Alteration of dopamine uptake into rat striatal vesicles and synaptosomes caused by an in vitro exposure to atrazine and some of its metabolites

Hossain, Muhammad M.; Filipov, Nikolay M.

doi:10.1016/j.tox.2008.03.007

Cited by 42 publications

(31 citation statements)

References 55 publications

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“…Using isolated synaptic vesicles preparations, we observed that ATR dose-dependently inhibited vesicular uptake of the neurotransmitter dopamine. The lowest effective concentration was 1 M (Hossain and Filipov, 2008), which is in the range of the brain ATR levels that we observed in the present study. DACT, at concentrations as high as 100 M, which is again in the range of the brain levels observed in the current study, was ineffective.…”

Section: Ross Et Alcontrasting

confidence: 43%

Disposition of the Herbicide 2-Chloro-4-(ethylamino)-6-(isopropylamino)-s-triazine (Atrazine) and Its Major Metabolites in Mice: A Liquid Chromatography/Mass Spectrometry Analysis of Urine, Plasma, and Tissue Levels

Ross¹,

Jones²,

Filipov³

2008

Drug Metab Dispos

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2-Chloro-4-(ethylamino)-6-(isopropylamino)-s-triazine (atrazine, ATR)is a toxicologically important and widely used herbicide. Recent studies have shown that it can elicit neurological, immunological, developmental, and biochemical alterations in several model organisms, including in mice. Because disposition data in mice are lacking, we evaluated ATR's metabolism and tissue dosimetry after single oral exposures (5-250 mg/kg) in C57BL/6 mice using liquid chromatography/mass spectrometry (Ross and Filipov, 2006). ATR was metabolized and cleared rapidly; didealkyl ATR (DACT) was the major metabolite detected in urine, plasma, and tissues. Plasma ATR peaked at 1 h postdosing and rapidly declined, whereas DACT peaked at 2 h and slowly declined. Most ATR and metabolite residues were excreted within the first 24 h. However, substantial amounts of DACT were still present in 25-to 48-h and 49-to 72-h urine. ATR reached maximal brain levels (0.06-1.5 M) at 4 h (5-125 mg/kg) and 1 h (250 mg/kg) after dosing, but levels quickly declined to <0.1 M by 12 h in all the groups. In contrast, strikingly high concentrations of DACT (1.5-50 M), which are comparable with liver DACT levels, were detectable in brain at 2 h. Brain DACT levels slowly declined, paralleling the kinetics of plasma DACT. Our findings suggest that in mice ATR is widely distributed and extensively metabolized and that DACT is a major metabolite detected in the brain at high levels and is ultimately excreted in urine. Our study provides a starting point for the establishment of models that link target tissue dose to biological effects caused by ATR and its in vivo metabolites.Atrazine (ATR) is a triazine herbicide that effectively inhibits photosynthesis in broadleaf weeds and grasses (Environmental Protection Agency, 2003). In the United States, ATR is applied on crops such as corn, sugarcane, pineapples, macadamia nuts, and sorghum, as well as on highway and railroad rights-of-way and on evergreen trees (Environmental Protection Agency, 2003). Several epidemiological studies have investigated the link between ATR exposure and adverse human health outcomes (Hoppin et al., 2002;MacLennan et al., 2002;De Roos et al., 2003;Hessel et al., 2004). However, the human data at present are equivocal. In some cases ATR exposure is associated with negative health outcomes, whereas in others it is not. One major drawback of virtually all the existing epidemiological studies is the fact that ATR exposure has not been precisely quantified or estimated. In this regard, exposure-only studies, i.e., studies where health outcomes have not been assessed, indicate that pesticide applicators and farmers during spraying are exposed to appreciable levels of ATR because detectable amounts of ATR and its metabolites are found in their saliva and urine (Hines et al., 2006). Moreover, a recent report indicated that not only ATR applicators but also their families are at risk of high level of ATR exposure (Curwin et al., 2007).Although data on health effects of ATR in humans ar...

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Section: Ross Et Alcontrasting

confidence: 43%

Disposition of the Herbicide 2-Chloro-4-(ethylamino)-6-(isopropylamino)-s-triazine (Atrazine) and Its Major Metabolites in Mice: A Liquid Chromatography/Mass Spectrometry Analysis of Urine, Plasma, and Tissue Levels

Ross¹,

Jones²,

Filipov³

2008

Drug Metab Dispos

Self Cite

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“…The only records available in literature refer to the neurotoxic kinetics of atrazine, a pesticide structurally similar to prometryne (23,24,26). Due to similar structure, the two compounds may share some toxicological properties (33,34).…”

Section: Discussionmentioning

confidence: 99%

“…Dosing was based previous toxicokinetic studies ( [22][23][24][25][26] that used doses higher than normally environmentally available to ensure detectable residue levels for our purposes.…”

Section: Treatment Of Experimental Animals With Prometrynementioning

confidence: 99%

Brain Toxicokinetics of Prometryne in Mice

Đikić

Sajli

Benković

et al. 2010

Archives of Industrial Hygiene and Toxicology

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Prometryne is a methylthio-s-triazine herbicide. Signifi cant trace amounts are found in the environment, mainly in water, soil, and food plants. The aim of this study was to establish brain and blood prometryne levels after single oral dose (1 g kg -1 ) in adult male and female mice. Prometryne was measured using the GC/MS assay at 1, 2, 4, 8, and 24 h after prometryne administration. Peak brain and blood prometryne values were observed 1 h after administration and they decreased in a time-dependent manner. Male mice had consistently higher brain and blood prometryne levels than female mice. The observed prometryne kinetics was similar to that reported for the structurally related herbicide atrazine.

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“…There is an indication that the reduction in dopamine could be associated with a decrease in dopamine-producing neurons in the substantia nigra . Additionally, the uptake and sequestration of dopamine into vesicles appeared impaired and perhaps as a consequence of this, the ratio of dopamine metabolites/dopamine increased Hossain & Filipov, 2008). PC12 cells are neuronal cells derived from a tumour of the rat adrenal medulla that produce catecholamines including dopamine.…”

Section: Toxic Effects and Mechanism Of Actionmentioning

confidence: 99%