Gestational atrazine exposure: Effects on male reproductive development and metabolite distribution in the dam, fetus, and neonate

Fraites, Melanie J.P.; Narotsky, Michael G.; Best, Deborah S.; Stoker, Tammy E.; Davis, Lori K.; Goldman, Jerome M.; Hotchkiss, Michelle G.; Klinefelter, Gary R.; Kamel, Amr; Qian, Yongchang; Podhorniak, Lynda V.; Cooper, Ralph L.

doi:10.1016/j.reprotox.2011.04.003

Cited by 36 publications

(46 citation statements)

References 34 publications

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“…4). Of note, compared to the ion intensities of ATR, DE and DIP in the 125 mg/kg group, the corresponding ion intensities were somewhat lower at the 250 mg/kg group, likely caused by the previously suggested autoinduction metabolism of ATR (Fraites et al 2011;Lin et al 2013b). …”

Section: Metabolites and Metabolic Pathways Altered By Atrazine Exposurementioning

confidence: 72%

“…In brief, adult male C57BL/6 mice were assigned randomly into 5 treatment groups (n = 4-5/group) and treated daily with corn oil vehicle or a dose range of atrazine (5, 25, 125, or 250 mg/kg) by oral gavage for 10 days. The rationale for this dose regimen selection and its relevance to occupational exposure have been justified in detail in our previous studies with similar or the same exposure paradigms (Coban and Filipov 2007;Filipov et al 2005;Lin et al 2013a); these doses are also in line with other short-term exposure studies of ATR's effects on the reproductive, endocrine, and nervous systems (Cooper et al 2007;Cooper et al 1996;Fraites et al 2011;Laws et al 2009;Rodriguez et al 2013), allowing parallel comparisons of study findings. Four hours after the last dosing on day 10, mice were deeply anesthetized with CO 2 , followed by blood collection and euthanasia by decapitation.…”

Section: Animals Experimental Design and Plasma Collectionmentioning

confidence: 93%

“…We (Ross and Filipov 2006;Ross et al 2009) and others (Barr et al 2007;Chevrier et al 2011;Fraites et al 2011) have generated rodent and human data on the ATR's kinetics and metabolite profile in plasma and/or urine that, with the help of PBPK modeling, can be used for ATR exposure dosimetry. However, at present, there are no mammalian data that can be used for peripheral biomarkers of ATR's adverse effects.…”

Section: Introductionmentioning

confidence: 99%

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Short-term oral atrazine exposure alters the plasma metabolome of male C57BL/6 mice and disrupts α-linolenate, tryptophan, tyrosine and other major metabolic pathways

Lin

Roede

et al. 2014

Toxicology

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, N. M. (2014). Short-term oral atrazine exposure alters the plasma metabolome of male C57BL/6 mice and disrupts α -linolenate, tryptophan, tyrosine and other major metabolic pathways. Retrieved from http://krex.ksu.edu Published Version InformationCitation: Lin, Z., Roede, J. R., He, C., Jones, D. P., & Filipov, N. M. (2014). Short-term oral atrazine exposure alters the plasma metabolome of male C57BL/6 mice and disrupts α -linolenate, tryptophan, tyrosine and other major metabolic pathways. Toxicology, 326, 130-141. adult male C57BL/6 mice, the present study aimed to investigate effects of a 10-day oral ATR exposure (0, 5, 25, 125, or 250 mg/kg) on the mouse plasma metabolome and to determine metabolic pathways affected by ATR that may be reflective of ATR's effects on the brain and useful to identify peripheral biomarkers of neurotoxicity. Four h after the last dosing on day 10, plasma was collected and analyzed with high-performance, dual chromatography-Fouriertransform mass spectrometry that was followed by biostatistical and bioinformatic analyses. CopyrightATR exposure (≥5 mg/kg) significantly altered plasma metabolite profile and resulted in a dosedependent increase in the number of metabolites with ion intensities significantly different from the control group. Pathway analyses revealed that ATR exposure strongly correlated with and disrupted multiple metabolic pathways. Tyrosine, tryptophan, linoleic acid and α-linolenic acid metabolic pathways were among the affected pathways, with α-linolenic acid metabolism being affected to the greatest extent. Observed effects of ATR on plasma tyrosine and tryptophan metabolism may be reflective of the previously reported perturbations of brain dopamine and serotonin homeostasis, respectively. ATR-caused alterations in the plasma profile of α-linolenic acid metabolism are a potential novel and sensitive plasma biomarker of ATR effect and plasma metabolomics could be used to better assess the risks, including to the brain, associated with ATR overexposure.

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Section: Metabolites and Metabolic Pathways Altered By Atrazine Exposurementioning

confidence: 72%

Section: Animals Experimental Design and Plasma Collectionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Short-term oral atrazine exposure alters the plasma metabolome of male C57BL/6 mice and disrupts α-linolenate, tryptophan, tyrosine and other major metabolic pathways

Lin

Roede

et al. 2014

Toxicology

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“…24 Thus disruption to various reproductive indices in laboratory rodents occurs only at concentrations of ATZ (1000 ppb-100 ppm) which are far above those of ecological relevance. 25,26 We therefore require other model species with which to examine the effects of ATZ in viviparous vertebrates.…”

Section: Introductionmentioning

confidence: 99%

Atrazine disrupts gonadal development in a live-bearing lizard

Parsley

Wapstra

Jones

2015

Endocrine Disruptors

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Atrazine (ATZ) is an endocrine disruptor that increases aromatase activity. In viviparous (live-bearing) vertebrates, embryos may be exposed to endocrine disruptors via the placenta. Studies of the effects of ATZ in viviparous amniotes have focused on rodents, which are relatively insensitive to ATZ: studies on other viviparous amniotes are therefore required. We aimed to determine the effects of gestational exposure to a single dose of ATZ at 10 ppb on gonadal development in a viviparous skink, Niveoscincus metallicus. Pregnant skinks were exposed to ATZ, the synthetic estrogen diethylstilbestrol (DES) (positive control), vehicle solvent or no treatment. Gonads were examined histologically at birth. Females born to ATZ and DES exposed mothers were more likely to exhibit ovaries with abnormal oocytes than were females whose mothers received vehicle solvent or no treatment. Males born to ATZ and DES exposed mothers were equally more likely to exhibit testes devoid of germ cells with reduced organization of seminiferous tubules (ST) compared to males born to mothers receiving vehicle solvent or no treatment. However, ATZ treatment significantly increased the number of male neonates born with testicular lesions compared to males born to mothers in any other group. We conclude that atrazine disrupts gonadal differentiation in the viviparous lizard, N. metallicus. The similar effects of DES and ATZ suggest that the developmental effects of ATZ in N. metallicus reflect increased estrogen signaling. Atrazine should be used with caution as exposure of wildlife to this EDC is likely to have adverse effects on reproductive health.

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“…ATR has been found to migrate to multiple tissues and organs, including the pituitary, caudate nucleus, hypothalamus, ovary, uterus, liver, and kidneys, among others (Stoker and Cooper, 2007;Ross et al, 2009;Fraites et al, 2011). Increasing evidence indicates that ATR selectively impacts the endocrine and reproductive systems (Juliani et al, 2008;Fraites et al, 2009b;Hayes, 2009;Abarikwu et al, 2010;Hayes et al, 2010;Foradori et al, 2011Foradori et al, , 2013.…”

Section: Introductionmentioning

confidence: 99%

Inflammatory reaction regulated by microglia plays a role in atrazine-induced dopaminergic neuron degeneration in the substantia nigra

Zhang

2015

J. Toxicol. Sci.

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-Atrazine (ATR) is a widely used herbicide, although it is potentially ecotoxic. Increasing evidence indicates that ATR plays a critical role in inducing physiological changes to the endocrine and reproductive systems, and further may affect the nigrostriatal dopaminergic system in the diencephalon, resulting in altered dopamine (DA) levels in the striatum, transport and storage-related protein abnormalities in the synaptic terminals, motor function deficits, and degeneration of DA neurons in the substantia nigra (SN). As the primary immunocytes in the central nervous system (CNS), microglial function to maintain the CNS microenvironment by preventing damage to healthy cells as well by regulating inflammatory responses. Several studies have demonstrated that microglial activation exerted an important effect on neuronal degeneration. In order to investigate dynamic changes of the microglial phenotype in the SN, rats received consecutive intraperitoneal injections of a vehicle or ATR at 25, 50, or 100 mg/kg body weight for a 14-day period and were then sacrificed at 1, 4, 7, or 14 days post-treatment, respectively. Here, we found that microglial activation by changes to phenotype emerged later in the low ATR exposure group than in the medium and high ATR exposure groups, and proliferating microglia were observed as well. Moreover, as two major inflammatory cytokines, expression of tumor necrosis factor α and interleukin-1β, emerged earlier post-ATR exposure, and a significant upregulation was observed in the medium and high ATR exposure groups. These results suggested that inflammatory reactions regulated by microglia occurred in a dose-and time-dependent manner, which may explain the severe DA neuron degeneration with the phagocytic phenotype of microglia in the SN that emerged earlier in the medium and high ATR exposure groups than in the low ATR exposure group. Taken together, our findings suggest that microglial activation might be involved in the dose-and time-dependent ATR-induced DA neuron degeneration in the SN.

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Gestational atrazine exposure: Effects on male reproductive development and metabolite distribution in the dam, fetus, and neonate

Cited by 36 publications

References 34 publications

Short-term oral atrazine exposure alters the plasma metabolome of male C57BL/6 mice and disrupts α-linolenate, tryptophan, tyrosine and other major metabolic pathways

Short-term oral atrazine exposure alters the plasma metabolome of male C57BL/6 mice and disrupts α-linolenate, tryptophan, tyrosine and other major metabolic pathways

Atrazine disrupts gonadal development in a live-bearing lizard

Inflammatory reaction regulated by microglia plays a role in atrazine-induced dopaminergic neuron degeneration in the substantia nigra

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