Hormone-dependence of sarin lethality in rats: Sex differences and stage of the estrous cycle

Smith, Carl; Wright, Linnzi; Garcia, Gregory E.; Lee, Robyn B.; Lumley, Lucille A.

doi:10.1016/j.taap.2015.06.010

Cited by 25 publications

(21 citation statements)

References 33 publications

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“…By contrast, female rats in proestrus are less sensitive to the lethal effects of sarin compared with female rats in estrus, and females do not differ from males. 27 One proposed mechanism for this protection during estrus is that brain levels of progesterone and the neurosteroid allopregnanolone are elevated. 41 Neurosteroids, such as allopregnanolone, are modulators of the major inhibitory GABAA receptor (reviewed in Ref.…”

Section: Discussionmentioning

confidence: 99%

“…In rats, the lethal effects of subcutaneous (SC) exposure to sarin vary depending on the stage of the estrous cycle, with female rats having lower susceptibility during proestrus. 27 The etiology for the observed sexual dimorphism in CWNA toxicity is not fully understood, but the inclusion of female subjects in preclinical research of medical countermeasures against CWNA exposure should be of paramount importance as they are in general more susceptible to the toxic effects (reviewed in Ref. 21) and as sex may influence neuropathological outcomes and the effectiveness of therapeutics.…”

Section: Introductionmentioning

confidence: 99%

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Delayed midazolam dose effects against soman in male and female plasma carboxylesterase knockout mice

Kundrick¹,

Marrero‐Rosado²,

Stone³

et al. 2020

Annals of the New York Academy of Sciences

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Chemical warfare nerve agent exposure leads to status epilepticus that may progress to epileptogenesis and severe brain pathology when benzodiazepine treatment is delayed. We evaluated the dose−response effects of delayed midazolam (MDZ) on toxicity induced by soman (GD) in the plasma carboxylesterase knockout (Es1 −/−) mouse, which, similar to humans, lacks plasma carboxylesterase. Initially, we compared the median lethal dose (LD 50) of GD exposure in female Es1 −/− mice across estrous with male mice and observed a greater LD 50 during estrus compared with proestrus or with males. Subsequently, male and female GD-exposed Es1 −/− mice treated with a dose range of MDZ 40 min after seizure onset were evaluated for survivability, seizure activity, and epileptogenesis. GDinduced neuronal loss and microglial activation were evaluated 2 weeks after exposure. Similar to our previous observations in rats, delayed treatment with MDZ dose-dependently increased survival and reduced seizure severity in GD-exposed mice, but was unable to prevent epileptogenesis, neuronal loss, or gliosis. These results suggest that MDZ is beneficial against GD exposure, even when treatment is delayed, but that adjunct therapies to enhance protection need to be identified. The Es1 −/− mouse GD exposure model may be useful to screen for improved medical countermeasures against nerve agent exposure.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Delayed midazolam dose effects against soman in male and female plasma carboxylesterase knockout mice

Kundrick¹,

Marrero‐Rosado²,

Stone³

et al. 2020

Annals of the New York Academy of Sciences

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“…All procedures were approved by the Institute Animal Care and Use Committee (IACUC) of MRI Global, which is fully accredited by the American Association for the Accreditation of Laboratory Animal Care. Due to hormonal influences on the LD 50 of soman, only males were included in the studies [13] . Male, Sprague-Dawley (SD) rats (300–350 g) were purchased from Harlan Laboratories (Indianapolis, IN) and used for all experiments.…”

Section: Methodsmentioning

confidence: 99%

Neuroprotective effects of a catalytic antioxidant in a rat nerve agent model

et al. 2019

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Persistent inhibition of acetylcholinesterase resulting from exposure to nerve agents such as soman, is associated with prolonged seizure activity known as status epilepticus (SE). Without medical countermeasures, exposure to soman and resultant SE leads to high morbidity and mortality. Currently available therapeutics are effective in limiting mortality, however effects on morbidity are highly time-dependent and rely on the ability to suppress SE. We have previously demonstrated significant protection from secondary neuronal injury in surrogate nerve agent models by targeting oxidative stress. However, whether oxidative stress represents a relevant therapeutic target in genuine nerve agent toxicity is unknown. Here, we demonstrate that soman exposure results in robust region- and time-dependent oxidative stress. Targeting this oxidative stress in a post-exposure paradigm using a small molecular weight, broad spectrum catalytic antioxidant, was sufficient to attenuate brain and plasma oxidative stress, neuroinflammation and neurodegeneration. Thus, targeting of oxidative stress in a post-exposure paradigm can mitigate secondary neuronal injury following soman exposure.

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“…The surge of estrogen during puberty may have also had a protective effect irrespective of the skin as demonstrated by Smith et al [25] , who showed that the 24 h LD 50 value for sc exposure to sarin was highest in female rats during the proestrus stage of their hormonal cycle. Moreover, pretreating male rats with ethylestrenol caused a 150% increase in the LD 50 value for sc exposure to parathion [23] , an organophosphorus pesticide that inhibits AChE similar to VX but with less potency.…”

Section: Discussionmentioning

confidence: 91%

Female rats are less susceptible during puberty to the lethal effects of percutaneous exposure to VX

Wright

Lee²,

Clarkson³

et al. 2016

Toxicology Reports

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Nerve agents with low volatility such as VX are primarily absorbed through the skin when released during combat or a terrorist attack. The barrier function of the stratum corneum may be compromised during certain stages of development, allowing VX to more easily penetrate through the skin. However, age-related differences in the lethal potency of VX have yet to be evaluated using the percutaneous (pc) route of exposure. Thus, we estimated the 24 and 48 h median lethal dose for pc exposure to VX in male and female rats during puberty and early adulthood. Pubescent, female rats were less susceptible than both their male and adult counterparts to the lethal effects associated with pc exposure to VX possibly because of hormonal changes during that stage of development. This study emphasizes the need to control for both age and sex when evaluating the toxicological effects associated with nerve agent exposure in the rat model.

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Hormone-dependence of sarin lethality in rats: Sex differences and stage of the estrous cycle

Cited by 25 publications

References 33 publications

Delayed midazolam dose effects against soman in male and female plasma carboxylesterase knockout mice

Delayed midazolam dose effects against soman in male and female plasma carboxylesterase knockout mice

Neuroprotective effects of a catalytic antioxidant in a rat nerve agent model

Female rats are less susceptible during puberty to the lethal effects of percutaneous exposure to VX

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