2-Bromopropane Causes Ovarian Dysfunction by Damaging Primordial Follicles and Their Oocytes in Female Rats

Yu, Xiaozhong; Kamijima, Michihiro; Ichihara, Gaku; Li, Wenxin; Kitoh, Junzoh; Xie, Zhenlin; Shibata, Eiji; Hisanaga, Naomi; Takeuchi, Yasuhiro

doi:10.1006/taap.1999.8730

Cited by 56 publications

(34 citation statements)

References 23 publications

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“…According to these data, male rats were daily subcutaneously exposed to 2-BP at the doses of 135, 405, and 1,355 mg/kg/ day for 28 days. This range of dose levels encompassed the highest level used in the Omura et al [22], Ichihara et al [10,11], and Yu et al [34] study to target a dose that caused reproductive tract toxicity. Control rats received corn oil (1 ml/kg/day).…”

Section: Animalsmentioning

confidence: 99%

“…Yu et al [34] reported, in situ end labeling showed increased numbers of apoptotic oocytes and granulosa cells in primordial follicles at days 5 and 17 after inhalation exposure of 3,000 ppm 2-BP. This result suggested that ovarian dysfunction induced by 2-BP was caused by the destruction of primordial follicle and its oocyte due to the induction of apoptosis in female rats.…”

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confidence: 99%

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2-Bromopropane Induced Germ Cell Apoptosis during Spermatogenesis in Male Rat.

Kang

Lee

2001

The Journal of Veterinary Medical Science

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ABSTRACT. 2-Bromopropane (2-BP) causes testicular toxicity in humans and rats. However, the germ cell degeneration of testicular toxicity by 2-BP has not been understood. 2-BP at doses of 135, 405, and 1,355 mg/kg/day was daily injected subcutaneously into SpragueDawley rats for 28 days. At the dose of 1,355 mg/kg/day, 2-BP significantly decreased the weights of body and testes, eipididymis, seminal vesicle, and prostate, as well as daily sperm production. Atrophy of seminiferous tubules accompanied with degeneration of germ cells such as spermatogonia, spermatocytes, and elongated spermatids was observed in the testes of rats exposed to the 405 mg/ kg/day and 1,355 mg/kg/day of 2-BP. TUNEL-positive germ cells were appeared in the 405 and 1,355 mg/kg/day of 2-BP-treated groups. In addition, ultrastructure alterations of apoptotic germ cells were observed by the electron microscopy study. Dead elongated spermatids were observed at 1,355 mg/kg/day after 28 days exposure. These results suggest that 2-BP impair spermatogenesis may result from apoptotic germ cell death.

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Section: Animalsmentioning

confidence: 99%

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confidence: 99%

2-Bromopropane Induced Germ Cell Apoptosis during Spermatogenesis in Male Rat.

Kang

Lee

2001

The Journal of Veterinary Medical Science

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“…For example, smoking is known to be associated with early menopause, and polycyclic aromatic hydrocarbons, major toxic components of cigarette smoke, cause follicle destruction in experimental animals (31). Exposure to 2-bromopropane at the work place is linked to an increase in the incidence of early menopause and infertility in female workers; the chemical is selectively toxic to ovarian follicles in animal models (23,45). Thus, identifying genetic and environmental factors, as well as gene-environment interactions, that contribute to follicular destruction and POF is a particular health concern of women at work and in general populations.…”

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confidence: 99%

Accelerated Ovarian Failure Induced by 4-Vinyl Cyclohexene Diepoxide in Nrf2 Null Mice

Roberts

Apopa

et al. 2006

Molecular and Cellular Biology

105

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Genetic and biochemical analyses have uncovered an essential role for nuclear factor erythroid 2-related factor 2 (Nrf2) in regulating phase II xenobiotic metabolism and antioxidant response. Here we show that Nrf2 protects against the ovarian toxicity of 4-vinylcyclohexene diepoxide (VCD) in mice. Nrf2؊/؊ female mice exposed to VCD exhibit an age-dependent decline in reproduction leading to secondary infertility accompanied by hypergonadotropic hypogonadism after 30 weeks of age. VCD is shown to selectively destroy small ovarian follicles, resulting in early depletion of functional follicles. Treatment with VCD induces apoptotic death in cultured cells and in ovarian follicles, suggesting apoptosis as a mechanism of follicle loss. Loss of Nrf2 function blocks the basal and inducible expression of microsomal epoxide hydrolase, a key enzyme in the detoxification of VCD, and increases the oxidative stress in cells that is further exacerbated by VCD. Foxo3a, a repressor in the early stages of follicle activation, displays reduced expression in Nrf2 ؊/؊ ovaries, causing accelerated growth of follicles in the absence of exposure to exogenous chemicals. Furthermore, Foxo3a is degraded through the 26S proteasome pathway in untreated cells and is induced by VCD via both Nrf2-dependent transcription and protein stabilization. This study demonstrates that Nrf2 serves as an essential sensor and regulator of chemical homeostasis in ovarian cells, protecting the cells from toxic chemicals by controlling metabolic detoxification, reactive oxygen species defense, and Foxo3a expression. In addition, these findings raise the possibility that exposure to environmental or occupational ovotoxicants plays a role in the premature ovarian failure commonly associated with infertility and premature aging in women.

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“…Some workers in semiconductor factories in Korea were found to have affected in their reproductive functions after exposure to 2-bromopropane (2BP) 2,3) . Subsequently, the reproductive effects of 2BP were confirmed to the animal experimental studies [4][5][6][7] . These reports prompted close reappraisal of the efficacy and feasibility of mass screening for toxicity to male reproductive functions in industrial populations.…”

Section: Introductionmentioning

confidence: 83%

Comparative Investigation of Several Sperm Analysis Methods for Evaluation of Spermatotoxicity of Industrial Chemical: 2-Bromopropane as an Example.

et al. 2004

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Reproductive toxicity of 2-bromopropane (2BP), a substitute for ozone layer-depleting chloro-fluorocarbon, was found among the workers in an electronics factory in Korea in 1995. Furthermore the importance of testicular toxicity has been realized since the problem of endocrine disruptors arose all over the world, but manual methods must rely on subjective assessment. Recently, computer-assisted sperm analysis (CASA) was proposed but this system requires vast investment. We then investigated the applicability of the MTT method with a microplate and sperm quality analyzer (SQA) as simple, rapid, and economic instrumental methods for the examination of sperm quality in rats, comparing it with the manual microscopic method and CASA. Epididymal fluid derived from male F344/N Slc (Fischer) rats intraperitoneally injected with 2BP in the dose range of 125-1,000 mg/kg/d twice a week (total 8 times) were examined by these methods as a model experiment. Sperm count measured by the manual method and CASA in the epididymal fluid, absorbance by the MTT method and sperm motility index value by the SQA method were significantly lower in the 2BP 1,000 mg/kg administered group than in the control group. This result suggests that the MTT method can detect oligospermia. With the microplate and microplate reader, the efficiency of detection becomes much better. Sperm analyses by the MTT method with the microplate reader and the SQA method are available for reproductive toxicity study in rats.

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2-Bromopropane Causes Ovarian Dysfunction by Damaging Primordial Follicles and Their Oocytes in Female Rats

Cited by 56 publications

References 23 publications

2-Bromopropane Induced Germ Cell Apoptosis during Spermatogenesis in Male Rat.

2-Bromopropane Induced Germ Cell Apoptosis during Spermatogenesis in Male Rat.

Accelerated Ovarian Failure Induced by 4-Vinyl Cyclohexene Diepoxide in Nrf2 Null Mice

Comparative Investigation of Several Sperm Analysis Methods for Evaluation of Spermatotoxicity of Industrial Chemical: 2-Bromopropane as an Example.

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