Effect of zinc and paraquat co-exposure on neurodegeneration: Modulation of oxidative stress and expression of metallothioneins, toxicant responsive and transporter genes in rats

Kumar, Ashutosh; Ahmad, Israr; Shukla, Smriti; Singh, Brajesh Kumar; Patel, Devendra Kumar; Pandey, Harsh; Singh, Chetna

doi:10.3109/10715762.2010.492832

Cited by 53 publications

(25 citation statements)

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“…CpG sites more methylated in females were enriched near genes that respond to toxic exposures, possibly playing a role in the known sexual dimorphic responses to such exposures (46-49). Genes CYP1A1 and TH are known to respond to herbicide exposure (50, 51). Two of the three CpG sites near CYP1A1 that are more methylated in females are similarly more methylated in the cord blood of infants with prenatal tobacco exposure (52).…”

Section: Resultsmentioning

confidence: 99%

Sex-associated autosomal DNA methylation differences are wide-spread and stable throughout childhood

Suderman

Simpkin

Sharp

et al. 2017

Preprint

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Almost all species show sexual discordance in many traits and diseases. DNA methylation is known to contribute to these differences through well-established mechanisms including X-inactivation in females, imprinting and parent-of-origin effects. Here we investigate sex discordance in DNA methylation throughout childhood in a sample of 700 individuals from the Avon Longitudinal Study of Parents and Children. We show that autosomal sex-discordant methylation is widespread, affecting approximately 12,000 CpG sites at any given age, and stable; at least 8,500 sites are consistently different across all time points and a large proportion discordant in both the fetal and adult brain cortices. Just over 1,000 methylation differences change from birth to late adolescence, 90% of these between birth and around age seven. Sexually discordant CpG sites are enriched in genomic loci containing androgen but not estrogen targets and in genes involved in tissue development but not housekeeping functions. A methylation-derived sex score capturing the variance was calculated at each time point and found to be highly correlated between time points. This score is nominally associated with sex hormone levels in childhood as well as some phenotypes previously linked to sex hormone levels. These findings suggest that sex-discordant autosomal DNA methylation is widespread throughout the genome, likely due to the first androgen exposures in utero. It is then stably maintained from birth to late adolescence. Methylation variation at sex-discordant sites within the sexes, as summarized by the methylation sex score, likely reflects in utero androgen exposure which is relevant to human health.Significance StatementAlthough we know that sex hormones are critical for establishing sexual discordance, less is known about how this discordance is achieved and maintained. Here we present evidence for widespread differences in DNA methylation between male and female children. We show that most of these differences are established prenatally, likely due to the first androgen exposures in utero, and then stably maintained throughout childhood, despite extreme fluctuations in the levels of these very same hormones. Our results support a role for DNA methylation as a means for recording and maintaining the effects of exposure to sex hormones and thus to better understand sexual variation and how it is driven by the prenatal environment.

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Section: Resultsmentioning

confidence: 99%

Sex-associated autosomal DNA methylation differences are wide-spread and stable throughout childhood

Suderman

Simpkin

Sharp

et al. 2017

Preprint

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“…Serial coronal sections (30 μm thick) were collected to ensure capture of the entire SN/VTA region. Sections were then immunostained using a standard protocol [40]. The sections were mounted using Permount, and images were captured with a bright field microscope at 8× magnification.…”

Section: Methodsmentioning

confidence: 99%

Role of cytochrome c in α-synuclein radical formation: implications of α-synuclein in neuronal death in Maneb- and paraquat-induced model of Parkinson’s disease

Kumar

Ganini

Mason

2016

Mol Neurodegeneration

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BackgroundThe pathological features of Parkinson’s disease (PD) include an abnormal accumulation of α-synuclein in the surviving dopaminergic neurons. Though PD is multifactorial, several epidemiological reports show an increased incidence of PD with co-exposure to pesticides such as Maneb and paraquat (MP). In pesticide-related PD, mitochondrial dysfunction and α-synuclein oligomers have been strongly implicated, but the link between the two has not yet been understood. Similarly, the biological effects of α-synuclein or its radical chemistry in PD is largely unknown. Mitochondrial dysfunction during PD pathogenesis leads to release of cytochrome c in the cytosol. Once in the cytosol, cytochrome c has one of two fates: It either binds to apaf1 and initiates apoptosis or can act as a peroxidase. We hypothesized that as a peroxidase, cytochrome c leaked out from mitochondria can form radicals on α-synuclein and initiate its oligomerization.MethodSamples from controls, and MP co-exposed wild-type and α-synuclein knockout mice were studied using immuno-spin trapping, confocal microscopy, immunohistochemistry, and microarray experiments.ResultsExperiments with MP co-exposed mice showed cytochrome c release in cytosol and its co-localization with α-synuclein. Subsequently, we used immuno-spin trapping method to detect the formation of α-synuclein radical in samples from an in vitro reaction mixture consisting of cytochrome c, α-synuclein, and hydrogen peroxide. These experiments indicated that cytochrome c plays a role in α-synuclein radical formation and oligomerization. Experiments with MP co-exposed α-synuclein knockout mice, in which cytochrome c-α synuclein co-localization and interaction cannot occur, mice showed diminished protein radical formation and neuronal death, compared to wild-type MP co-exposed mice. Microarray data from MP co-exposed wild-type and α-synuclein knockout mice further showed that the absence of α-synuclein per se or its co-localization with cytochrome c confers protection from MP co-exposure, as several important pathways were unaffected in α-synuclein knockout mice.ConclusionsAltogether, these results show that peroxidase activity of cytochrome c contributes to α-synuclein radical formation and oligomerization, and that α-synuclein, through its co-localization with cytochrome c or on its own, affects several biological pathways which contribute to increased neuronal death in an MP-induced model of PD.Electronic supplementary materialThe online version of this article (doi:10.1186/s13024-016-0135-y) contains supplementary material, which is available to authorized users.

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“…PQ induced the levels of CYP2E1 and GST A4-4 mRNA expressions as reported previously. CYP2E1 induces free radical generation by mixed-function oxidase activity; however, increased expression of GSTA4-4 could be an adaptive mechanism to counteract oxidative stress induced by PQ [ 47 ] . Exposure of PQ is known to activate Bax pathway, which leads to mitochondrial outer membrane permeabilization, which in turn allows cytochrome c release from mitochondria.…”

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confidence: 99%

Hepatoprotective Effect of Matricaria chamomilla.L in Paraquat Induced Rat Liver Injury

et al. 2014

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Paraquat (PQ), an effective and widely used herbicide, has been proven to be safe when appropriately applied to eliminate weeds. However, PQ poisoning is an extremely frustrating clinical condition with a high mortality and with a lack of effective treatments in humans. PQ is known to induce injury via a redox cyclic reaction. The purpose of this study was to investigate the effect of aqueous extract Matricaria chamomilla.L (M. chamomilla) against PQ-induced liver injury in association with its antioxidant activity.The male rats were treated by gastric gavage daily with PQ (5 mg/kg/day) and M. chamomilla (50 mg/kg/day) were administered alone or in combination for 7 days. After treatments, total antioxidant capacity (TAC), total thiol molecules (TTG) levels and catalase (CAT) activity in liver tissue were measured. At the end of the experiment, plasma and lung tissue of the animals was separated. The activity of enzymatic scavengers such as CAT, TAC and TTG were measured in liver homogenate.In this sample, the TAC and TTG were lower in the PQ group as compared with control group. Co-administration of PQ with M. chamomilla extract increased TAC and TTG in liver tissue as compared with PQ group.In conclusion, M. chamomilla as natural antioxidant may be considered beneficial for the protection oxidative liver injury in PQ poisoning.

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Effect of zinc and paraquat co-exposure on neurodegeneration: Modulation of oxidative stress and expression of metallothioneins, toxicant responsive and transporter genes in rats

Cited by 53 publications

References 76 publications

Sex-associated autosomal DNA methylation differences are wide-spread and stable throughout childhood

Sex-associated autosomal DNA methylation differences are wide-spread and stable throughout childhood

Role of cytochrome c in α-synuclein radical formation: implications of α-synuclein in neuronal death in Maneb- and paraquat-induced model of Parkinson’s disease

Hepatoprotective Effect of Matricaria chamomilla.L in Paraquat Induced Rat Liver Injury

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