槲皮素缓解镉和硝基酚诱导的生精细胞毒性作用的研究
|
摘要
现代化工业进程的快速发展导致人类及各种生物接触到越来越多的内分泌干扰物(endocrine disrupting chemical, EDC),从而对人类及动物的健康,尤其是生殖健康造成巨大的潜在危害。氧化损伤是EDC产生毒性作用的重要机制之一,因此积极探索可以有效预防及缓解氧化损伤方法是生殖毒理学研究的热点。黄酮类物质是植物界普遍存在的一种多酚类物质,研究表明,抗氧化功能是黄酮类物质的一个基本性质。它可以直接清除自由基,或通过螯合过渡性金属离子来抑制活性氧物质的生成。然而,黄酮类物质的对生殖系统的保护机制尚未完全阐明,因此,本研究从在体实验及体外细胞培养实验两方面研究了黄酮类物质槲皮素(quercetin)对两种典型的EDC,包括无机物镉(cadmium)和有机物3-甲基-4-硝基酚(3-methyl-4-nitrophenol, PNMC)生殖毒性的缓解作用,为探明EDC的毒性机制及防治提供了理论指导。
1.镉对性腺的作用及槲皮素对镉引起的小鼠睾丸损伤的缓解作用
镉是一种有毒重金属,作为无机内分泌干扰物的典型代表,广泛存在于人类的生活环境中。镉可以对生殖系统如睾丸组织造成损害,因此本试验对镉的睾丸毒性作用机理进行了探讨,研究了抗氧化物槲皮素对镉引起睾丸毒性的缓解作用。比较了饮水及腹腔注射两种染毒途径下镉对性成熟小鼠睾丸的损伤作用。饮水染镉2周后,4 mg/kg剂量的镉可引起睾丸生殖细胞的损伤及脱落,8 mg/kg剂量的镉可引起睾丸生精上皮的严重破坏。而一次性腹腔注射染毒后,25 mg/kg剂量的镉可引起睾丸的严重损伤,睾丸充血肿胀,血细胞分布于整个睾丸间质中,且生精上皮遭到严重破坏。以上两种途径及剂量染镉都会造成附睾内精子的损伤。对睾丸组织生化指标的检测显示,镉导致睾丸活性氧生成及脂质过氧化程度增加,同时耗竭抗氧化物质谷胱甘肽(glutathione, GSH)及抗氧化酶超氧化物歧化酶(superoxide dismutase. SOD)、谷胱甘肽过氧化物酶(glutathione peroxidase, GSH-Px)。镉还激活了促凋亡蛋白Bax和caspase-3的表达并抑制抗凋亡蛋白Bcl-2的表达,经线粒体信号途径引起生殖细胞的凋亡。槲皮素作为天然抗氧化物质,可以有效缓解镉的睾丸毒性。本研究发现,槲皮素(75 mg/kg)可以有效降低镉引起的活性氧的生成,并抑制脂质过氧化的发生。槲皮素可以有效改善组织的抗氧化能力,增加GSH水平并提高SOD和GSH-Px活力,从而增强组织清除活性氧的能力。此外,槲皮素还可以有效调节镉引起的生殖细胞的凋亡,提高抗凋亡蛋白Bcl-XL的表达并抑制促凋亡蛋白Bax及凋亡效应因子caspase-3表达,进而阻止凋亡信号的启动。研究了可导致成熟雄性小鼠睾丸损伤剂量的镉对成熟雌性小鼠卵巢的影响。病理组织切片结果显示,所有处理组小鼠的卵巢形态良好,有不同发育阶段的卵泡存在。但镉处理后小鼠卵巢内发育中的卵泡数量似乎增多,总的卵泡数量明显多余对照组小鼠,且存在剂量依赖性,最高剂量的镉处理后总的卵泡数量有下降的趋势。通过TUNEL免疫组织化学染色鉴定细胞凋亡发现,所有处理小鼠的卵巢内未发现有凋亡细胞存在。说明雌性动物对内分泌干扰物的损伤作用的抵抗力要比雄性动物强。
2.槲皮素对镉引起的精原细胞氧化损伤的缓解作用
前期的研究结果表明镉可以引起多种生殖细胞的损伤,其中精原细胞是成年雄性动物生殖细胞产生的源泉,通过研究镉对精原细胞的毒性作用机理可以为保护雄性精子发生提供理论指导。利用6日龄小鼠建立了睾丸精原细胞-体细胞共培养模型。以DMEM为基础培养基,并添加L-谷氨酰胺、胰岛素、转铁蛋白及亚硒酸钠等因子可以维持精原细胞在体外的存活及增殖。精原细胞称圆形且粘附于体细胞之上生长,常以一个或多个聚集在一起的形式存在。不同剂量的镉处理精原细胞后发现(1、2和4μmol/L),当镉剂量超过2μmol/L时可以剂量依赖性地引起精原细胞的损伤,且氧化应激是导致精原细胞损伤的重要原因。镉处理后精原细胞数量减少,细胞活性降低,脂质过氧化程度提高,抗氧化物质GSH及抗氧化酶SOD酶活性受到显著抑制。槲皮素可以有效缓解镉对精原细胞的损伤作用。槲皮素增加了精原细胞的数量及活性,抑制了MDA的生成,并恢复了GSH水平及SOD活性。这些结果表明,无论是在体还是离体试验,都证明了氧化应激是镉产生生殖毒性的原因之一,而槲皮素可以通过有效清除活性氧的产生,抑制脂质过氧化,提高抗氧化系统的能力,抑制细胞的凋亡等对细胞及组织形成保护作用。
3.槲皮素对PNMC引起的睾丸损伤的缓解作用
随着交通工具的日益普及,汽车尾气的污染问题日益严重。除了气体污染外,在尾气中还含有大量有机颗粒性物质,这些颗粒物可对人类及各种动物的生殖功能造成危害。本试验研究了柴油尾气成分之一的PNMC的生殖毒性作用,并探讨了抗氧化物槲皮素对PNMC引起的睾丸毒性的缓解作用。通过腹腔注射方式使小鼠染毒,研究了PNMC对性成熟小鼠的睾丸毒性作用。发现一次性高剂量(100 mg/kg)接触后,PNMC可以引起小鼠睾丸的局部严重损伤,表现为睾丸曲细精管的损伤,生精上皮中生殖细胞数量显著减少。PNMC显著增加睾丸组织羟自由基(hydroxyl radical,·OH)、过氧化氢(H2O2)等活性氧的生成,导致脂质过氧化发生,破坏了抗氧化系统,并改变线粒体中抗凋亡蛋白Bcl-XL及促凋亡蛋白Bax的表达水平,激活细胞caspase-3活性,引起生殖细胞的DNA损伤,最终导致生殖细胞的凋亡。而抗氧化物槲皮素与PNMC联合处理则可以有效缓解后者造成的睾丸毒性作用。槲皮素联合处理后,小鼠睾丸生精上皮形态完整,睾丸组织羟自由基、过氧化氢等活性氧水平显著降低,组织脂质过氧化程度显著受到抑制,Bcl-XL阳性细胞数量显著增多,而Bax阳性细胞数量显著减少,caspase-3活性也受到明显的抑制,生殖细胞TUNEL阳性数量显著降低。这些结果说明氧化损伤是PNMC引起雄性生殖毒理的重要原因之一,而槲皮素因具有抗氧化及抗凋亡等作用不但可以缓解无机物镉的睾丸毒性,也可以有效缓解有机物PNMC引起的睾丸损伤。
以上结果表明,镉及PNMC都可以引起雄性小鼠的睾丸损伤,且损伤与氧化应激有关,表现为活性氧生成的增加,脂质过氧化提高,组织抗氧化能力的抑制,线粒体凋亡途径(Bax/Bcl-XL)的激活,凋亡效应酶caspase-3的活化,并引发生殖细胞凋亡的发生。而槲皮素作为一种天然抗氧化物质可以有效清除活性氧的生成,抑制脂质过氧化,调节凋亡相关蛋白的表达,并有效缓解镉及PNMC引发的生殖细胞凋亡。
A variety of endocrine disrupting chemicals (EDC) has been released to the environment in the industrial progress; which may exert adverse health effects in human and animals, especially in reproduction system. Oxidative stress may be playing a key role in the mechanism of these adverse effects. Antioxidants may prevent negative effects induced by these chemicals. Flavonoids comprise the most common group of plant polyphenols and widerly distributed in plant kingdom. Owing to their potent antioxidant, free-radical scavenging activities and metal chelating ability, flavonoids can inhibit the production of reactive oxygen species. However, the protective mechanism of flavonoids on reproductive system is not well defined. The present study evaluated the oxidative toxicity of cadmium and 3-methyle-4-nitrophenol (PNMC) on testis in male mice, the effect of cadmium on oogenesis in female mice and studied the protective effect of quercetin on the reproductive toxicity induced by cadmium and 3-methyle-4-nitrophenol on testis.
1. Protective effect of quercetin on cadmium-induced oxidative toxicity in germ cells
Cadmium is a toxic heavy metal that is widely distributed in the environment. As a critical process, oxidative toxicity mediates the morphological and functional damages in germ cells after cadmium exposure. In this study the protective effect of quercetin on cadmium-induced oxidative toxicity was investigated in mouse testicular germ cells. After oral administration of cadmium chloride at 4 mg/kg body weight for 2 weeks, damages in spermatocytes and spermatozoa occurred in the seminiferous epithelium. Cadmium treatment significantly decreased the testicular antioxidant system, including decreases in the glutathione (GSH) level, superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities. Moreover, exposure to cadmium resulted in an increase of hydrogen peroxide (H2O2) level and lipid peroxidation in testes. In addition, cadmium provoked germ cell apoptosis by upregulating expression of the pro-apoptotic protein Bax and caspase-3, and downregulating expression of the anti-apoptotic protein Bcl-XL. However, combined administration of a common flavonoid quercetin at 75 mg/kg body weight significantly attenuated cadmium-induced germ cell apoptosis by suppressing the H2O2 production and lipid peroxidation in testicular tissue. Simultaneous supplementation of quercetin markedly reduced the decrease in GSH level and SOD and GSH-Px activities elicited by cadmium treatment. Additionally, quercetin protected germ cells from cadmium-induced apoptosis by downregulating the expression of Bax and caspase-3 and upregulating Bcl-XL expression. These results indicate that quercetin, due to its antioxidative and antiapoptotic character may impose effective protective action against cadmium-induced oxidative toxicity in mouse testicular germ cells. Cadmium, at the dose of which induced germ cell damage in male mice, was given to female mice for 2 weeks. Morphological results showed that there were no remarkable changes of ovary in all treatment. However, cadmium induced dose-dependent increase of number of developing oocyte. TUNEL immunohistochemistry staining revealed that there were no apoptotic cells in all treatment. Cadmium is suspected of exerting hormonic activity in female mice.
2. Protective effect of quercetin on cadmium-induced oxidative damage in spermatogonia in mice
The spermatogonial-somatic cell coculture system was established with 6-day-old male mice. The medium of DMEM supplemented with L-glutamide, insulin, transferrin and selenite could maintain spermatogonial survival and proliferation. Spermatogonial cell maintains round shape and attach to somatic cells. Cadmium (1,2, and 4μM) treatment exerts toxic effect on spermatogonial at a dose-dependent manner. Cadmium induced the decrease in testicular cell viability and spermatogonial cell number. Cadmium induced lipid peroxidation by an elevation of thiobarbituric acid reactive substances as well as decreasing GSH-Px activity and SOD activity. However, supplement with quercetin restored cell viability and cell number, and alleviated cadmium-induced oxidative damage with inhibition of production of MDA and increase of GSH level as well as SOD activity. These results indicate that quercetin can protect germ cells from oxidative stress not only in vivo but alse in vitro, owing to its antioxidative bioactivity.
3. Alleviative effect of quercetin on mouse germ cells intoxicated by PNMC
As a component of diesel exhaust particles, PNMC is a metabolite of the insecticide fenitrothion. In the present study, we found that a single intraperitoneal injection of PNMC at 100 mg/kg body weight induced severe testicular damage in mice after 1 week treatment. Exposure to PNMC induced an increase of hydroxyl radical (·OH) and H2O2 production, and induced lipid peroxidation, as well as a decrease in GSH level, SOD and GSH-Px activity. Furthermore, treatment of PNMC resulted in increased expression of the pro-apoptotic protein Bax and decrease expression of the anti-apoptotic protein Bcl-XL in germ cells. The testicular caspase-3 activity was significantly up-regulated in the PNMC-treated mice. Germ cell apoptosis was detected by TUNEL assay and the apoptotic cell was significantly increased in the PNMC-treated mice. In contrast, combined administration of a common flavonoid quercetin at 75 mg/kg body weight significantly attenuated PNMC-induced toxicity. These results indicated that the antioxidant quercetin displays a protective effect on PNMC-induced oxidative damage in mouse testes and may represent an efficient supplement to attenuate reproductive toxicity by environmental toxicants to ensure healthy sperm production.
In conclusion, cadmium and PNMC are proved harmful to the testes of male mice. Exposure to cadmium and PNMC resulted in an increase of reactive oxygen species and lipid peroxidation, decreased the testicular antioxidant abilities, including decreases in the GSH level, SOD and GSH-Px activities. Moreover, cadmium and PNMC provoked germ cell apoptosis by upregulating expression of the pro-apoptotic protein Bax and caspase-3, and downregulating expression of the anti-apoptotic protein Bcl-XL. In contrast, combined administration of a common flavonoid quercetin at 75 mg/kg body weight significantly attenuated cadmium and PNMC-induced toxicity. These results indicated that the antioxidant quercetin displays a protective effect on PNMC-induced oxidative damage in mouse testes and may represent an efficient supplement to attenuate reproductive toxicity by environmental toxicants to ensure healthy sperm production.
1.镉对性腺的作用及槲皮素对镉引起的小鼠睾丸损伤的缓解作用
镉是一种有毒重金属,作为无机内分泌干扰物的典型代表,广泛存在于人类的生活环境中。镉可以对生殖系统如睾丸组织造成损害,因此本试验对镉的睾丸毒性作用机理进行了探讨,研究了抗氧化物槲皮素对镉引起睾丸毒性的缓解作用。比较了饮水及腹腔注射两种染毒途径下镉对性成熟小鼠睾丸的损伤作用。饮水染镉2周后,4 mg/kg剂量的镉可引起睾丸生殖细胞的损伤及脱落,8 mg/kg剂量的镉可引起睾丸生精上皮的严重破坏。而一次性腹腔注射染毒后,25 mg/kg剂量的镉可引起睾丸的严重损伤,睾丸充血肿胀,血细胞分布于整个睾丸间质中,且生精上皮遭到严重破坏。以上两种途径及剂量染镉都会造成附睾内精子的损伤。对睾丸组织生化指标的检测显示,镉导致睾丸活性氧生成及脂质过氧化程度增加,同时耗竭抗氧化物质谷胱甘肽(glutathione, GSH)及抗氧化酶超氧化物歧化酶(superoxide dismutase. SOD)、谷胱甘肽过氧化物酶(glutathione peroxidase, GSH-Px)。镉还激活了促凋亡蛋白Bax和caspase-3的表达并抑制抗凋亡蛋白Bcl-2的表达,经线粒体信号途径引起生殖细胞的凋亡。槲皮素作为天然抗氧化物质,可以有效缓解镉的睾丸毒性。本研究发现,槲皮素(75 mg/kg)可以有效降低镉引起的活性氧的生成,并抑制脂质过氧化的发生。槲皮素可以有效改善组织的抗氧化能力,增加GSH水平并提高SOD和GSH-Px活力,从而增强组织清除活性氧的能力。此外,槲皮素还可以有效调节镉引起的生殖细胞的凋亡,提高抗凋亡蛋白Bcl-XL的表达并抑制促凋亡蛋白Bax及凋亡效应因子caspase-3表达,进而阻止凋亡信号的启动。研究了可导致成熟雄性小鼠睾丸损伤剂量的镉对成熟雌性小鼠卵巢的影响。病理组织切片结果显示,所有处理组小鼠的卵巢形态良好,有不同发育阶段的卵泡存在。但镉处理后小鼠卵巢内发育中的卵泡数量似乎增多,总的卵泡数量明显多余对照组小鼠,且存在剂量依赖性,最高剂量的镉处理后总的卵泡数量有下降的趋势。通过TUNEL免疫组织化学染色鉴定细胞凋亡发现,所有处理小鼠的卵巢内未发现有凋亡细胞存在。说明雌性动物对内分泌干扰物的损伤作用的抵抗力要比雄性动物强。
2.槲皮素对镉引起的精原细胞氧化损伤的缓解作用
前期的研究结果表明镉可以引起多种生殖细胞的损伤,其中精原细胞是成年雄性动物生殖细胞产生的源泉,通过研究镉对精原细胞的毒性作用机理可以为保护雄性精子发生提供理论指导。利用6日龄小鼠建立了睾丸精原细胞-体细胞共培养模型。以DMEM为基础培养基,并添加L-谷氨酰胺、胰岛素、转铁蛋白及亚硒酸钠等因子可以维持精原细胞在体外的存活及增殖。精原细胞称圆形且粘附于体细胞之上生长,常以一个或多个聚集在一起的形式存在。不同剂量的镉处理精原细胞后发现(1、2和4μmol/L),当镉剂量超过2μmol/L时可以剂量依赖性地引起精原细胞的损伤,且氧化应激是导致精原细胞损伤的重要原因。镉处理后精原细胞数量减少,细胞活性降低,脂质过氧化程度提高,抗氧化物质GSH及抗氧化酶SOD酶活性受到显著抑制。槲皮素可以有效缓解镉对精原细胞的损伤作用。槲皮素增加了精原细胞的数量及活性,抑制了MDA的生成,并恢复了GSH水平及SOD活性。这些结果表明,无论是在体还是离体试验,都证明了氧化应激是镉产生生殖毒性的原因之一,而槲皮素可以通过有效清除活性氧的产生,抑制脂质过氧化,提高抗氧化系统的能力,抑制细胞的凋亡等对细胞及组织形成保护作用。
3.槲皮素对PNMC引起的睾丸损伤的缓解作用
随着交通工具的日益普及,汽车尾气的污染问题日益严重。除了气体污染外,在尾气中还含有大量有机颗粒性物质,这些颗粒物可对人类及各种动物的生殖功能造成危害。本试验研究了柴油尾气成分之一的PNMC的生殖毒性作用,并探讨了抗氧化物槲皮素对PNMC引起的睾丸毒性的缓解作用。通过腹腔注射方式使小鼠染毒,研究了PNMC对性成熟小鼠的睾丸毒性作用。发现一次性高剂量(100 mg/kg)接触后,PNMC可以引起小鼠睾丸的局部严重损伤,表现为睾丸曲细精管的损伤,生精上皮中生殖细胞数量显著减少。PNMC显著增加睾丸组织羟自由基(hydroxyl radical,·OH)、过氧化氢(H2O2)等活性氧的生成,导致脂质过氧化发生,破坏了抗氧化系统,并改变线粒体中抗凋亡蛋白Bcl-XL及促凋亡蛋白Bax的表达水平,激活细胞caspase-3活性,引起生殖细胞的DNA损伤,最终导致生殖细胞的凋亡。而抗氧化物槲皮素与PNMC联合处理则可以有效缓解后者造成的睾丸毒性作用。槲皮素联合处理后,小鼠睾丸生精上皮形态完整,睾丸组织羟自由基、过氧化氢等活性氧水平显著降低,组织脂质过氧化程度显著受到抑制,Bcl-XL阳性细胞数量显著增多,而Bax阳性细胞数量显著减少,caspase-3活性也受到明显的抑制,生殖细胞TUNEL阳性数量显著降低。这些结果说明氧化损伤是PNMC引起雄性生殖毒理的重要原因之一,而槲皮素因具有抗氧化及抗凋亡等作用不但可以缓解无机物镉的睾丸毒性,也可以有效缓解有机物PNMC引起的睾丸损伤。
以上结果表明,镉及PNMC都可以引起雄性小鼠的睾丸损伤,且损伤与氧化应激有关,表现为活性氧生成的增加,脂质过氧化提高,组织抗氧化能力的抑制,线粒体凋亡途径(Bax/Bcl-XL)的激活,凋亡效应酶caspase-3的活化,并引发生殖细胞凋亡的发生。而槲皮素作为一种天然抗氧化物质可以有效清除活性氧的生成,抑制脂质过氧化,调节凋亡相关蛋白的表达,并有效缓解镉及PNMC引发的生殖细胞凋亡。
A variety of endocrine disrupting chemicals (EDC) has been released to the environment in the industrial progress; which may exert adverse health effects in human and animals, especially in reproduction system. Oxidative stress may be playing a key role in the mechanism of these adverse effects. Antioxidants may prevent negative effects induced by these chemicals. Flavonoids comprise the most common group of plant polyphenols and widerly distributed in plant kingdom. Owing to their potent antioxidant, free-radical scavenging activities and metal chelating ability, flavonoids can inhibit the production of reactive oxygen species. However, the protective mechanism of flavonoids on reproductive system is not well defined. The present study evaluated the oxidative toxicity of cadmium and 3-methyle-4-nitrophenol (PNMC) on testis in male mice, the effect of cadmium on oogenesis in female mice and studied the protective effect of quercetin on the reproductive toxicity induced by cadmium and 3-methyle-4-nitrophenol on testis.
1. Protective effect of quercetin on cadmium-induced oxidative toxicity in germ cells
Cadmium is a toxic heavy metal that is widely distributed in the environment. As a critical process, oxidative toxicity mediates the morphological and functional damages in germ cells after cadmium exposure. In this study the protective effect of quercetin on cadmium-induced oxidative toxicity was investigated in mouse testicular germ cells. After oral administration of cadmium chloride at 4 mg/kg body weight for 2 weeks, damages in spermatocytes and spermatozoa occurred in the seminiferous epithelium. Cadmium treatment significantly decreased the testicular antioxidant system, including decreases in the glutathione (GSH) level, superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities. Moreover, exposure to cadmium resulted in an increase of hydrogen peroxide (H2O2) level and lipid peroxidation in testes. In addition, cadmium provoked germ cell apoptosis by upregulating expression of the pro-apoptotic protein Bax and caspase-3, and downregulating expression of the anti-apoptotic protein Bcl-XL. However, combined administration of a common flavonoid quercetin at 75 mg/kg body weight significantly attenuated cadmium-induced germ cell apoptosis by suppressing the H2O2 production and lipid peroxidation in testicular tissue. Simultaneous supplementation of quercetin markedly reduced the decrease in GSH level and SOD and GSH-Px activities elicited by cadmium treatment. Additionally, quercetin protected germ cells from cadmium-induced apoptosis by downregulating the expression of Bax and caspase-3 and upregulating Bcl-XL expression. These results indicate that quercetin, due to its antioxidative and antiapoptotic character may impose effective protective action against cadmium-induced oxidative toxicity in mouse testicular germ cells. Cadmium, at the dose of which induced germ cell damage in male mice, was given to female mice for 2 weeks. Morphological results showed that there were no remarkable changes of ovary in all treatment. However, cadmium induced dose-dependent increase of number of developing oocyte. TUNEL immunohistochemistry staining revealed that there were no apoptotic cells in all treatment. Cadmium is suspected of exerting hormonic activity in female mice.
2. Protective effect of quercetin on cadmium-induced oxidative damage in spermatogonia in mice
The spermatogonial-somatic cell coculture system was established with 6-day-old male mice. The medium of DMEM supplemented with L-glutamide, insulin, transferrin and selenite could maintain spermatogonial survival and proliferation. Spermatogonial cell maintains round shape and attach to somatic cells. Cadmium (1,2, and 4μM) treatment exerts toxic effect on spermatogonial at a dose-dependent manner. Cadmium induced the decrease in testicular cell viability and spermatogonial cell number. Cadmium induced lipid peroxidation by an elevation of thiobarbituric acid reactive substances as well as decreasing GSH-Px activity and SOD activity. However, supplement with quercetin restored cell viability and cell number, and alleviated cadmium-induced oxidative damage with inhibition of production of MDA and increase of GSH level as well as SOD activity. These results indicate that quercetin can protect germ cells from oxidative stress not only in vivo but alse in vitro, owing to its antioxidative bioactivity.
3. Alleviative effect of quercetin on mouse germ cells intoxicated by PNMC
As a component of diesel exhaust particles, PNMC is a metabolite of the insecticide fenitrothion. In the present study, we found that a single intraperitoneal injection of PNMC at 100 mg/kg body weight induced severe testicular damage in mice after 1 week treatment. Exposure to PNMC induced an increase of hydroxyl radical (·OH) and H2O2 production, and induced lipid peroxidation, as well as a decrease in GSH level, SOD and GSH-Px activity. Furthermore, treatment of PNMC resulted in increased expression of the pro-apoptotic protein Bax and decrease expression of the anti-apoptotic protein Bcl-XL in germ cells. The testicular caspase-3 activity was significantly up-regulated in the PNMC-treated mice. Germ cell apoptosis was detected by TUNEL assay and the apoptotic cell was significantly increased in the PNMC-treated mice. In contrast, combined administration of a common flavonoid quercetin at 75 mg/kg body weight significantly attenuated PNMC-induced toxicity. These results indicated that the antioxidant quercetin displays a protective effect on PNMC-induced oxidative damage in mouse testes and may represent an efficient supplement to attenuate reproductive toxicity by environmental toxicants to ensure healthy sperm production.
In conclusion, cadmium and PNMC are proved harmful to the testes of male mice. Exposure to cadmium and PNMC resulted in an increase of reactive oxygen species and lipid peroxidation, decreased the testicular antioxidant abilities, including decreases in the GSH level, SOD and GSH-Px activities. Moreover, cadmium and PNMC provoked germ cell apoptosis by upregulating expression of the pro-apoptotic protein Bax and caspase-3, and downregulating expression of the anti-apoptotic protein Bcl-XL. In contrast, combined administration of a common flavonoid quercetin at 75 mg/kg body weight significantly attenuated cadmium and PNMC-induced toxicity. These results indicated that the antioxidant quercetin displays a protective effect on PNMC-induced oxidative damage in mouse testes and may represent an efficient supplement to attenuate reproductive toxicity by environmental toxicants to ensure healthy sperm production.
引文
Acharya, U.R., Mishra, M., Tripathy, R.R., Mishra, I.,2006. Testicular dysfunction and antioxidative defense system of Swiss mice after chromic acid exposure. Reprod Toxicol 22, 87-91.
Adams, J.M., Cory, S.,1998. The Bcl-2 protein family:Arbiters of cell survival. Science 281, 1322-1326.
Afanas'ev, I.B., Ostrachovitch, E.A., Abramova, N.E., Korkina, L.G.,1995. Different antioxidant activities of bioflavonoid rutin in normal and iron-overloading rats. Biochem Pharmacol 50, 627-635.
Agarwal, A., Prabakaran, S., Allamaneni, S.S.,2006. Relationship between oxidative stress, varicocele and infertility:a meta-analysis. Reprod Biomed Online 12,630-633.
Agostinho, P., Duarte, C.B., Oliveira, C.R.,1997. Impairment of excitatory amino acid transporter activity by oxidative stress conditions in retinal cells:effect of antioxidants. Faseb J 11, 154-163.
Akinloye, O., Arowojolu, A.O., Shittu, O.B., Anetor, J.I.,2006. Cadmium toxicity:a possible cause of male infertility in Nigeria. Reprod Biol 6,17-30.
Alia, M., Mateos, R., Ramos, S., Lecumberri, E., Bravo, L., Goya, L.,2006. Influence of quercetin and rutin on growth and antioxidant defense system of a human hepatoma cell line (HepG2). Eur J Nutr 45,19-28.
Amara, S., Abdelmelek, H., Garrel, C., Guiraud, P., Douki, T., Ravanat, J.L., Favier, A., Sakly, M., Ben Rhouma, K.,2008. Preventive effect of zinc against cadmium-induced oxidative stress in the rat testis. J Reprod Develop 54,129-134.
Arai, Y., Watanabe, S., Kimira, M., Shimoi, K., Mochizuki, R., Kinae, N.,2000. Dietary intakes of flavonols, flavones and isoflavones by Japanese women and the inverse correlation between quercetin intake and plasma LDL cholesterol concentration. J Nutr 130,2243-2250.
Arts, I.C., Hollman, P.C.,2005. Polyphenols and disease risk in epidemiologic studies. Am J Clin Nutr 81,317S-325S.
Arts, I.C., Hollman, P.C., Feskens, E.J., Bueno de Mesquita, H.B., Kromhout, D.,2001. Catechin intake might explain the inverse relation between tea consumption and ischemic heart disease: the Zutphen Elderly Study. Am J Clin Nutr 74,227-232.
Aruldhas, M.M., Subramanian, S., Sekar, P., Vengatesh, G., Chandrahasan, G., Govindarajulu, P., Akbarsha, M.A.,2005. Chronic chromium exposure-induced changes in testicular histoarchitecture are associated with oxidative stress:study in a non-human primate(Macaca radiata Geoffroy). Hum Reprod 20,2801-2813.
Atanassova, N., McKinnell, C., Walker, M., Turner, K.J., Fisher, J.S., Morley, M., Millar, M.R., Groome, N.P., Sharpe, R.M.,1999. Permanent effects of neonatal estrogen exposure in rats on reproductive hormone levels, Sertoli cell number, and the efficiency of spermatogenesis in adulthood. Endocrinology 140,5364-5373.
Atik, E., Gorur, S., Kiper, A.N.,2006. The effect of caffeic acid phenethyl ester (CAPE) on histopathological changes in testicular ischemia-reperfusion injury. Pharmacol Res 54, 293-297.
Auger, J., Kunstmann, J.M., Czyglik, F., Jouannet, P.,1995. Decline in semen quality among fertile men in Paris during the past 20 years. N Engl J Med 332,281-285.
Baek, I.J., Seo, D.S., Yon, J.M., Lee, S.R., Jin, Y., Nahm, S.S., Jeong, J.H., Choo, Y.K., Kang, J.K., Lee, B.J., Yun, Y.W., Nam, S.Y.,2007. Tissue expression and cellular localization of phospholipid hydroperoxide glutathione peroxidase (PHGPx) mRNA in male mice. J Mol Histol 38,237-244.
Banfi, B., Molnar, G., Maturana, A., Steger, K., Hegedus, B., Demaurex, N., Krause, K.H.,2001. A Ca(2+)-activated NADPH oxidase in testis, spleen, and lymph nodes. J Biol Chem 276, 37594-37601.
Baulig, A., Garlatti, M., Bonvallot, V., Marchand, A., Barouki, R., Marano, F., Baeza-Squiban, A., 2003. Involvement of reactive oxygen species in the metabolic pathways triggered by diesel exhaust particles in human airway epithelial cells. Am J Physiol Lung Cell Mol Physiol 285, L671-679.
Bellve, A.R., Cavicchia, J.C., Millette, C.F., O'Brien, D.A., Bhatnagar, Y.M., Dym, M.,1977. Spermatogenic cells of the prepuberal mouse. Isolation and morphological characterization. J Cell Biol 74,68-85.
Benoff, S., Jacob, A., Hurley, I.R.,2000. Male infertility and environmental exposure to lead and cadmium. Hum Reprod Update 6,107-121.
Bu, T., Mi, Y., Zeng, W., Zhang, C.,2010. Protective Effect of quercetin on cadmium-induced oxidative toxicity on germ cells in male mice. Anat Rec (Hoboken).
Bujan, L., Mansat, A., Pontonnier, F., Mieusset, R.,1996. Time series analysis of sperm concentration in fertile men in Toulouse, France between 1977 and 1992. BMJ 312,471-472.
Caltagirone, S., Rossi, C., Poggi, A., Ranelletti, F.O., Natali, P.G., Brunetti, M., Aiello, F.B., Piantelli, M.,2000. Flavonoids apigenin and quercetin inhibit melanoma growth and metastatic potential. Int J Cancer 87,595-600.
Carlsen, E., Giwercman, A., Keiding, N., Skakkebaek, N.E.,1992. Evidence for decreasing quality of semen during past 50 years. BMJ 305,609-613.
Celino, F.T., Yamaguchi, S., Miura, C., Ohta, T., Tozawa, Y., Iwai, T., Miura, T.,2011. Tolerance of spermatogonia to oxidative stress is due to high levels of Zn and Cu/Zn superoxide dismutase. PLoS One 6, e16938.
Chaki, S.P., Ghosh, D., Misro, M.M.,2003. Simultaneous increase in germ cell apoptosis and oxidative stress under acute unilateral testicular ischaemia in rats. Int J Androl 26,319-328.
Chao, C.L., Hou, Y.C., Chao, P.D.L., Weng, C.S., Ho, F.M.,2009. The antioxidant effects of quercetin metabolites on the prevention of high glucose-induced apoptosis of human umbilical vein endothelial cells. Brit J Nutr 101,1165-1170.
Cheng, I.F., Breen, K.,2000. On the ability of four flavonoids, baicilein, luteolin, naringenin, and quercetin, to suppress the Fenton reaction of the iron-ATP complex. Biometals 13,77-83.
Chiquoine, A.D.,1964. Observations on the early events of cadmium necrosis of the testis. Anat Rec 149,23-35
Choe, S.Y., Kim, S.J., Kim, H.G., Lee, J.H., Choi, Y., Lee, H., Kim, Y.,2003. Evaluation of estrogenicity of major heavy metals. Sci Total Environ 312,15-21.
Chung, N.P., Cheng, C.Y.,2001. Is cadmium chloride-induced inter-sertoli tight junction permeability barrier disruption a suitable in vitro model to study the events of junction disassembly during spermatogenesis in the rat testis? Endocrinology 142,1878-1888.
Damstra T, Barlow S, Bergman A, et al. Global assessment of the state of the science of endocrine disruptors [R].2002, WHO IPCS,25-26.
Danzo, B.J.,1997. Environmental xenobiotics may disrupt normal endocrine function by interfering with the binding of physiological ligands to steroid receptors and binding proteins. Environ Health Perspect 105,294-301.
de Groot, H.,1994. Reactive oxygen species in tissue injury. Hepatogastroenterology 41,328-332.
Denier, X., Hill, E.M., Rotchell, J., Minier, C.,2009. Estrogenic activity of cadmium, copper and zinc in the yeast estrogen screen. Toxicol In Vitro 23,569-573.
Donaldson, K., Stone, V., Borm, P.J., Jimenez, L.A., Gilmour, P.S., Schins, R.P., Knaapen, A.M., Rahman, I., Faux, S.P., Brown, D.M., MacNee, W.,2003. Oxidative stress and calcium signaling in the adverse effects of environmental particles (PM10). Free Radic Biol Med 34, 1369-1382.
Dudley, R.E., Gammal, L.M., Klaassen, C.D.,1985. Cadmium-induced hepatic and renal injury in chronically exposed rats-likely role of hepatic cadmium-metallothionein in nephrotoxicity. Toxicol Appl Pharm 77,414-426.
Duthie, G., Crozier, A.,2000. Plant-derived phenolic antioxidants. Curr Opin Lipidol 11,43-47.
Evers, D.L., Chao, C.F., Wang, X., Zhang, Z., Huong, S.M., Huang, E.S.,2005. Human cytomegalovirus-inhibitory flavonoids:studies on antiviral activity and mechanism of action. Antiviral Res 68,124-134.
Facino, R.M., Carini, M., Aldini, G., Berti, F., Rossoni, G., Bombardelli, E., Morazzoni, P.,1999. Diet enriched with procyanidins enhances antioxidant activity and reduces myocardial post-ischaemic damage in rats. Life Sci 64,627-642.
Fan, T.P., Jaggar, R., Bicknell, R.,1995. Controlling the vasculature:angiogenesis, anti-angiogenesis and vascular targeting of gene therapy. Trends Pharmacol Sci 16,57-66.
Fiander, H., Schneider, H.,2000. Dietary ortho phenols that induce glutathione S-transferase and increase the resistance of cells to hydrogen peroxide are potential cancer chemopreventives that act by two mechanisms:the alleviation of oxidative stress and the detoxification of mutagenic xenobiotics. Cancer Lett 156,117-124.
Fiorani, M., De Sanctis, R., Menghinello, P., Cucchiarini, L., Cellini, B., Dacha, M.,2001. Quercetin prevents glutathione depletion induced by dehydroascorbic acid in rabbit red blood cells. Free Radic Res 34,639-648.
Fisch, H., Goluboff, E.T., Olson, J.H., Feldshuh, J., Broder, S.J., Barad, D.H.,1996. Semen analyses in 1,283 men from the United States over a 25-year period:no decline in quality. Fertil Steril 65,1009-1014.
Fort, D.J., Stover, E.L., Bantle, J.A., Dumont, J.N., Finch, R.A.,2001. Evaluation of a reproductive toxicity assay using Xenopus laevis:boric acid, cadmium and ethylene glycol monomethyl ether. J Appl Toxicol 21,41-52.
Fouad, A.A., Qureshi, H.A., Al-Sultan, A.I., Yacoubi, M.T., Ali, A.A.,2009. Protective effect of hemin against cadmium-induced testicular damage in rats. Toxicology 257,153-160.
Fraga, C.G., Motchnik, P.A., Wyrobek, A.J., Rempel, D.M., Ames, B.N.,1996. Smoking and low antioxidant levels increase oxidative damage to sperm DNA. Mutat Res 351,199-203.
Friedmann, A.S.,2002. Atrazine inhibition of testosterone production in rat males following peripubertal exposure. Reprod Toxicol 16,275-279.
Furuta, C., Li, C., Taneda, S., Suzuki, A.K., Kamata, K., Watanabe, G., Taya, K.,2005. Immunohistological study for estrogenic activities of nitrophenols in diesel exhaust particles. Endocrine 27,33-36.
Furuta, C., Suzuki, A.K., Taneda, S., Kamata, K., Hayashi, H., Mori, Y., Li, C., Watanabe, G., Taya, K.,2004. Estrogenic activities of nitrophenols in diesel exhaust particles. Biol Reprod 70, 1527-1533.
Galan, A., Garcia-Bermejo, L., Troyano, A., Vilaboa, N.E., Fernandez, C., de Blas, E., Aller, P., 2001. The role of intracellular oxidation in death induction (apoptosis and necrosis) in human promonocytic cells treated with stress inducers (cadmium, heat, X-rays). Eur J Cell Biol 80, 312-320.
Galey, J.B.,1997. Potential use of iron chelators against oxidative damage. Adv Pharmacol 38, 167-203.
Garcia-Morales, P., Saceda, M., Kenney, N., Kim, N., Salomon, D.S., Gottardis, M.M., Solomon, H.B., Sholler, P.F., Jordan, V.C., Martin, M.B.,1994. Effect of cadmium on estrogen receptor levels and estrogen-induced responses in human breast cancer cells. J Biol Chem 269, 16896-16901.
Gustafsson, A.B., Gottlieb, R.A.,2007. Bcl-2 family members and apoptosis, taken to heart. Am J Physiol-Cell Physiol 292, C45-C51.
Han, J.Y., Takeshita, K., Utsumi, H.,2001. Noninvasive detection of hydroxyl radical generation in lung by diesel exhaust particles. Free Radic Biol Med 30,516-525.
Hendin, B.N., Kolettis, P.N., Sharma, R.K., Thomas, A.J., Jr., Agarwal, A.,1999. Varicocele is associated with elevated spermatozoal reactive oxygen species production and diminished seminal plasma antioxidant capacity. J Urol 161,1831-1834.
Hengartner, M.O.,2000. The biochemistry of apoptosis. Nature 407,770-776.
Hertog, M.G., Feskens, E.J., Hollman, P.C., Katan, M.B., Kromhout, D.,1993. Dietary antioxidant flavonoids and risk of coronary heart disease:the Zutphen Elderly Study. Lancet 342, 1007-1011.
Hertog, M.G., Kromhout, D., Aravanis, C., Blackburn, H., Buzina, R., Fidanza, F., Giampaoli, S., Jansen, A., Menotti, A., Nedeljkovic, S., et al.,1995. Flavonoid intake and long-term risk of coronary heart disease and cancer in the seven countries study. Arch Intern Med 155,381-386.
Hew, K.W., Ericson, W.A., Welsh, M.J.,1993. A single low cadmium dose causes failure of spermiation in the rat. Toxicol Appl Pharmacol 121,15-21.
Hiura, T.S., Kaszubowski, M.P., Li, N., Nel, A.E.,1999. Chemicals in diesel exhaust particles generate reactive oxygen radicals and induce apoptosis in macrophages. J Immunol 163, 5582-5591.
Hsu, P.C., Li, M.H., Guo, Y.L.,2003. Postnatal exposure of 2,2',3,3',4,6'-hexachlorobiphenyl and 2,2',3,4',5',6-hexachlorobiphenyl on sperm function and hormone levels in adult rats. Toxicology 187,117-126.
Huang, C.H., Lin, L.Y., Tsai, M.S., Hsu, C.Y., Chen, H.W., Wang, T.D., Chang, W.T., Cheng, T.J., Chen, W.J.,2010. Acute cardiac dysfunction after short-term diesel exhaust particles exposure. Toxicol Lett 192,349-355.
Hughes, P.J., McLellan, H., Lowes, D.A., Kahn, S.Z., Bilmen, J.G., Tovey, S.C., Godfrey, R.E., Michell, R.H., Kirk, C.J., Michelangeli, F.,2000. Estrogenic alkylphenols induce cell death by inhibiting testis endoplasmic reticulum Ca(2+) pumps. Biochem Biophys Res Commun 277, 568-574.
Ikeda, M., Kodama, H., Fukuda, J., Shimizu, Y., Murata, M., Kumagai, J., Tanaka, T.,1999. Role of radical oxygen species in rat testicular germ cell apoptosis induced by heat stress. Biol Reprod 61,393-399.
Inal, M.E., Kahraman, A.,2000. The protective effect of flavonol quercetin against ultraviolet a induced oxidative stress in rats. Toxicology 154,21-29.
Ishii, T., Matsuki, S., Iuchi, Y., Okada, F., Toyosaki, S., Tomita, Y., Ikeda, Y., Fujii, J.,2005. Accelerated impairment of spermatogenic cells in SOD 1-knockout mice under heat stress. Free Radic Res 39,697-705.
Ishikawa, T., Fujioka, H., Ishimura, T., Takenaka, A., Fujisawa, M.,2007. Increased testicular 8-hydroxy-2'-deoxyguanosine in patients with varicocele. BJU Int 100,863-866.
Izawa, H., Kohara, M., Aizawa, K., Suganuma, H., Inakuma, T., Watanabe, G., Taya, K., Sagai, M., 2008. Alleviative effects of quercetin and onion on male reproductive toxicity induced by diesel exhaust particles. Biosci Biotechnol Biochem 72,1235-1241.
Kanaly, R.A., Kim, I.S., Hur, H.G.,2005. Biotransformation of 3-methyl-4-nitrophenol, a main product of the insecticide fenitrothion, by Aspergillus niger. J Agric Food Chem 53, 6426-6431.
Kaur, P., Bansal, M.P.,2004. Influence of selenium induced oxidative stress on spermatogenesis and lactate dehydrogenase-X in mice testis. Asian J Androl 6,227-232.
Kaur, P., Kaur, G., Bansal, M.P.,2006. Tertiary-butyl hydroperoxide induced oxidative stress and male reproductive activity in mice:role of transcription factor NF-kappaB and testicular antioxidant enzymes. Reprod Toxicol 22,479-484.
Khan, I.A., Mathews, S., Okuzawa, K., Kagawa, H., Thomas, P.,2001. Alterations in the GnRH-LH system in relation to gonadal stage and Aroclor 1254 exposure in Atlantic croaker. Comp Biochem Physiol B Biochem Mol Biol 129,251-259.
Khurana, S., Ranmal, S., Ben-Jonathan, N.,2000. Exposure of newborn male and female rats to environmental estrogens:delayed and sustained hyperprolactinemia and alterations in estrogen receptor expression. Endocrinology 141,4512-4517.
Kim, B.M., Choi, Y.J., Han, Y., Yun, Y.S., Hong, S.H.,2009. N,N-dimethyl phytosphingosine induces caspase-8-dependent cytochrome c release and apoptosis through ROS generation in human leukemia cells. Toxicol Appl Pharm 239,87-97.
Kim, S.K., Kim, H.J., Choi, S.E., Park, K.H., Choi, H.K., Lee, M.W.,2008. Anti-oxidative and inhibitory activities on nitric oxide (NO) and prostaglandin E2 (COX-2) production of flavonoids from seeds of Prunus tomentosa Thunberg. Arch Pharm Res 31,424-428.
Klaassen CD. Casarett and Doull's Toxicology-The Basic Science of Poisons. New York:The M cGraw-Hill Inc,2001.
Kumagai, A., Kodama, H., Kumagai, J., Fukuda, J., Kawamura, K., Tanikawa, H., Sato, N., Tanaka, T.,2002. Xanthine oxidase inhibitors suppress testicular germ cell apoptosis induced by experimental cryptorchidism. Mol Hum Reprod 8,118-123.
Kwak, H.I., Bae, M.O., Lee, M.H., Lee, Y.S., Lee, B.J., Kang, K.S., Chae, C.H., Sung, H.J., Shin, J.S., Kim, J.H., Mar, W.C., Sheen, Y.Y., Cho, M.H.,2001. Effects of nonylphenol, bisphenol A, and their mixture on the viviparous swordtail fish(Xiphophorus helleri). Environ Toxicol Chem 20,787-795.
Landvik, N.E., Gorria, M., Arlt, V.M., Asare, N., Solhaug, A., Lagadic-Gossmann, D., Holme, J.A., 2007. Effects of nitrated-polycyclic aromatic hydrocarbons and diesel exhaust particle extracts on cell signalling related to apoptosis:possible implications for their mutagenic and carcinogenic effects. Toxicology 231,159-174.
Latchoumycandane, C., Mathur, P.P.,2002. Induction of oxidative stress in the rat testis after short-term exposure to the organochlorine pesticide methoxychlor. Arch Toxicol 76,692-698.
Lespade, L., Bercion, S.,2010. Theoretical study of the mechanism of inhibition of xanthine oxidase by flavonoids and gallic acid derivatives. J Phys Chem B 114,921-928.
Li, C., Takahashi, S., Taneda, S., Furuta, C., Watanabe, G., Suzuki, A.K., Taya, K.,2006a. Impairment of testicular function in adult male Japanese quail(Coturnix japonica) after a single administration of 3-methyl-4-nitrophenol in diesel exhaust particles. J Endocrinol 189, 555-564.
Li, C., Taneda, S., Suzuki, A.K., Furuta, C., Watanabe, G., Taya, K.,2006b. Anti-androgenic activity of 3-methyl-4-nitrophenol in diesel exhaust particles. Eur J Pharmacol 543,194-199.
Li, N., Wang, M., Oberley, T.D., Sempf, J.M., Nel, A.E.,2002. Comparison of the pro-oxidative and proinflammatory effects of organic diesel exhaust particle chemicals in bronchial epithelial cells and macrophages. J Immunol 169,4531-4541.
Liu, C.M., Zheng, Y.L., Lu, J., Zhang, Z.F., Fan, S.H., Wu, D.M., Ma, J.Q.,2010. Quercetin protects rat liver against lead-induced oxidative stress and apoptosis. Environ Toxicol Phar 29, 158-166.
Liu, Z., Lin, H., Ye, S., Liu, Q.Y., Meng, Z., Zhang, C.M., Xia, Y., Margoliash, E., Rao, Z., Liu, X.J.,2006. Remarkably high activities of testicular cytochrome c in destroying reactive oxygen species and in triggering apoptosis. Proc Natl Acad Sci USA 103,8965-8970.
Ljutakova, S.G.,1984. Effects of detergents on indirect assays for superoxide-dismutase activity. Method Find Exp Clin 6,125-129.
Lysiak, J.J., Zheng, S., Woodson, R., Turner, T.T.,2007. Caspase-9-dependent pathway to murine germ cell apoptosis:mediation by oxidative stress, BAX, and caspase 2. Cell Tissue Res 328, 411-419.
Marchlewicz, M., Wiszniewska, B., Gonet, B., Baranowska-Bosiacka, I., Safranow, K., Kolasa, A., Glabowski, W., Kurzawa, R., Jakubowska, K., Rac, M.E.,2007. Increased lipid peroxidation and ascorbic Acid utilization in testis and epididymis of rats chronically exposed to lead. Biometals20,13-19.
Mazur, A., Bayle, D., Lab, C., Rock, E., Rayssiguier, Y.,1999. Inhibitory effect of procyanidin-rich extracts on LDL oxidation in vitro. Atherosclerosis 145,421-422.
McAnlis, G.T., McEneny, J., Pearce, J., Young, I.S.,1997. The effect of various dietary flavonoids on the susceptibility of low density lipoproteins to oxidation in vitro using both metallic and non-metallic oxidising agents. Biochem Soc Trans 25,142S.
Mi, Y., Zhang, C., Li, C., Taneda, S., Watanabe, G., Suzuki, A.K., Taya, K.,2009. Quercetin protects embryonic chicken spermatogonial cells from oxidative damage intoxicated with 3-methyl-4-nitrophenol in primary culture. Toxicol Lett 190,61-65.
Mi, Y., Zhang, C., Taya, K.,2007. Quercetin protects spermatogonial cells from 2,4-d-induced oxidative damage in embryonic chickens. J Reprod Dev 53,749-754.
Mi, Y.L., Zhang, C.Q.,2005a. Protective effect of quercetin on aroclor 1254-induced oxidative damage in cultured chicken spermatogonial cells. Toxicol Sci 88,545-550.
Mi, Y.L., Zhang, C.Q.,2005b. Toxic and hormonal effects of polychlorinated biphenyls on cultured testicular germ cells of embryonic chickens. Toxicol Lett 155,297-305.
Mitropoulos, D., Deliconstantinos, G., Zervas, A., Villiotou, V., Dimopoulos, C., Stavrides, J., 1996. Nitric oxide synthase and xanthine oxidase activities in the spermatic vein of patients with varicocele:a potential role for nitric oxide and peroxynitrite in sperm dysfunction. J Urol 156,1952-1958.
Mladenka, P., Macakova, K., Filipsky, T., Zatloukalova, L., Jahodar, L., Bovicelli, P., Silvestri, I.P., Hrdina, R., Saso, L.,2011. In vitro analysis of iron chelating activity of flavonoids. J Inorg Biochem 105,693-701.
Monsefi, M., Alaee, S., Moradshahi, A., Rohani, L.,2010. Cadmium-induced infertility in male mice. EnvironToxicol 25,94-102.
Moore, R.W., Rudy, T.A., Lin, T.M., Ko, K., Peterson, R.E.,2001. Abnormalities of sexual development in male rats with in utero and lactational exposure to the antiandrogenic plasticizer Di(2-ethylhexyl) phthalate. Environ Health Perspect 109,229-237.
Morales, A.I., Vicente-Sanchez, C., Sandoval, J.M.S., Egido, J., Mayoral, P., Arevalo, M.A., Fernandez-Tagarro, M., Lopez-Novoa, J.M., Perez-Barriocanal, F.,2006. Protective effect of quercetin on experimental chronic cadmium nephrotoxicity in rats is based on its antioxidant properties. Food Chem Toxicol 44,2092-2100.
Morel, I., Lescoat, G., Cogrel, P., Sergent, O., Pasdeloup, N., Brissot, P., Cillard, P., Cillard, J., 1993. Antioxidant and iron-chelating activities of the flavonoids catechin, quercetin and diosmetin on iron-loaded rat hepatocyte cultures. Biochem Pharmacol 45,13-19.
Mori, Y., Kamata, K., Toda, N., Hayashi, H., Seki, K., Taneda, S., Yoshino, S., Sakushima, A., Sakata, M., Suzuki, A.K.,2003. Isolation of nitrophenols from diesel exhaust particles (DEP) as vasodilatation compounds. Biol Pharm Bull 26,394-395.
Mruk, D.D., Silvestrini, B., Mo, M.Y., Cheng, C.Y.,2002. Antioxidant superoxide dismutase-a review:its function, regulation in the testis, and role in male fertility. Contraception 65, 305-311.
Nair, N., Bedwal, S., Prasad, S., Saini, M.R., Bedwal, R.S.,2005. Short-term zinc deficiency in diet induces increased oxidative stress in testes and epididymis of rats. Indian J Exp Biol 43, 786-794.
Nesatyy, V.J., Ammann, A.A., Rutishauser, B.V., Suter, M.J.,2006. Effect of cadmium on the interaction of 17beta-estradiol with the rainbow trout estrogen receptor. Environ Sci Technol 40,1358-1363.
Oikawa, T., Shimamura, M., Ashino, H., Nakamura, O., Kanayasu, T., Morita, I., Murota, S.,1992. Inhibition of angiogenesis by staurosporine, a potent protein kinase inhibitor. J Antibiot (Tokyo) 45,1155-1160.
Ola-Mudathir, K.F., Suru, S.M., Fafunso, M.A., Obioha, U.E., Faremi, T.Y.,2008. Protective roles of onion and garlic extracts on cadmium-induced changes in sperm characteristics and testicular oxidative damage in rats. Food Chem Toxicol 46,3604-3611.
Ozcelik, B., Kartal, M., Orhan, I.,2011. Cytotoxicity, antiviral and antimicrobial activities of alkaloids, flavonoids, and phenolic acids. Pharm Biol 49,396-402.
Ozyurt, H., Pekmez, H., Parlaktas, B.S., Kus, I., Ozyurt, B., Sarsilmaz, M.,2006. Oxidative stress in testicular tissues of rats exposed to cigarette smoke and protective effects of caffeic acid phenethyl ester. Asian J Androl 8,189-193.
Park, S., Nam, H., Chung, N., Park, J.D., Lim, Y.,2006. The role of iron in reactive oxygen species generation from diesel exhaust particles. Toxicol In Vitro 20,851-857.
Paulsen, C.A., Berman, N.G., Wang, C.,1996. Data from men in greater Seattle area reveals no downward trend in semen quality:further evidence that deterioration of semen quality is not geographically uniform. Fertil Steril 65,1015-1020.
Peltola, V., Huhtaniemi, I., Ahotupa, M.,1992. Antioxidant enzyme activity in the maturing rat testis. J Androl 13,450-455.
Peltola, V., Mantyla, E., Huhtaniemi, I., Ahotupa, M.,1994. Lipid peroxidation and antioxidant enzyme activities in the rat testis after cigarette smoke inhalation or administration of polychlorinated biphenyls or polychlorinated naphthalenes. J Androl 15,353-361.
Pflieger-Bruss, S., Hanf, V., Behnisch, P., Hagenmaier, H., Rune, G.M.,1999. Effects of single polychlorinated biphenyls on the morphology of cultured rat tubuli seminiferi. Andrologia 31, 77-82.
Rao, M., Narayana, K., Benjamin, S., Bairy, K.L.,2005. L-ascorbic acid ameliorates postnatal endosulfan induced testicular damage in rats. Indian J Physiol Pharmacol 49,331-336.
Raychoudhury, S.S., Blake, C.A., Millette, C.F.,1999. Toxic effects of octylphenol on cultured rat spermatogenic cells and Sertoli cells. Toxicol Appl Pharmacol 157,192-202.
Renugadevi, J., Milton Prabu, S.,2009. Quercetin protects against oxidative stress-related renal dysfunction by cadmium in rats. Exp Toxicol Pathol.
Rice-Evans CA, M.N., Paganga G,1996. Structure-antioxidant activity relationships of flavonoids and phenolic acids. Free Radic Biol Med 20,933-956.
Romao PR, T.J., Fonseca SG, Morales RH, Cruz AK, Hothersall JS, et al.,2006. Glutathione and the redox control system trypanothione/trypanothione reductase are involved in the protection of Leishmania spp. against nitrosothiol-induced cytotoxicity. Braz J Med Biol Res 39, 355-363.
Ross, J.A., Kasum, C.M.,2002. Dietary flavonoids:bioavailability, metabolic effects, and safety. Annu Rev Nutr 22,19-34.
Sagai, M., Saito, H., Ichinose, T., Kodama, M., Mori, Y.,1993. Biological effects of diesel exhaust particles. I. In vitro production of superoxide and in vivo toxicity in mouse. Free Radic Biol Med 14.37-47.
Santos, F.W., Oro, T., Zeni, G., Rocha, J.B., do Nascimento, P.C., Nogueira, C.W.,2004. Cadmium induced testicular damage and its response to administration of succimer and diphenyl diselenide in mice. Toxicol Lett 152,255-263.
Sastre, J., Pallardo, F.V., Vina, J.,2000. Mitochondrial oxidative stress plays a key role in aging and apoptosis. IUBMB Life 49,427-435.
Semercioz, A., Onur, R., Ogras, S., Orhan, I.,2003. Effects of melatonin on testicular tissue nitric oxide level and antioxidant enzyme activities in experimentally induced left varicocele. Neuro Endocrinol Lett 24,86-90.
Sen Gupta, R., Sen Gupta, E., Dhakal, B.K., Thakur, A.R., Ahnn, J.,2004a. Vitamin C and vitamin E protect the rat testes from cadmium-induced reactive oxygen species. Mol Cell 17,132-139.
Sen Gupta, R., Sen Gupta, E., Dhakal, B.K., Thakur, A.R., Ahnn, J.,2004b. Vitamin C and vitamin E protect the rat testes from cadmium-induced reactive oxygen species. Mol Cells 17, 132-139.
Senthil kumar, J., Banudevi, S., Sharmila, M., Murugesan, P., Srinivasan, N., Balasubramanian, K., Aruldhas, M.M., Arunakaran, J.,2004. Effects of Vitamin C and E on PCB (Aroclor 1254) induced oxidative stress, androgen binding protein and lactate in rat Sertoli cells. Reprod Toxicol 19,201-208.
Shrestha, S.P., Amano, Y., Narukawa, Y., Takeda, T.,2008. Nitric oxide production inhibitory activity of flavonoids contained in trunk exudates of Dalbergia sissoo. J Nat Prod 71,98-101.
Smith, R., Kaune, H., Parodi, D., Madariaga, M., Morales, I., Rios, R., Castro, A.,2007. Extent of sperm DNA damage in spermatozoa from men examined for infertility. Relationship with oxidative stress. Rev Med Chil 135,279-286.
Smith, R., Kaune, H., Parodi, D., Madariaga, M., Rios, R., Morales, I., Castro, A.,2006. Increased sperm DNA damage in patients with varicocele:relationship with seminal oxidative stress. Hum Reprod 21,986-993.
Soczynska-Kordala, M., Bakowska, A., Oszmianski, J., Gabrielska, J.,2001. Metal ion-flavonoid associations in bilayer phospholipid membranes. Cell Mol Biol Lett 6,277-281.
Stefani, E.D., Boffetta, P., Deneo-Pellegrini, H., Mendilaharsu, M., Carzoglio, J.C., Ronco, A., Olivera, L.,1999. Dietary antioxidants and lung cancer risk:a case-control study in Uruguay. Nutr Cancer 34,100-110.
Stohs SJ, B.D., Hassoun E, Bagchi M.,2000. Oxidative mechanisms in the toxicity of chromium and cadmium ions. J Environ Pathol Toxicol Oncol 19,201-213.
Swan, S.H., Elkin, E.P., Fenster, L.,1997. Have sperm densities declined? A reanalysis of global trend data. Environ Health Perspect 105,1228-1232.
Takahashi, O., Oishi, S.,2003. Testicular toxicity of dietarily or parenterally administered bisphenol A in rats and mice. Food Chem Toxicol 41,1035-1044.
Taneli, F., Vatansever, S., Ulman, C., Yilmaz, O., Giray, G., Gene, A., Taneli, C.,2005. The effect of spermatic vessel ligation on testicular nitric oxide levels and germ cell-specific apoptosis in rat testis. Acta Histochem 106,459-466.
Tegelenbosch, R.A., de Rooij, D.G.,1993. A quantitative study of spermatogonial multiplication and stem cell renewal in the C3H/101 F1 hybrid mouse. Mutat Res 290,193-200.
Terao, J., Piskula, M.K.,1999. Flavonoids and membrane lipid peroxidation inhibition. Nutrition 15,790-791.
Vaisberg, C.N., Jelezarsky, L.V., Dishlianova, B., Chaushev, T.A.,2005. Activity, substrate detection and immunolocalization of glutathione peroxidase (GPx) in bovine reproductive organs and semen. Theriogenology 64,416-428.
Verma, R.J., Nair, A.,2001. Ameliorative effect of vitamin E on aflatoxin-induced lipid peroxidation in the testis of mice. Asian J Androl 3,217-221.
Watanabe, M., Henmi, K., Ogawa, K., Suzuki, T.,2003. Cadmium-dependent generation of reactive oxygen species and mitochondrial DNA breaks in photosynthetic and non-photosynthetic strains of Euglena gracilis. Comp Biochem Phys C 134,227-234.
Watanabe, N., Oonuki, Y.,1999. Inhalation of diesel engine exhaust affects spermatogenesis in growing male rats. Environ Health Perspect 107,539-544.
Wright, J.A., Hermonat, M.W., Hards, R.G.,1982. A degradation product of fenitrothion, 3-methyl-4-nitrophenol, is an inhibitor of mammalian ribonucleotide reductase. Bull Environ Contam Toxicol 28,480-483.
Yochum, L., Kushi, L.H., Meyer, K., Folsom, A.R.,1999. Dietary flavonoid intake and risk of cardiovascular disease in postmenopausal women. Am J Epidemiol 149,943-949.
Yoganathan, T., Eskild, W., Hansson, V,1989. Investigation of detoxification capacity of rat testicular germ cells and Sertoli cells. Free Radic Biol Med 7,355-359.
Yoshida, S., Sagai, M., Oshio, S., Umeda, T., Ihara, T., Sugamata, M., Sugawara, I., Takeda, K., 1999. Exposure to diesel exhaust affects the male reproductive system of mice. Int J Androl 22,307-315.
Yu, X., Filardo, E.J., Shaikh, Z.A.,2010. The membrane estrogen receptor GPR30 mediates cadmium-induced proliferation of breast cancer cells. Toxicol Appl Pharmacol 245,83-90.
Yu, X., Hong, S., Faustman, E.M.,2008. Cadmium-induced activation of stress signaling pathways, disruption of ubiquitin-dependent protein degradation and apoptosis in primary rat Sertoli cell-gonocyte cocultures. Toxicol Sci 104,385-396.
Zhang, C., Fang, C., Liu, L., Xia, G., Qiao, H.,2002. Disrupting effects of polychlorinated biphenyls on gonadal development and reproductive functions in chickens. J Environ Sci Health A 37,509-519.
Zhang, C.Q., Qiao, H.L.,2004. Effect of polychlorinated biphenyls on spermatogenesis and testosterone secretion in adult cocks. J Zhejiang Univ Sci 5,193-197.
白凤梅,蔡同一.类黄酮生物活性及其机理的研究进展.食品科学1999,(8)：11-13.
卞建春,镉对雄性动物生殖毒理学的研究东北农业大学[D]2003
刁书永,袁慧镉对小鼠卵巢颗粒细胞凋亡的影响研究.畜牧兽医学报2005,11：1155-1158.
费前进,黄学锋,李澄棣.大鼠睾丸精子发生过程中抗氧化酶活性水平的变化浙江临床医学2005,7(3)：229-230.
封传悦,朱俊东.大豆异黄酮摄入与乳腺癌发生风险的Meta分析.中华乳腺病杂志2010,03：43-46.
孔志明,张国栋,孙立伟.环境内分泌干扰物诱发小鼠睾丸细胞DNA损伤的研究.环境污染与防治2002,24：76-78.
李卫华.环境内分泌干扰物毒理研究的现状及展望.卫生毒理学2000,14：13-15.
李维信,寥晓岗,唐宜,包大干.镉对大鼠睾丸的损伤及锌保护作用的超微结构研究.解剖学报1998,19：74-78
凌关庭.抗氧化食品与健康[M]北京：化学工业出版社,2004.4
徐国刚,蒋学之.镉的雄(男)性生殖毒性.中国公共卫生学报1996,15：17-18.
俞鸣,贾真琳,王宝亭,史玉荣,郝继辉NF-κB与Caspase-9在大豆异黄酮诱导人乳腺癌细胞凋亡中的作用.中国慢性病预防与控制2010,03：270-272.
杨建明,陈琼宇,曾样斌,许江琳,逢兵,周袁芬,金泰,蒋学之.镉对雄性生育功能的影响.中国公共卫生2000,16(4)：313-314.
张大雷,杨蓓,吴磊,邹挺.人参皂苷保护小鼠精原细胞氧化损伤的研究.中国药理学通报2010,26(8)：1014-1016.
张明,袁慧镉对小鼠生精细胞凋亡及bax和bcl-2基因表达的影响中国兽医科学2007,37(03)：251-254.
张树成,王弘毅,王介东.1981-1996年我国有生育力男性精液质量的变化分析.生殖与避孕1991,19(1)：27-33.
Adams, J.M., Cory, S.,1998. The Bcl-2 protein family:Arbiters of cell survival. Science 281, 1322-1326.
Afanas'ev, I.B., Ostrachovitch, E.A., Abramova, N.E., Korkina, L.G.,1995. Different antioxidant activities of bioflavonoid rutin in normal and iron-overloading rats. Biochem Pharmacol 50, 627-635.
Agarwal, A., Prabakaran, S., Allamaneni, S.S.,2006. Relationship between oxidative stress, varicocele and infertility:a meta-analysis. Reprod Biomed Online 12,630-633.
Agostinho, P., Duarte, C.B., Oliveira, C.R.,1997. Impairment of excitatory amino acid transporter activity by oxidative stress conditions in retinal cells:effect of antioxidants. Faseb J 11, 154-163.
Akinloye, O., Arowojolu, A.O., Shittu, O.B., Anetor, J.I.,2006. Cadmium toxicity:a possible cause of male infertility in Nigeria. Reprod Biol 6,17-30.
Alia, M., Mateos, R., Ramos, S., Lecumberri, E., Bravo, L., Goya, L.,2006. Influence of quercetin and rutin on growth and antioxidant defense system of a human hepatoma cell line (HepG2). Eur J Nutr 45,19-28.
Amara, S., Abdelmelek, H., Garrel, C., Guiraud, P., Douki, T., Ravanat, J.L., Favier, A., Sakly, M., Ben Rhouma, K.,2008. Preventive effect of zinc against cadmium-induced oxidative stress in the rat testis. J Reprod Develop 54,129-134.
Arai, Y., Watanabe, S., Kimira, M., Shimoi, K., Mochizuki, R., Kinae, N.,2000. Dietary intakes of flavonols, flavones and isoflavones by Japanese women and the inverse correlation between quercetin intake and plasma LDL cholesterol concentration. J Nutr 130,2243-2250.
Arts, I.C., Hollman, P.C.,2005. Polyphenols and disease risk in epidemiologic studies. Am J Clin Nutr 81,317S-325S.
Arts, I.C., Hollman, P.C., Feskens, E.J., Bueno de Mesquita, H.B., Kromhout, D.,2001. Catechin intake might explain the inverse relation between tea consumption and ischemic heart disease: the Zutphen Elderly Study. Am J Clin Nutr 74,227-232.
Aruldhas, M.M., Subramanian, S., Sekar, P., Vengatesh, G., Chandrahasan, G., Govindarajulu, P., Akbarsha, M.A.,2005. Chronic chromium exposure-induced changes in testicular histoarchitecture are associated with oxidative stress:study in a non-human primate(Macaca radiata Geoffroy). Hum Reprod 20,2801-2813.
Atanassova, N., McKinnell, C., Walker, M., Turner, K.J., Fisher, J.S., Morley, M., Millar, M.R., Groome, N.P., Sharpe, R.M.,1999. Permanent effects of neonatal estrogen exposure in rats on reproductive hormone levels, Sertoli cell number, and the efficiency of spermatogenesis in adulthood. Endocrinology 140,5364-5373.
Atik, E., Gorur, S., Kiper, A.N.,2006. The effect of caffeic acid phenethyl ester (CAPE) on histopathological changes in testicular ischemia-reperfusion injury. Pharmacol Res 54, 293-297.
Auger, J., Kunstmann, J.M., Czyglik, F., Jouannet, P.,1995. Decline in semen quality among fertile men in Paris during the past 20 years. N Engl J Med 332,281-285.
Baek, I.J., Seo, D.S., Yon, J.M., Lee, S.R., Jin, Y., Nahm, S.S., Jeong, J.H., Choo, Y.K., Kang, J.K., Lee, B.J., Yun, Y.W., Nam, S.Y.,2007. Tissue expression and cellular localization of phospholipid hydroperoxide glutathione peroxidase (PHGPx) mRNA in male mice. J Mol Histol 38,237-244.
Banfi, B., Molnar, G., Maturana, A., Steger, K., Hegedus, B., Demaurex, N., Krause, K.H.,2001. A Ca(2+)-activated NADPH oxidase in testis, spleen, and lymph nodes. J Biol Chem 276, 37594-37601.
Baulig, A., Garlatti, M., Bonvallot, V., Marchand, A., Barouki, R., Marano, F., Baeza-Squiban, A., 2003. Involvement of reactive oxygen species in the metabolic pathways triggered by diesel exhaust particles in human airway epithelial cells. Am J Physiol Lung Cell Mol Physiol 285, L671-679.
Bellve, A.R., Cavicchia, J.C., Millette, C.F., O'Brien, D.A., Bhatnagar, Y.M., Dym, M.,1977. Spermatogenic cells of the prepuberal mouse. Isolation and morphological characterization. J Cell Biol 74,68-85.
Benoff, S., Jacob, A., Hurley, I.R.,2000. Male infertility and environmental exposure to lead and cadmium. Hum Reprod Update 6,107-121.
Bu, T., Mi, Y., Zeng, W., Zhang, C.,2010. Protective Effect of quercetin on cadmium-induced oxidative toxicity on germ cells in male mice. Anat Rec (Hoboken).
Bujan, L., Mansat, A., Pontonnier, F., Mieusset, R.,1996. Time series analysis of sperm concentration in fertile men in Toulouse, France between 1977 and 1992. BMJ 312,471-472.
Caltagirone, S., Rossi, C., Poggi, A., Ranelletti, F.O., Natali, P.G., Brunetti, M., Aiello, F.B., Piantelli, M.,2000. Flavonoids apigenin and quercetin inhibit melanoma growth and metastatic potential. Int J Cancer 87,595-600.
Carlsen, E., Giwercman, A., Keiding, N., Skakkebaek, N.E.,1992. Evidence for decreasing quality of semen during past 50 years. BMJ 305,609-613.
Celino, F.T., Yamaguchi, S., Miura, C., Ohta, T., Tozawa, Y., Iwai, T., Miura, T.,2011. Tolerance of spermatogonia to oxidative stress is due to high levels of Zn and Cu/Zn superoxide dismutase. PLoS One 6, e16938.
Chaki, S.P., Ghosh, D., Misro, M.M.,2003. Simultaneous increase in germ cell apoptosis and oxidative stress under acute unilateral testicular ischaemia in rats. Int J Androl 26,319-328.
Chao, C.L., Hou, Y.C., Chao, P.D.L., Weng, C.S., Ho, F.M.,2009. The antioxidant effects of quercetin metabolites on the prevention of high glucose-induced apoptosis of human umbilical vein endothelial cells. Brit J Nutr 101,1165-1170.
Cheng, I.F., Breen, K.,2000. On the ability of four flavonoids, baicilein, luteolin, naringenin, and quercetin, to suppress the Fenton reaction of the iron-ATP complex. Biometals 13,77-83.
Chiquoine, A.D.,1964. Observations on the early events of cadmium necrosis of the testis. Anat Rec 149,23-35
Choe, S.Y., Kim, S.J., Kim, H.G., Lee, J.H., Choi, Y., Lee, H., Kim, Y.,2003. Evaluation of estrogenicity of major heavy metals. Sci Total Environ 312,15-21.
Chung, N.P., Cheng, C.Y.,2001. Is cadmium chloride-induced inter-sertoli tight junction permeability barrier disruption a suitable in vitro model to study the events of junction disassembly during spermatogenesis in the rat testis? Endocrinology 142,1878-1888.
Damstra T, Barlow S, Bergman A, et al. Global assessment of the state of the science of endocrine disruptors [R].2002, WHO IPCS,25-26.
Danzo, B.J.,1997. Environmental xenobiotics may disrupt normal endocrine function by interfering with the binding of physiological ligands to steroid receptors and binding proteins. Environ Health Perspect 105,294-301.
de Groot, H.,1994. Reactive oxygen species in tissue injury. Hepatogastroenterology 41,328-332.
Denier, X., Hill, E.M., Rotchell, J., Minier, C.,2009. Estrogenic activity of cadmium, copper and zinc in the yeast estrogen screen. Toxicol In Vitro 23,569-573.
Donaldson, K., Stone, V., Borm, P.J., Jimenez, L.A., Gilmour, P.S., Schins, R.P., Knaapen, A.M., Rahman, I., Faux, S.P., Brown, D.M., MacNee, W.,2003. Oxidative stress and calcium signaling in the adverse effects of environmental particles (PM10). Free Radic Biol Med 34, 1369-1382.
Dudley, R.E., Gammal, L.M., Klaassen, C.D.,1985. Cadmium-induced hepatic and renal injury in chronically exposed rats-likely role of hepatic cadmium-metallothionein in nephrotoxicity. Toxicol Appl Pharm 77,414-426.
Duthie, G., Crozier, A.,2000. Plant-derived phenolic antioxidants. Curr Opin Lipidol 11,43-47.
Evers, D.L., Chao, C.F., Wang, X., Zhang, Z., Huong, S.M., Huang, E.S.,2005. Human cytomegalovirus-inhibitory flavonoids:studies on antiviral activity and mechanism of action. Antiviral Res 68,124-134.
Facino, R.M., Carini, M., Aldini, G., Berti, F., Rossoni, G., Bombardelli, E., Morazzoni, P.,1999. Diet enriched with procyanidins enhances antioxidant activity and reduces myocardial post-ischaemic damage in rats. Life Sci 64,627-642.
Fan, T.P., Jaggar, R., Bicknell, R.,1995. Controlling the vasculature:angiogenesis, anti-angiogenesis and vascular targeting of gene therapy. Trends Pharmacol Sci 16,57-66.
Fiander, H., Schneider, H.,2000. Dietary ortho phenols that induce glutathione S-transferase and increase the resistance of cells to hydrogen peroxide are potential cancer chemopreventives that act by two mechanisms:the alleviation of oxidative stress and the detoxification of mutagenic xenobiotics. Cancer Lett 156,117-124.
Fiorani, M., De Sanctis, R., Menghinello, P., Cucchiarini, L., Cellini, B., Dacha, M.,2001. Quercetin prevents glutathione depletion induced by dehydroascorbic acid in rabbit red blood cells. Free Radic Res 34,639-648.
Fisch, H., Goluboff, E.T., Olson, J.H., Feldshuh, J., Broder, S.J., Barad, D.H.,1996. Semen analyses in 1,283 men from the United States over a 25-year period:no decline in quality. Fertil Steril 65,1009-1014.
Fort, D.J., Stover, E.L., Bantle, J.A., Dumont, J.N., Finch, R.A.,2001. Evaluation of a reproductive toxicity assay using Xenopus laevis:boric acid, cadmium and ethylene glycol monomethyl ether. J Appl Toxicol 21,41-52.
Fouad, A.A., Qureshi, H.A., Al-Sultan, A.I., Yacoubi, M.T., Ali, A.A.,2009. Protective effect of hemin against cadmium-induced testicular damage in rats. Toxicology 257,153-160.
Fraga, C.G., Motchnik, P.A., Wyrobek, A.J., Rempel, D.M., Ames, B.N.,1996. Smoking and low antioxidant levels increase oxidative damage to sperm DNA. Mutat Res 351,199-203.
Friedmann, A.S.,2002. Atrazine inhibition of testosterone production in rat males following peripubertal exposure. Reprod Toxicol 16,275-279.
Furuta, C., Li, C., Taneda, S., Suzuki, A.K., Kamata, K., Watanabe, G., Taya, K.,2005. Immunohistological study for estrogenic activities of nitrophenols in diesel exhaust particles. Endocrine 27,33-36.
Furuta, C., Suzuki, A.K., Taneda, S., Kamata, K., Hayashi, H., Mori, Y., Li, C., Watanabe, G., Taya, K.,2004. Estrogenic activities of nitrophenols in diesel exhaust particles. Biol Reprod 70, 1527-1533.
Galan, A., Garcia-Bermejo, L., Troyano, A., Vilaboa, N.E., Fernandez, C., de Blas, E., Aller, P., 2001. The role of intracellular oxidation in death induction (apoptosis and necrosis) in human promonocytic cells treated with stress inducers (cadmium, heat, X-rays). Eur J Cell Biol 80, 312-320.
Galey, J.B.,1997. Potential use of iron chelators against oxidative damage. Adv Pharmacol 38, 167-203.
Garcia-Morales, P., Saceda, M., Kenney, N., Kim, N., Salomon, D.S., Gottardis, M.M., Solomon, H.B., Sholler, P.F., Jordan, V.C., Martin, M.B.,1994. Effect of cadmium on estrogen receptor levels and estrogen-induced responses in human breast cancer cells. J Biol Chem 269, 16896-16901.
Gustafsson, A.B., Gottlieb, R.A.,2007. Bcl-2 family members and apoptosis, taken to heart. Am J Physiol-Cell Physiol 292, C45-C51.
Han, J.Y., Takeshita, K., Utsumi, H.,2001. Noninvasive detection of hydroxyl radical generation in lung by diesel exhaust particles. Free Radic Biol Med 30,516-525.
Hendin, B.N., Kolettis, P.N., Sharma, R.K., Thomas, A.J., Jr., Agarwal, A.,1999. Varicocele is associated with elevated spermatozoal reactive oxygen species production and diminished seminal plasma antioxidant capacity. J Urol 161,1831-1834.
Hengartner, M.O.,2000. The biochemistry of apoptosis. Nature 407,770-776.
Hertog, M.G., Feskens, E.J., Hollman, P.C., Katan, M.B., Kromhout, D.,1993. Dietary antioxidant flavonoids and risk of coronary heart disease:the Zutphen Elderly Study. Lancet 342, 1007-1011.
Hertog, M.G., Kromhout, D., Aravanis, C., Blackburn, H., Buzina, R., Fidanza, F., Giampaoli, S., Jansen, A., Menotti, A., Nedeljkovic, S., et al.,1995. Flavonoid intake and long-term risk of coronary heart disease and cancer in the seven countries study. Arch Intern Med 155,381-386.
Hew, K.W., Ericson, W.A., Welsh, M.J.,1993. A single low cadmium dose causes failure of spermiation in the rat. Toxicol Appl Pharmacol 121,15-21.
Hiura, T.S., Kaszubowski, M.P., Li, N., Nel, A.E.,1999. Chemicals in diesel exhaust particles generate reactive oxygen radicals and induce apoptosis in macrophages. J Immunol 163, 5582-5591.
Hsu, P.C., Li, M.H., Guo, Y.L.,2003. Postnatal exposure of 2,2',3,3',4,6'-hexachlorobiphenyl and 2,2',3,4',5',6-hexachlorobiphenyl on sperm function and hormone levels in adult rats. Toxicology 187,117-126.
Huang, C.H., Lin, L.Y., Tsai, M.S., Hsu, C.Y., Chen, H.W., Wang, T.D., Chang, W.T., Cheng, T.J., Chen, W.J.,2010. Acute cardiac dysfunction after short-term diesel exhaust particles exposure. Toxicol Lett 192,349-355.
Hughes, P.J., McLellan, H., Lowes, D.A., Kahn, S.Z., Bilmen, J.G., Tovey, S.C., Godfrey, R.E., Michell, R.H., Kirk, C.J., Michelangeli, F.,2000. Estrogenic alkylphenols induce cell death by inhibiting testis endoplasmic reticulum Ca(2+) pumps. Biochem Biophys Res Commun 277, 568-574.
Ikeda, M., Kodama, H., Fukuda, J., Shimizu, Y., Murata, M., Kumagai, J., Tanaka, T.,1999. Role of radical oxygen species in rat testicular germ cell apoptosis induced by heat stress. Biol Reprod 61,393-399.
Inal, M.E., Kahraman, A.,2000. The protective effect of flavonol quercetin against ultraviolet a induced oxidative stress in rats. Toxicology 154,21-29.
Ishii, T., Matsuki, S., Iuchi, Y., Okada, F., Toyosaki, S., Tomita, Y., Ikeda, Y., Fujii, J.,2005. Accelerated impairment of spermatogenic cells in SOD 1-knockout mice under heat stress. Free Radic Res 39,697-705.
Ishikawa, T., Fujioka, H., Ishimura, T., Takenaka, A., Fujisawa, M.,2007. Increased testicular 8-hydroxy-2'-deoxyguanosine in patients with varicocele. BJU Int 100,863-866.
Izawa, H., Kohara, M., Aizawa, K., Suganuma, H., Inakuma, T., Watanabe, G., Taya, K., Sagai, M., 2008. Alleviative effects of quercetin and onion on male reproductive toxicity induced by diesel exhaust particles. Biosci Biotechnol Biochem 72,1235-1241.
Kanaly, R.A., Kim, I.S., Hur, H.G.,2005. Biotransformation of 3-methyl-4-nitrophenol, a main product of the insecticide fenitrothion, by Aspergillus niger. J Agric Food Chem 53, 6426-6431.
Kaur, P., Bansal, M.P.,2004. Influence of selenium induced oxidative stress on spermatogenesis and lactate dehydrogenase-X in mice testis. Asian J Androl 6,227-232.
Kaur, P., Kaur, G., Bansal, M.P.,2006. Tertiary-butyl hydroperoxide induced oxidative stress and male reproductive activity in mice:role of transcription factor NF-kappaB and testicular antioxidant enzymes. Reprod Toxicol 22,479-484.
Khan, I.A., Mathews, S., Okuzawa, K., Kagawa, H., Thomas, P.,2001. Alterations in the GnRH-LH system in relation to gonadal stage and Aroclor 1254 exposure in Atlantic croaker. Comp Biochem Physiol B Biochem Mol Biol 129,251-259.
Khurana, S., Ranmal, S., Ben-Jonathan, N.,2000. Exposure of newborn male and female rats to environmental estrogens:delayed and sustained hyperprolactinemia and alterations in estrogen receptor expression. Endocrinology 141,4512-4517.
Kim, B.M., Choi, Y.J., Han, Y., Yun, Y.S., Hong, S.H.,2009. N,N-dimethyl phytosphingosine induces caspase-8-dependent cytochrome c release and apoptosis through ROS generation in human leukemia cells. Toxicol Appl Pharm 239,87-97.
Kim, S.K., Kim, H.J., Choi, S.E., Park, K.H., Choi, H.K., Lee, M.W.,2008. Anti-oxidative and inhibitory activities on nitric oxide (NO) and prostaglandin E2 (COX-2) production of flavonoids from seeds of Prunus tomentosa Thunberg. Arch Pharm Res 31,424-428.
Klaassen CD. Casarett and Doull's Toxicology-The Basic Science of Poisons. New York:The M cGraw-Hill Inc,2001.
Kumagai, A., Kodama, H., Kumagai, J., Fukuda, J., Kawamura, K., Tanikawa, H., Sato, N., Tanaka, T.,2002. Xanthine oxidase inhibitors suppress testicular germ cell apoptosis induced by experimental cryptorchidism. Mol Hum Reprod 8,118-123.
Kwak, H.I., Bae, M.O., Lee, M.H., Lee, Y.S., Lee, B.J., Kang, K.S., Chae, C.H., Sung, H.J., Shin, J.S., Kim, J.H., Mar, W.C., Sheen, Y.Y., Cho, M.H.,2001. Effects of nonylphenol, bisphenol A, and their mixture on the viviparous swordtail fish(Xiphophorus helleri). Environ Toxicol Chem 20,787-795.
Landvik, N.E., Gorria, M., Arlt, V.M., Asare, N., Solhaug, A., Lagadic-Gossmann, D., Holme, J.A., 2007. Effects of nitrated-polycyclic aromatic hydrocarbons and diesel exhaust particle extracts on cell signalling related to apoptosis:possible implications for their mutagenic and carcinogenic effects. Toxicology 231,159-174.
Latchoumycandane, C., Mathur, P.P.,2002. Induction of oxidative stress in the rat testis after short-term exposure to the organochlorine pesticide methoxychlor. Arch Toxicol 76,692-698.
Lespade, L., Bercion, S.,2010. Theoretical study of the mechanism of inhibition of xanthine oxidase by flavonoids and gallic acid derivatives. J Phys Chem B 114,921-928.
Li, C., Takahashi, S., Taneda, S., Furuta, C., Watanabe, G., Suzuki, A.K., Taya, K.,2006a. Impairment of testicular function in adult male Japanese quail(Coturnix japonica) after a single administration of 3-methyl-4-nitrophenol in diesel exhaust particles. J Endocrinol 189, 555-564.
Li, C., Taneda, S., Suzuki, A.K., Furuta, C., Watanabe, G., Taya, K.,2006b. Anti-androgenic activity of 3-methyl-4-nitrophenol in diesel exhaust particles. Eur J Pharmacol 543,194-199.
Li, N., Wang, M., Oberley, T.D., Sempf, J.M., Nel, A.E.,2002. Comparison of the pro-oxidative and proinflammatory effects of organic diesel exhaust particle chemicals in bronchial epithelial cells and macrophages. J Immunol 169,4531-4541.
Liu, C.M., Zheng, Y.L., Lu, J., Zhang, Z.F., Fan, S.H., Wu, D.M., Ma, J.Q.,2010. Quercetin protects rat liver against lead-induced oxidative stress and apoptosis. Environ Toxicol Phar 29, 158-166.
Liu, Z., Lin, H., Ye, S., Liu, Q.Y., Meng, Z., Zhang, C.M., Xia, Y., Margoliash, E., Rao, Z., Liu, X.J.,2006. Remarkably high activities of testicular cytochrome c in destroying reactive oxygen species and in triggering apoptosis. Proc Natl Acad Sci USA 103,8965-8970.
Ljutakova, S.G.,1984. Effects of detergents on indirect assays for superoxide-dismutase activity. Method Find Exp Clin 6,125-129.
Lysiak, J.J., Zheng, S., Woodson, R., Turner, T.T.,2007. Caspase-9-dependent pathway to murine germ cell apoptosis:mediation by oxidative stress, BAX, and caspase 2. Cell Tissue Res 328, 411-419.
Marchlewicz, M., Wiszniewska, B., Gonet, B., Baranowska-Bosiacka, I., Safranow, K., Kolasa, A., Glabowski, W., Kurzawa, R., Jakubowska, K., Rac, M.E.,2007. Increased lipid peroxidation and ascorbic Acid utilization in testis and epididymis of rats chronically exposed to lead. Biometals20,13-19.
Mazur, A., Bayle, D., Lab, C., Rock, E., Rayssiguier, Y.,1999. Inhibitory effect of procyanidin-rich extracts on LDL oxidation in vitro. Atherosclerosis 145,421-422.
McAnlis, G.T., McEneny, J., Pearce, J., Young, I.S.,1997. The effect of various dietary flavonoids on the susceptibility of low density lipoproteins to oxidation in vitro using both metallic and non-metallic oxidising agents. Biochem Soc Trans 25,142S.
Mi, Y., Zhang, C., Li, C., Taneda, S., Watanabe, G., Suzuki, A.K., Taya, K.,2009. Quercetin protects embryonic chicken spermatogonial cells from oxidative damage intoxicated with 3-methyl-4-nitrophenol in primary culture. Toxicol Lett 190,61-65.
Mi, Y., Zhang, C., Taya, K.,2007. Quercetin protects spermatogonial cells from 2,4-d-induced oxidative damage in embryonic chickens. J Reprod Dev 53,749-754.
Mi, Y.L., Zhang, C.Q.,2005a. Protective effect of quercetin on aroclor 1254-induced oxidative damage in cultured chicken spermatogonial cells. Toxicol Sci 88,545-550.
Mi, Y.L., Zhang, C.Q.,2005b. Toxic and hormonal effects of polychlorinated biphenyls on cultured testicular germ cells of embryonic chickens. Toxicol Lett 155,297-305.
Mitropoulos, D., Deliconstantinos, G., Zervas, A., Villiotou, V., Dimopoulos, C., Stavrides, J., 1996. Nitric oxide synthase and xanthine oxidase activities in the spermatic vein of patients with varicocele:a potential role for nitric oxide and peroxynitrite in sperm dysfunction. J Urol 156,1952-1958.
Mladenka, P., Macakova, K., Filipsky, T., Zatloukalova, L., Jahodar, L., Bovicelli, P., Silvestri, I.P., Hrdina, R., Saso, L.,2011. In vitro analysis of iron chelating activity of flavonoids. J Inorg Biochem 105,693-701.
Monsefi, M., Alaee, S., Moradshahi, A., Rohani, L.,2010. Cadmium-induced infertility in male mice. EnvironToxicol 25,94-102.
Moore, R.W., Rudy, T.A., Lin, T.M., Ko, K., Peterson, R.E.,2001. Abnormalities of sexual development in male rats with in utero and lactational exposure to the antiandrogenic plasticizer Di(2-ethylhexyl) phthalate. Environ Health Perspect 109,229-237.
Morales, A.I., Vicente-Sanchez, C., Sandoval, J.M.S., Egido, J., Mayoral, P., Arevalo, M.A., Fernandez-Tagarro, M., Lopez-Novoa, J.M., Perez-Barriocanal, F.,2006. Protective effect of quercetin on experimental chronic cadmium nephrotoxicity in rats is based on its antioxidant properties. Food Chem Toxicol 44,2092-2100.
Morel, I., Lescoat, G., Cogrel, P., Sergent, O., Pasdeloup, N., Brissot, P., Cillard, P., Cillard, J., 1993. Antioxidant and iron-chelating activities of the flavonoids catechin, quercetin and diosmetin on iron-loaded rat hepatocyte cultures. Biochem Pharmacol 45,13-19.
Mori, Y., Kamata, K., Toda, N., Hayashi, H., Seki, K., Taneda, S., Yoshino, S., Sakushima, A., Sakata, M., Suzuki, A.K.,2003. Isolation of nitrophenols from diesel exhaust particles (DEP) as vasodilatation compounds. Biol Pharm Bull 26,394-395.
Mruk, D.D., Silvestrini, B., Mo, M.Y., Cheng, C.Y.,2002. Antioxidant superoxide dismutase-a review:its function, regulation in the testis, and role in male fertility. Contraception 65, 305-311.
Nair, N., Bedwal, S., Prasad, S., Saini, M.R., Bedwal, R.S.,2005. Short-term zinc deficiency in diet induces increased oxidative stress in testes and epididymis of rats. Indian J Exp Biol 43, 786-794.
Nesatyy, V.J., Ammann, A.A., Rutishauser, B.V., Suter, M.J.,2006. Effect of cadmium on the interaction of 17beta-estradiol with the rainbow trout estrogen receptor. Environ Sci Technol 40,1358-1363.
Oikawa, T., Shimamura, M., Ashino, H., Nakamura, O., Kanayasu, T., Morita, I., Murota, S.,1992. Inhibition of angiogenesis by staurosporine, a potent protein kinase inhibitor. J Antibiot (Tokyo) 45,1155-1160.
Ola-Mudathir, K.F., Suru, S.M., Fafunso, M.A., Obioha, U.E., Faremi, T.Y.,2008. Protective roles of onion and garlic extracts on cadmium-induced changes in sperm characteristics and testicular oxidative damage in rats. Food Chem Toxicol 46,3604-3611.
Ozcelik, B., Kartal, M., Orhan, I.,2011. Cytotoxicity, antiviral and antimicrobial activities of alkaloids, flavonoids, and phenolic acids. Pharm Biol 49,396-402.
Ozyurt, H., Pekmez, H., Parlaktas, B.S., Kus, I., Ozyurt, B., Sarsilmaz, M.,2006. Oxidative stress in testicular tissues of rats exposed to cigarette smoke and protective effects of caffeic acid phenethyl ester. Asian J Androl 8,189-193.
Park, S., Nam, H., Chung, N., Park, J.D., Lim, Y.,2006. The role of iron in reactive oxygen species generation from diesel exhaust particles. Toxicol In Vitro 20,851-857.
Paulsen, C.A., Berman, N.G., Wang, C.,1996. Data from men in greater Seattle area reveals no downward trend in semen quality:further evidence that deterioration of semen quality is not geographically uniform. Fertil Steril 65,1015-1020.
Peltola, V., Huhtaniemi, I., Ahotupa, M.,1992. Antioxidant enzyme activity in the maturing rat testis. J Androl 13,450-455.
Peltola, V., Mantyla, E., Huhtaniemi, I., Ahotupa, M.,1994. Lipid peroxidation and antioxidant enzyme activities in the rat testis after cigarette smoke inhalation or administration of polychlorinated biphenyls or polychlorinated naphthalenes. J Androl 15,353-361.
Pflieger-Bruss, S., Hanf, V., Behnisch, P., Hagenmaier, H., Rune, G.M.,1999. Effects of single polychlorinated biphenyls on the morphology of cultured rat tubuli seminiferi. Andrologia 31, 77-82.
Rao, M., Narayana, K., Benjamin, S., Bairy, K.L.,2005. L-ascorbic acid ameliorates postnatal endosulfan induced testicular damage in rats. Indian J Physiol Pharmacol 49,331-336.
Raychoudhury, S.S., Blake, C.A., Millette, C.F.,1999. Toxic effects of octylphenol on cultured rat spermatogenic cells and Sertoli cells. Toxicol Appl Pharmacol 157,192-202.
Renugadevi, J., Milton Prabu, S.,2009. Quercetin protects against oxidative stress-related renal dysfunction by cadmium in rats. Exp Toxicol Pathol.
Rice-Evans CA, M.N., Paganga G,1996. Structure-antioxidant activity relationships of flavonoids and phenolic acids. Free Radic Biol Med 20,933-956.
Romao PR, T.J., Fonseca SG, Morales RH, Cruz AK, Hothersall JS, et al.,2006. Glutathione and the redox control system trypanothione/trypanothione reductase are involved in the protection of Leishmania spp. against nitrosothiol-induced cytotoxicity. Braz J Med Biol Res 39, 355-363.
Ross, J.A., Kasum, C.M.,2002. Dietary flavonoids:bioavailability, metabolic effects, and safety. Annu Rev Nutr 22,19-34.
Sagai, M., Saito, H., Ichinose, T., Kodama, M., Mori, Y.,1993. Biological effects of diesel exhaust particles. I. In vitro production of superoxide and in vivo toxicity in mouse. Free Radic Biol Med 14.37-47.
Santos, F.W., Oro, T., Zeni, G., Rocha, J.B., do Nascimento, P.C., Nogueira, C.W.,2004. Cadmium induced testicular damage and its response to administration of succimer and diphenyl diselenide in mice. Toxicol Lett 152,255-263.
Sastre, J., Pallardo, F.V., Vina, J.,2000. Mitochondrial oxidative stress plays a key role in aging and apoptosis. IUBMB Life 49,427-435.
Semercioz, A., Onur, R., Ogras, S., Orhan, I.,2003. Effects of melatonin on testicular tissue nitric oxide level and antioxidant enzyme activities in experimentally induced left varicocele. Neuro Endocrinol Lett 24,86-90.
Sen Gupta, R., Sen Gupta, E., Dhakal, B.K., Thakur, A.R., Ahnn, J.,2004a. Vitamin C and vitamin E protect the rat testes from cadmium-induced reactive oxygen species. Mol Cell 17,132-139.
Sen Gupta, R., Sen Gupta, E., Dhakal, B.K., Thakur, A.R., Ahnn, J.,2004b. Vitamin C and vitamin E protect the rat testes from cadmium-induced reactive oxygen species. Mol Cells 17, 132-139.
Senthil kumar, J., Banudevi, S., Sharmila, M., Murugesan, P., Srinivasan, N., Balasubramanian, K., Aruldhas, M.M., Arunakaran, J.,2004. Effects of Vitamin C and E on PCB (Aroclor 1254) induced oxidative stress, androgen binding protein and lactate in rat Sertoli cells. Reprod Toxicol 19,201-208.
Shrestha, S.P., Amano, Y., Narukawa, Y., Takeda, T.,2008. Nitric oxide production inhibitory activity of flavonoids contained in trunk exudates of Dalbergia sissoo. J Nat Prod 71,98-101.
Smith, R., Kaune, H., Parodi, D., Madariaga, M., Morales, I., Rios, R., Castro, A.,2007. Extent of sperm DNA damage in spermatozoa from men examined for infertility. Relationship with oxidative stress. Rev Med Chil 135,279-286.
Smith, R., Kaune, H., Parodi, D., Madariaga, M., Rios, R., Morales, I., Castro, A.,2006. Increased sperm DNA damage in patients with varicocele:relationship with seminal oxidative stress. Hum Reprod 21,986-993.
Soczynska-Kordala, M., Bakowska, A., Oszmianski, J., Gabrielska, J.,2001. Metal ion-flavonoid associations in bilayer phospholipid membranes. Cell Mol Biol Lett 6,277-281.
Stefani, E.D., Boffetta, P., Deneo-Pellegrini, H., Mendilaharsu, M., Carzoglio, J.C., Ronco, A., Olivera, L.,1999. Dietary antioxidants and lung cancer risk:a case-control study in Uruguay. Nutr Cancer 34,100-110.
Stohs SJ, B.D., Hassoun E, Bagchi M.,2000. Oxidative mechanisms in the toxicity of chromium and cadmium ions. J Environ Pathol Toxicol Oncol 19,201-213.
Swan, S.H., Elkin, E.P., Fenster, L.,1997. Have sperm densities declined? A reanalysis of global trend data. Environ Health Perspect 105,1228-1232.
Takahashi, O., Oishi, S.,2003. Testicular toxicity of dietarily or parenterally administered bisphenol A in rats and mice. Food Chem Toxicol 41,1035-1044.
Taneli, F., Vatansever, S., Ulman, C., Yilmaz, O., Giray, G., Gene, A., Taneli, C.,2005. The effect of spermatic vessel ligation on testicular nitric oxide levels and germ cell-specific apoptosis in rat testis. Acta Histochem 106,459-466.
Tegelenbosch, R.A., de Rooij, D.G.,1993. A quantitative study of spermatogonial multiplication and stem cell renewal in the C3H/101 F1 hybrid mouse. Mutat Res 290,193-200.
Terao, J., Piskula, M.K.,1999. Flavonoids and membrane lipid peroxidation inhibition. Nutrition 15,790-791.
Vaisberg, C.N., Jelezarsky, L.V., Dishlianova, B., Chaushev, T.A.,2005. Activity, substrate detection and immunolocalization of glutathione peroxidase (GPx) in bovine reproductive organs and semen. Theriogenology 64,416-428.
Verma, R.J., Nair, A.,2001. Ameliorative effect of vitamin E on aflatoxin-induced lipid peroxidation in the testis of mice. Asian J Androl 3,217-221.
Watanabe, M., Henmi, K., Ogawa, K., Suzuki, T.,2003. Cadmium-dependent generation of reactive oxygen species and mitochondrial DNA breaks in photosynthetic and non-photosynthetic strains of Euglena gracilis. Comp Biochem Phys C 134,227-234.
Watanabe, N., Oonuki, Y.,1999. Inhalation of diesel engine exhaust affects spermatogenesis in growing male rats. Environ Health Perspect 107,539-544.
Wright, J.A., Hermonat, M.W., Hards, R.G.,1982. A degradation product of fenitrothion, 3-methyl-4-nitrophenol, is an inhibitor of mammalian ribonucleotide reductase. Bull Environ Contam Toxicol 28,480-483.
Yochum, L., Kushi, L.H., Meyer, K., Folsom, A.R.,1999. Dietary flavonoid intake and risk of cardiovascular disease in postmenopausal women. Am J Epidemiol 149,943-949.
Yoganathan, T., Eskild, W., Hansson, V,1989. Investigation of detoxification capacity of rat testicular germ cells and Sertoli cells. Free Radic Biol Med 7,355-359.
Yoshida, S., Sagai, M., Oshio, S., Umeda, T., Ihara, T., Sugamata, M., Sugawara, I., Takeda, K., 1999. Exposure to diesel exhaust affects the male reproductive system of mice. Int J Androl 22,307-315.
Yu, X., Filardo, E.J., Shaikh, Z.A.,2010. The membrane estrogen receptor GPR30 mediates cadmium-induced proliferation of breast cancer cells. Toxicol Appl Pharmacol 245,83-90.
Yu, X., Hong, S., Faustman, E.M.,2008. Cadmium-induced activation of stress signaling pathways, disruption of ubiquitin-dependent protein degradation and apoptosis in primary rat Sertoli cell-gonocyte cocultures. Toxicol Sci 104,385-396.
Zhang, C., Fang, C., Liu, L., Xia, G., Qiao, H.,2002. Disrupting effects of polychlorinated biphenyls on gonadal development and reproductive functions in chickens. J Environ Sci Health A 37,509-519.
Zhang, C.Q., Qiao, H.L.,2004. Effect of polychlorinated biphenyls on spermatogenesis and testosterone secretion in adult cocks. J Zhejiang Univ Sci 5,193-197.
白凤梅,蔡同一.类黄酮生物活性及其机理的研究进展.食品科学1999,(8)：11-13.
卞建春,镉对雄性动物生殖毒理学的研究东北农业大学[D]2003
刁书永,袁慧镉对小鼠卵巢颗粒细胞凋亡的影响研究.畜牧兽医学报2005,11：1155-1158.
费前进,黄学锋,李澄棣.大鼠睾丸精子发生过程中抗氧化酶活性水平的变化浙江临床医学2005,7(3)：229-230.
封传悦,朱俊东.大豆异黄酮摄入与乳腺癌发生风险的Meta分析.中华乳腺病杂志2010,03：43-46.
孔志明,张国栋,孙立伟.环境内分泌干扰物诱发小鼠睾丸细胞DNA损伤的研究.环境污染与防治2002,24：76-78.
李卫华.环境内分泌干扰物毒理研究的现状及展望.卫生毒理学2000,14：13-15.
李维信,寥晓岗,唐宜,包大干.镉对大鼠睾丸的损伤及锌保护作用的超微结构研究.解剖学报1998,19：74-78
凌关庭.抗氧化食品与健康[M]北京：化学工业出版社,2004.4
徐国刚,蒋学之.镉的雄(男)性生殖毒性.中国公共卫生学报1996,15：17-18.
俞鸣,贾真琳,王宝亭,史玉荣,郝继辉NF-κB与Caspase-9在大豆异黄酮诱导人乳腺癌细胞凋亡中的作用.中国慢性病预防与控制2010,03：270-272.
杨建明,陈琼宇,曾样斌,许江琳,逢兵,周袁芬,金泰,蒋学之.镉对雄性生育功能的影响.中国公共卫生2000,16(4)：313-314.
张大雷,杨蓓,吴磊,邹挺.人参皂苷保护小鼠精原细胞氧化损伤的研究.中国药理学通报2010,26(8)：1014-1016.
张明,袁慧镉对小鼠生精细胞凋亡及bax和bcl-2基因表达的影响中国兽医科学2007,37(03)：251-254.
张树成,王弘毅,王介东.1981-1996年我国有生育力男性精液质量的变化分析.生殖与避孕1991,19(1)：27-33.