Triazine herbicides inhibit relaxin signaling and disrupt nitric oxide homeostasis

Park, Si Eun; Lim, Sa Rang; Choi, Hyung‐Kyoon; Bae, Jang–Ho

doi:10.1016/j.taap.2016.07.010

Cited by 14 publications

(9 citation statements)

References 32 publications

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“…RXFP1 is predominantly expressed in endothelial cells of mesenteric arteries and veins, but also expressed in the aorta and vena cava ( Novak et al, 2006 ; Jelinic et al, 2014 ). In our experiments, the RXFP1 antagonist simazine ( Park et al, 2016 ) largely inhibited the endothelium-dependent relaxation induced by relaxin-2, which supports the idea that relaxin-2 produces relaxation primarily through binding to and activation of RXFP1 in the endothelium ( Figure 9 ). The remaining relaxation of about 25% in simazine-treated vessels may represent spontaneous relaxation or caused by RXFP activation distinct from RXFP1 in the vasculature or both of them.…”

Section: Discussionsupporting

confidence: 86%

RXFP1 Receptor Activation by Relaxin-2 Induces Vascular Relaxation in Mice via a Gαi2-Protein/PI3Kß/γ/Nitric Oxide-Coupled Pathway

et al. 2018

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Background: Relaxins are small peptide hormones, which are novel candidate molecules that play important roles in cardiometablic syndrome. Relaxins are structurally related to the insulin hormone superfamily, which provide vasodilatory effects by activation of G-protein-coupled relaxin receptors (RXFPs) and stimulation of endogenous nitric oxide (NO) generation. Recently, relaxin could be demonstrated to activate Gi proteins and phosphoinositide 3-kinase (PI3K) pathways in cultured endothelial cells in vitro. However, the contribution of the Gi-PI3K pathway and their individual components in relaxin-dependent relaxation of intact arteries remains elusive.Methods: We used Gαi2- (Gnai2-/-) and Gαi3-deficient (Gnai3-/-) mice, pharmacological tools and wire myography to study G-protein-coupled signaling pathways involved in relaxation of mouse isolated mesenteric arteries by relaxins. Human relaxin-1, relaxin-2, and relaxin-3 were tested.Results: Relaxin-2 (∼50% relaxation at 10-11 M) was the most potent vasodilatory relaxin in mouse mesenteric arteries, compared to relaxin-1 and relaxin-3. The vasodilatory effects of relaxin-2 were inhibited by removal of the endothelium or treatment of the vessels with N (G)-nitro-L-arginine methyl ester (L-NAME, endothelial nitric oxide synthase (eNOS) inhibitor) or simazine (RXFP1 inhibitor). The vasodilatory effects of relaxin-2 were absent in arteries of mice treated with pertussis toxin (PTX). They were also absent in arteries isolated from Gnai2-/- mice, but not from Gnai3-/- mice. The effects were not affected by FR900359 (Gαq protein inhibitor) or PI-103 (PI3Kα inhibitor), but inhibited by TGX-221 (PI3Kβ inhibitor) or AS-252424 (PI3Kγ inhibitor). Simazine did not influence the anti-contractile effect of perivascular adipose tissue.Conclusion: Our data indicate that relaxin-2 produces endothelium- and NO-dependent relaxation of mouse mesenteric arteries by activation of RXFP1 coupled to Gi2-PI3K-eNOS pathway. Targeting vasodilatory Gi-protein-coupled RXFP1 pathways may provide promising opportunities for drug discovery in endothelial dysfunction and cardiometabolic disease.

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Section: Discussionsupporting

confidence: 86%

RXFP1 Receptor Activation by Relaxin-2 Induces Vascular Relaxation in Mice via a Gαi2-Protein/PI3Kß/γ/Nitric Oxide-Coupled Pathway

et al. 2018

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“…Conversely to the observations of Park et al (2016) about simazine suppressive effect on NO production in human granulosa cells, in our experiment this molecule appeared ineffective in modulating NO levels, while significantly enhanced AOC growth in the in vitro angiogenesis bioassay. The present results lead us to hypothesize that also simazine can be possibly qualified as a pro-angiogenic molecule, as already suggested for different endocrine disruptors (Grasselli et al, 2010;Durando et al, 2011;Basini et al, 2012).…”

Section: Discussioncontrasting

confidence: 99%

“…Even if in vitro studies have highlighted time- and dose-dependent effects on steroidogenesis in murine Leydig cell lines ( Forgacs et al ., 2013 ) and a disruption on relaxin signaling and nitric oxide production in human granulosa cells ( Park et al ., 2016 ), a comprehensive understanding of simazine effects on ovarian physiology is lacking. Granulosa cells represent a valuable model to investigate ovarian function: they are essential for ovarian follicle growth, steroidogenesis, oocyte survival and nourishment.…”

Section: Introductionmentioning

confidence: 99%

Simazine, a triazine herbicide, disrupts swine granulosa cell functions

Grasselli¹,

Bussolati²,

Ramoni³

et al. 2017

Anim Reprod

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The triazine herbicide simazine is a pesticide commonly detected in surface and ground waters, although banned in most European countries since 2004. Concerns for humans and animal health result from its potential endocrine disrupting action, that can lead to reproductive disorders. The present in vitro study was undertaken to study simazine effects on swine granulosa cell function, namely cell viability, proliferation, steroidogenesis and NO production. Moreover, the ability of this substance to interfere with the angiogenetic process, a crucial event in reproductive function, was taken into account. Our data document that simazine treatment, at 0.1 or 10 μM concentration levels, stimulates granulosa cell proliferation and viability and impairs steroidogenesis, increasing in particular progesterone production. In addition, the in vitro angiogenesis bioassay revealed a significant simazine stimulatory effect on immortalized porcine Aortic Endothelial Cell proliferation. Collectively, these results show that simazine can display disruptive effects on ovarian cell functional parameters, possibly resulting in reproductive dysfunction. This hypothesis is also supported by the observed pro-angiogenetic properties of this herbicide, as already suggested for different endocrine disruptors.

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“…For instance, atrazine was regarded as a potential carcinogen that caused hormonal disorders and affected the normal mammalian reproductive function [5–7]. Likewise, exposure to simazine resulted in neonatal birth defects and the potential for developmental disorders [8]. Currently, studies of pesticides have largely focused on the effects of a single pesticide exposure.…”

Section: Introductionmentioning

confidence: 99%

Antibiotics may increase triazine herbicide exposure risk via disturbing gut microbiota

et al. 2018

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BackgroundAntibiotics are commonly used worldwide, and pesticide is a kind of xenobiotic to which humans are frequently exposed. The interactive impact of antibiotics on pesticides has rarely been studied. We aim to investigate the effects of antibiotics on the pesticide exposure risk and whether gut microbiota altered by antibiotics has an influence on pesticide bioavailability. Furthermore, we explored the mechanisms of gut microbiota affecting the fate of pesticides in the host.ResultsThe oral bioavailability of triazine herbicides significantly increased in the rats treated with ampicillin or antibiotic cocktails. The antibiotic-altered gut microbiota directly influenced the increased pesticide bioavailability through downregulating hepatic metabolic enzyme gene expression and upregulating intestinal absorption-related proteins.ConclusionsAntibiotics could increase the pesticide bioavailability and thereby may increase the pesticide exposure risk. The antibiotic-altered gut microbiota that could alter the hepatic metabolic enzyme gene expression and intestinal absorption-related proteome was a critical cause of the increased bioavailability. This study revealed an undiscovered potential health impact of antibiotics and reminded people to consider the co-exposed xenobiotics when taking antibiotics.Electronic supplementary materialThe online version of this article (10.1186/s40168-018-0602-5) contains supplementary material, which is available to authorized users.

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Triazine herbicides inhibit relaxin signaling and disrupt nitric oxide homeostasis

Cited by 14 publications

References 32 publications

RXFP1 Receptor Activation by Relaxin-2 Induces Vascular Relaxation in Mice via a Gαi2-Protein/PI3Kß/γ/Nitric Oxide-Coupled Pathway

RXFP1 Receptor Activation by Relaxin-2 Induces Vascular Relaxation in Mice via a Gαi2-Protein/PI3Kß/γ/Nitric Oxide-Coupled Pathway

Simazine, a triazine herbicide, disrupts swine granulosa cell functions

Antibiotics may increase triazine herbicide exposure risk via disturbing gut microbiota

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