic potential when administered during the period of organogenesis. Pregnant adult female rats were allocated into 4 experimental groups (n = 10 group (TC) of metolachlor, by gavage, from the 6th to 15th gestational day (GD). There is reduction in the weight gain of the animals from TB and TC groups compared to the control group. Liver and placenta weights were reduced in TB and TC groups, respectively, while the percentage of post-implantation loss was increased in the TC group. There were no external malformations in either rat of the control or treated groups. However, an increased incidence of skeletal anomalies and visceral anomalies (especially in the urogenital system) was observed in TC group. These results demonstrate that exposure of pregnant rats to metolachlor can lead to signs of general toxicity, late embryonic losses and congenital anomalies.Keywords: pesticide, reproduction, teratogenicity, fetus.Toxicidade materna e fetal de ratas Wistar expostas ao herbicida metolacloro RESUMO. O metolacloro é um herbicida seletivo de pré-emergência, amplamente usado na agricultura para controlar ervas daninhas. O objetivo deste estudo foi avaliar os possíveis efeitos do metolacloro sobre o desempenho reprodutivo de ratas adultas, bem como o seu potencial teratogênico quando administrado durante o período da organogênese. Ratas adultas prenhes foram divididas em quatro grupos experimentais (n = 10 grupo -1 ), que receberam 0 (controle); 150 (TA); 300 (TB); ou 1.000 mg kg -1 dia -1 (TC) do metolacloro, via gavagem, do sexto ao 15º dia de gestação (DG). Foi observada redução no ganho de peso dos animais dos grupos TB e TC em comparação ao grupo controle. Os pesos do fígado e placenta foram reduzidos nos grupos TB e TC, respectivamente, enquanto que a percentagem de perda pós-implantação foi aumentada no grupo TC. Não foram observadas malformações externas nos ratos dos grupos controle e tratados. No entanto, foi observado aumento da incidência de anomalias esqueléticas e anomalias viscerais (especialmente no sistema urogenital) no grupo TC. Estes resultados demonstram que a exposição de ratas prenhes ao metolacloro pode levar a sinais de toxicidade geral, perdas embrionárias tardias e anomalias congênitas.Palavras-chave: praguicida, reprodução, teratogênese, feto.

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“…Следовательно, можно предполагать, что увеличение количества этих фокусов обусловлено пролиферацией инициированных НДЕА гепатоцитов до детектируемых размеров. Данных о влиянии S -метолахлора на пролиферацию гепатоцитов в доступ- [10,11]. Снижение синтетических процессов в гепатоцитах связано с угнетением энергетического обмена метолахлором [12].…”

Section: результаты и обсуждениеunclassified

Promotor effect of S-metolachlor generics with different hepatotoxicity in liver carcinogenesis in rats

Bagley

Nedopytanska

Lisovska

et al. 2019

UJMTA

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Metolachlor and currently its biological active isomer S–metolachlor is one of the most widely used herbicides in the world. Chronic experiments in rats have found hepatocarcinogenic effect of metolachlor, and epidemiological studies have found positive relationship between enzyme exposure to metolachlor and prevalence of liver cancer. Possibility of the influence of harmful impurities contained in technical products on the detected effects is emphasized. Objective is to study promotor effect of S–metolachlor generics with different hepatotoxicity in carcinogenesis of liver in rats induced by nitrosodiethylamine (NDEA) and analyse possibility of its realisation in human. Materials and Methods. Experiments were performed in male Wistar Han rats on hepatocarcinogenesis model “NDEA — hepatectomy”. Two specimens of S–metolachlor generics were studied; and their ratio of S/R enantiomers was 87/13 % with different hepatotoxicity. Substances were administered intragastrically in the doses of 1.5,15 and 150 mg/kg body weight for 8 weeks. Animals of the negative control group received water, and positive control — phenobarbital. Promotor effect was evaluated by the standardised parameters of the total area and number of hepatocyte foci expressing γ-glutamyl transpeptidase (GTP). Results. No clinical signs of the toxic action of S–metolachlor on the rat body induced to carcinogenesis by NDEA were found. Increase in the number and total area of γ-GTP positive foci in the liver of animals on tumorogenic dose of both specimens of S–metolachlor as well as phenobarbital was found. Mean area of focus in the liver of rats on more toxic specimen was lower. The threshold of promotor action of S–metolachlor on hepatocarcinogenesis has been established at the level of γ 15 mg/kg body weight. Analysis of literature data on the mechanism of hepatotoxic action of metolachlor allowed to make a conclusion aboutphenobarbital-like mechanism of promotor action that is realised through constitutive androstane receptor (CAR). This mechanism is species-specific for rodents; therefore, the results of epidemiological studies on the possibility of liver cancer in human cannot be confirmed experimentally. Conclusion. Tumorogenic dose of S–metolachlor generics with different degree of hepatotoxicity shows promotor effect in NDEA induced carcinogenesis in rat liver. Hepatotoxicity of S–metolachlor inhibits growth of γ-GTP positive foci. The threshold of hepatocarcinogenesis promotion has been established at the level of γ 15 mg/kg body weight. The mechanism of the observed effect is not relevant for human. Key Words: S–metolachlor, hepatocarcinogenesis initiated by nitrosodiethylamine, Wistar Han rats, γ-glutamyltranspeptidase.

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Mechanism of metolachlor action due to alterations in cell cycle progression

Cited by 11 publications

References 26 publications

Inhibition of cell growth and induction of inflammation by endosulfan in HUVEC-C cells

Inhibition of cell growth and induction of inflammation by endosulfan in HUVEC-C cells

<b>Maternal and fetal toxicity of Wistar rats exposed to herbicide metolachlor

Promotor effect of S-metolachlor generics with different hepatotoxicity in liver carcinogenesis in rats

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