Development of a Rat Model of Toluene-Abuse Embryopathy

Gospe, Sídney M.; Zhou, Shan; Saeed, Dianne B; Zeman, Frances J.

doi:10.1203/00006450-199607000-00015

Cited by 23 publications

(12 citation statements)

References 26 publications

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“…In animal models of FAS, selective microencephaly results following ethanol exposure [Samson, 1986;Renò et al, 1994]. Our results, however, are in agreement with those obtained by other investigators, after either high in utero exposures [Gospe et al, 1994[Gospe et al, , 1996Gospe and Zhou, 2000], or subabuse level of postnatal toluene exposures [Da Silva et al, 1991;Stumph et al, 1985].…”

Section: Discussioncontrasting

confidence: 36%

“…In recent years, an animal model for toluene embryopathy has been developed [Gospe et al, 1994[Gospe et al, , 1996Zhou, 1998, 2000]. In this rat model, dams are exposed to toluene by gavage from gestational day 6 to 19.…”

Section: Introductionmentioning

confidence: 99%

“…In this rat model, dams are exposed to toluene by gavage from gestational day 6 to 19. Abnormalities found in fetuses of embryonic day 19 or pups of postnatal day (PND) 10 or 21 included growth retardation, decreases in forebrain protein and DNA content, a decrease in forebrain cholesterol/DNA ratio (suggestive of an effect of toluene on myelin development), and significant alterations of the cortical cytoarchitecture and neuronal generation [Gospe et al, 1994[Gospe et al, , 1996Zhou, 1998, 2000].…”

Section: Introductionmentioning

confidence: 99%

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Developmental Neurotoxicity of Toluene: in vivo and in vitro Effects on Astroglial Cells

et al. 2003

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Toluene, an inexpensive and available industrial solvent, has become increasingly popular as a drug of abuse. Inhaling toluene leads to a feeling of euphoria and several reports have shown that children born to women who had abused toluene during pregnancy present a syndrome (toluene embryopathy or fetal solvent syndrome) that is characterized by CNS effects (e.g. microencephaly), growth retardation and facial dysmorphologies. The characteristics of the fetal solvent syndrome are very similar to those observed in the fetal alcohol syndrome. As exposure of rats to ethanol during the brain growth spurt has been shown to cause microencephaly and to affect glial cell proliferation and maturation, the present study examines the effects of toluene administration (250, 500 and 750 mg/kg) in neonatal rats from postnatal day 4 to 10. This treatment resulted in a significant decrease in both brain and body weights, and in a significant reduction of levels of glial fibrillary acidic protein, but not of neuron-specific enolase in rat brain. In vitro experiments demonstrate that pharmacologically relevant concentrations of toluene (250–1,000 µM) significantly inhibit proliferation of rat cortical astrocytes without causing overt cytotoxicity. These results indicate that toluene does not cause selective microencephaly; however, it affects brain weight, and appears to target developing astrocytes, possibly by inhibiting their proliferation.

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Section: Discussioncontrasting

confidence: 36%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Developmental Neurotoxicity of Toluene: in vivo and in vitro Effects on Astroglial Cells

et al. 2003

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“…Repeated 30-and 45-min exposures to 8,000 ppm or 12,000 ppm resulted in ∼35% and ∼70% decreases in BTLs, respectively, by GD20 compared to initial levels on GD8. Some other studies have exposed pregnant animals to toluene on a single day during gestation via intragastric intubation [24][25][26], systemic injection [13,14,38], or in drinking water [38], none of which produce pharmacokinetic functions that faithfully represent those following the inhalation route of administration that defines solvent abuse. Several studies have demonstrated that repeated toluene inhalations yield progressively lower blood and brain toluene levels consistent with tolerance due to up-regulation of hepatic catabolism by cytochrome P450 [37,44,58].…”

Section: Discussionmentioning

confidence: 99%

Maternal and fetal blood and organ toluene levels in rats following acute and repeated binge inhalation exposure☆

Bowen¹,

Hannigan²,

Irtenkauf³

2007

Reproductive Toxicology

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Inhalation of organic solvents is a persistent form of drug abuse with particular concern being the abuse of inhalants by women of child-bearing age. While studies have begun assessing postnatal outcomes of offspring exposed prenatally to inhalants, relatively little is known about the distribution of toluene in blood and body tissues of pregnant, inhalant-abusing women, or in the fetuses. The present study assessed the tissue toluene levels attained following brief toluene exposures using a pre-clinical rat model of maternal inhalant abuse. Timed-pregnant Sprague-Dawley rats were exposed to toluene at 8,000 or 12,000 parts per million (ppm) for 15, 30 or 45 min/exposure. Exposures occurred twice each day from gestational day 8 (GD8) through GD20. Immediately following the second exposure on GD8, GD14 and GD20 blood was taken from the saphenous vein of the dams. Following saphenous vein blood collection on GD20, dams were sacrificed and trunk blood was collected along with maternal tissue specimens from cerebellum, heart, lung, kidney and liver. The placenta, amniotic fluid and fetal brain were also collected. Results demonstrated that maternal saphenous blood toluene levels increased as the inhaled concentration of toluene and duration of exposure increased. The maternal cerebellum, heart, kidney and liver appeared to be saturated after 30 min on GD20 such that toluene levels in those organs were equivalent across all ambient concentrations of inhaled toluene. Toluene levels also increased in fetal brain as the inhaled concentration of toluene increased and in placenta and amniotic fluid as the duration of exposure increased. Toluene levels in all tissues at GD20, except maternal lung and amniotic fluid, were higher than in maternal saphenous blood suggesting that toluene concentrated in those organs. Measurement of toluene levels in blood and other tissues following repeated toluene exposure demonstrated that toluene readily reaches a variety of potential sites of action throughout the maternal-placental-fetal unit.

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“…Pregnant solvent abusers are exposing themselves and their fetuses to very high concentrations, inhaling up to 15 000 ppm per binge episode, and our animal model is mimicking these patterns of periodic, acute, very high-dose prenatal toluene exposures necessary to evaluate teratogenic risk of abused toluene -or other related inhaled organic solvents. Noninhalation models can produce BTCs approximating average levels attained via chronic inhalation, 55 but the pharmacodynamics of intragastric intubation, for example, will yield peak BTCs that vary substantially from acute inhalation because of differential diffusion and absorption, susceptibility to gastric metabolism, access to storage depots, excretion, and the kinetics of repeated administration, 56 resulting in a different shape to the " dose/concentration-BTC " curve over time, and different outcomes.…”

Section: Future Perspectives and Conclusionmentioning

confidence: 99%

Developmental Toxicity of Prenatal Exposure to Toluene

Bowen

Hannigan

2006

AAPS J

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Organic solvents have become ubiquitous in our environment and are essential for industry. Many women of reproductive age are increasingly exposed to solvents such as toluene in occupational settings (ie, long-term, lowconcentration exposures) or through inhalant abuse (eg, episodic, binge exposures to high concentrations). The risk for teratogenic outcome is much less with low to moderate occupational solvent exposure compared with the greater potential for adverse pregnancy outcomes, developmental delays, and neurobehavioral problems in children born to women exposed to high concentrations of abused organic solvents such as toluene, 1,1,1-trichloroethane, xylenes, and nitrous oxide. Yet the teratogenic effects of abuse patterns of exposure to toluene and other inhalants remain understudied. We briefl y review how animal models can aid substantially in clarifying the developmental risk of exposure to solvents for adverse biobehavioral outcomes following abuse patterns of use and in the absence of associated health problems and co-drug abuse (eg, alcohol). Our studies also begin to establish the importance of dose (concentration) and critical perinatal periods of exposure to specifi c outcomes. The present results with our clinically relevant animal model of repeated, brief, high-concentration binge prenatal toluene exposure demonstrate the dose-dependent effect of toluene on prenatal development, early postnatal maturation, spontaneous exploration, and amphetamine-induced locomotor activity. The results imply that abuse patterns of toluene exposure may be more deleterious than typical occupational exposure on fetal development and suggest that animal models are effective in studying the mechanisms and risk factors of organic solvent teratogenicity.

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Development of a Rat Model of Toluene-Abuse Embryopathy

Cited by 23 publications

References 26 publications

Developmental Neurotoxicity of Toluene: in vivo and in vitro Effects on Astroglial Cells

Developmental Neurotoxicity of Toluene: in vivo and in vitro Effects on Astroglial Cells

Maternal and fetal blood and organ toluene levels in rats following acute and repeated binge inhalation exposure☆

Developmental Toxicity of Prenatal Exposure to Toluene

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