Development of Secondary Sex Characteristics in Male Rats after Fetal and Perinatal Cimetidine Exposure

Hoie, Eric B.; Swigart, Scott A.; Nelson, Robert M.; Leuschen, M. Patricia

doi:10.1002/jps.2600830125

Cited by 6 publications

(2 citation statements)

References 10 publications

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“…Vitamin B 12 -deficient rats showed significant reductions of testis weight, atrophy of the seminiferous tubules, and aplasia of spermatids and sperms [13]. Therefore, besides the questionable antiandrogenic effect of cimetidine, nonendocrine factors could also be involved in testicular changes since unaltered levels of plasma testosterone were observed in the present study as well as in previous reports [5,8,32].…”

Section: Discussionsupporting

confidence: 44%

Morphological Alterations and Intratubular Lipid Inclusions as Indicative of Spermatogenic Damage in Cimetidine-Treated Rats

Sasso-Cerri¹,

Giovanoni²,

Hayashi³

et al. 2001

Archives of Andrology

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Doses of cimetidine (50 mg/kg b/w) were administered to adult male Wistar rats over 52 consecutive days. Besides plasma testosterone levels, morphological and morphometric aspects of the seminiferous tubules as well as histochemical analysis of the lipid content by oil red O were emphasized. Abnormal tubules exhibiting disorganization of their cellular association, loss of germ cells, and multinucleated giant spermatids were usually found. Significant reductions of testis weight and tubular diameter at specific stages (VII-IX), as well as lack of contact between Sertoli cells and spermatids in tubules at stage IX, suggest a possible interference of cimetidine on the histoarchitecture of the seminiferous epithelium. The dense concentration of lipid inclusions in tubules at postspermiation stages indicates phagocytosis and degradation of germ cells. Since no change in serum testosterone levels was verified in cimetidine-treated rats, the authors could not exclude the possibility that besides an antiandrogenic effect, other biochemical factors necessary for normal spermatogenesis could be involved in the testicular alterations.

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Section: Discussionsupporting

confidence: 44%

Morphological Alterations and Intratubular Lipid Inclusions as Indicative of Spermatogenic Damage in Cimetidine-Treated Rats

Sasso-Cerri¹,

Giovanoni²,

Hayashi³

et al. 2001

Archives of Andrology

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“…Cimetidine crosses the placenta by passive diffusion [ 38 ] and has been allocated to pregnancy category B by the FDA, which means that cimetidine is not expected to be harmful to the fetus. There are conflicting reports on anti-androgenic effects of cimetidine in animals exposed in utero [ 61 – 64 ]; however, no anti-androgenic effects of cimetidine have so far been reported in human pregnancy.…”

Section: Discussionmentioning

confidence: 99%

A Mechanism for the Inhibition of Neural Progenitor Cell Proliferation by Cocaine

et al. 2008

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BackgroundPrenatal exposure of the developing brain to cocaine causes morphological and behavioral abnormalities. Recent studies indicate that cocaine-induced proliferation inhibition and/or apoptosis in neural progenitor cells may play a pivotal role in causing these abnormalities. To understand the molecular mechanism through which cocaine inhibits cell proliferation in neural progenitors, we sought to identify the molecules that are responsible for mediating the effect of cocaine on cell cycle regulation.Methods and FindingsMicroarray analysis followed by quantitative real-time reverse transcription PCR was used to screen cocaine-responsive and cell cycle-related genes in a neural progenitor cell line where cocaine exposure caused a robust anti-proliferative effect by interfering with the G1-to-S transition. Cyclin A2, among genes related to the G1-to-S cell cycle transition, was most strongly down-regulated by cocaine. Down-regulation of cyclin A was also found in cocaine-treated human primary neural and A2B5+ progenitor cells, as well as in rat fetal brains exposed to cocaine in utero. Reversing cyclin A down-regulation by gene transfer counteracted the proliferation inhibition caused by cocaine. Further, we found that cocaine-induced accumulation of reactive oxygen species, which involves N-oxidation of cocaine via cytochrome P450, promotes cyclin A down-regulation by causing an endoplasmic reticulum (ER) stress response, as indicated by increased phosphorylation of eIF2α and expression of ATF4. In the developing rat brain, the P450 inhibitor cimetidine counteracted cocaine-induced inhibition of neural progenitor cell proliferation as well as down-regulation of cyclin A.ConclusionsOur results demonstrate that down-regulation of cyclin A underlies cocaine-induced proliferation inhibition in neural progenitors. The down-regulation of cyclin A is initiated by N-oxidative metabolism of cocaine and consequent ER stress. Inhibition of cocaine N-oxidative metabolism by P450 inhibitors may provide a preventive strategy for counteracting the adverse effects of cocaine on fetal brain development.

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Pre- and Postnatal Oral Toxicity of Vinclozolin in Wistar and Long–Evans Rats

Hellwig

Ravenzwaay

Mayer

et al. 2000

Regulatory Toxicology and Pharmacology

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Development of Secondary Sex Characteristics in Male Rats after Fetal and Perinatal Cimetidine Exposure

Cited by 6 publications

References 10 publications

Morphological Alterations and Intratubular Lipid Inclusions as Indicative of Spermatogenic Damage in Cimetidine-Treated Rats

Morphological Alterations and Intratubular Lipid Inclusions as Indicative of Spermatogenic Damage in Cimetidine-Treated Rats

A Mechanism for the Inhibition of Neural Progenitor Cell Proliferation by Cocaine

Pre- and Postnatal Oral Toxicity of Vinclozolin in Wistar and Long–Evans Rats

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