全氟辛烷磺酸等环境污染物染毒哺乳期大鼠对成年期Leydig细胞影响的实验研究
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摘要
全氟有机化合物(PFOCs)和邻苯二甲酸盐作为人造材料在工业上的应用已有几十年的历史,其中以全氟辛烷磺酸盐(PFOCs)全氟辛酸(PFOA)和邻苯二甲酸盐应用最为广泛。PFOS和：PFOA同时具备疏脂、疏水等特性,被广泛用于日常生活近千种产品。通常条件下PFOS和PFOA极难分解,而且在有机生物体内有聚积效应。邻苯二甲酸盐这一类化合物,主要用于聚氯乙烯材料,被普遍应用于日常生活数百种产品中,在人体和动物体内发挥着类似雌性激素的作用,可干扰生殖内分泌系统功能,是造成男子生殖问题的“罪魁祸首”。在大部分动物体内,邻苯二甲酸盐会快速分解成邻苯二甲酸单体,如DMP可分解成MMP单体,DEHP分解成MEHP。并且,这些单体的毒性远远大于其前体。
本研究采用多种实验手段观察到,PFOA显著抑制大鼠睾丸微粒体和Leydig细胞中的3β-羟基脱氢酶(3p-HSD) HSD和17β羟基脱氢酶3(17β-HSD3)活性,并抑制Leydig细胞睾丸酮的产生。PFOA抑制这两种酶活性,进而抑制睾丸酮的生成。
PFOS和PFOSK抑制大鼠3β-HSD,而PFHxSK和PFBSK无抑制能力。同时,5种不同的全氟烃基物质对人3β-HSD均无抑制作用。PFOS及PFOSK对人睾丸中17β羟基脱氢酶有显著的抑制作用,而且存在结构和种属的特异性。
PFOS高剂量组大鼠体重及睾丸重量显著性降低。高、低剂量组血清睾丸酮显著性降低。Real-time PCR检测Cypllal表达显著降低。酶学检测P450c17和17βHSD活性显著降低。在高、低剂量组Leydig细胞数目显著降低。PFOS染毒哺乳期大鼠,成年期生殖内分泌功能发生明显改变。
DPrP和DBP明显抑制人和大鼠11βHSD2。DCHP明显抑制大鼠11βHSD2。单体MEHP明显抑制人和大鼠11βHSD2。邻苯二甲酸类化合物对11β-HSD2有明显的抑制作用,且这种抑制作用与邻苯二甲酸类化合物的空间结构有一定的相关性。
本研究结果为政府环保部门制定相应的环保政策、法规提供科学依据,对我国保护环境、提高人口素质具有重要的科学意义。
The term' testicular dysgenesis syndrome'(TDS) refers to a spectrum of reproductive disorders that originate in male fetal life. TDS includes cryptorchidism (undescended testes) and hypospadias (abnormal formation of the urethral meatus) in newborn boys and testicular cancer and reduced fertility in adult males. Environmental endocrine disruptors are suspected contributors to the increase in TDS, perfluorooctane sulfonate (PFOS) is wildly used, and their reproductive toxicity and reproductive endocrine toxicity begun to attract the attention of scientists. The present study was to test the effects of PFOS on male reproductive in Long-Evans rats after exposure to PFOS in lactational. The aim of this study was to test the foetus body weight and testis weight; measure testosterone with radioimmunoassay, enzyme assay and biomarker of Leydig cells with realtime PCR, and evaluate the spectrum of protein of testis with proteinomics. Our objective was to study the effects of PFOS on male reproductive endocrine toxicity and discover the mechanism of affect of PFOS on Leydig stem cells.
1 Inhibition of 3β-and 17β-hydroxysteroid dehydrogenase activities in rat Leydig cells by perfluorooctane acid
Aim:PFOA interferes with Leydig cell steroidogenic enzymes by measuring its effect on 3β-hydroxysteroid dehydrogenase (3β-HSD) and 17(3-hydroxysteroid dehydrogenase 3 (17β-HSD3) activities in rat testis microsomes and Leydig cells.
Method:Testicular microsome and Leydig cells from SD rats were prepared. The experiment was divided into control and positive groups. We incubated DMEM and PFOA with testicular microsome and Leydig cells, enzyme assay for 3β-hydroxysteroid dehydrogenase (3β-HSD) and 17β-hydroxysteroid dehydrogenase 3 (17β-HSD3) activities, and tritium-based radioimmunoassay to test testosterone concentration.
Results:PFOA inhibited microsomal 3β-HSD activity with an IC50 of 53.2±25.9μmol/L and 17β-HSD3 activity with an IC50 17.7±6.8μmol/L. PFOA inhibited intact Leydig cell 3p-HSD activity with an IC50 of 146.1±0.9μmol/L and 17β-HSD3 activity with an IC50 of 194.8±1.0μmol/L. The inhibitions of 3P-HSD and 17p-HSD3 activities by PFOA were competitive for the substrates.
Conclusion:PFOA inhibits 3β-HSD and 17β-HSD3 activities in rat Leydig cells.
2 Comparison of the potencies of perfluoroalkylated substances inhibiting of 3β-and 17β-hydroxysteroid dehydrogenase 3 activities in human and rat testes
Aim:The objective of the present study was to compare the potencies of five different PFASs including PFOA, PFOS, potassium perfluorooctylsulfonate (PFOSK), potassium perfluorohexanesulfonate (PFHxSK) and potassium perfluorobutane sulfonate (PFBSK) in the inhibition of 3β-hydroxysteroid dehydrogenase (βP-HSD) and 17p-hydroxysteroid dehydrogenase 3 (17β-HSD3) in human and rat testes. Human or rat microsomal enzyme was subjected to the exposure to various PFASs.
Method:Microsomal preparations of human and rat testes were done according to the author published before which was treated by DMEM and different perfluoroalkylated substances respectively. The experiment was divided into control and positive groups. The activities of 3β-hydroxysteroid dehydrogenase (3β-HSD) and 17β-hydroxysteroid dehydrogenase 3 (17β-HSD3) in human and rat testes were tested with enzyme assay.
Result:PFOS and PFOSK inhibited rat 3P-HSD activity with IC50 of 1.35±0.05 and 1.77±0.04μmol/L, respectively, and PFHxSK and PFBSK did not inhibit the enzyme at concentrations up to 250μmol/L. However, all of these chemicals weakly inhibited human 3β-HSD activity with IC50s over 250μmol/L. PFOS, PFOSK and PFOA inhibited human 17P-HSD3 activity with IC50s of 6.02±1.02,4.39±0.46 and 127.60±28.52μmol/L, respectively. The potencies of inhibiting 17β-HSD3 activity were PFOSK> PFOS> PFOA> PFHSK= PFBSK for human 17p-HSD3. There was a species difference in the sensitivity to PFAS-mediated inhibition of 17β-HSD3 activity. For example, the IC50s of inhibiting rat 17β-HSD3 activity for PFOS(K) were over 250μmol/L. PFOS(K) showed competitive inhibition of rat 3β-HSD and human 17p-HSD3.
Conclusion:In conclusion, the present study shows that PFOS and PFOSK are the potent inhibitors of human 17β-HSD3 and that there are structure-and species-dependent differences for the potency inhibiting 17β-HSD3 activity.
3 The effects of PFOS on adult Leydig cells in lactational in male Long-Evans rat
Aim:The aims of the present study were to detect whether PFOS exposure results in toxic effects in the adult male reproductive system and determine the mechanism of the PFOS toxicity in the testis when PFOS exposed in lactation.
Method:Adult dams were treated from PND1 to PND8 with 0 (control, n= 6),5 (= 6) or 10(n= 6) mg/kg PFOS (Sigma-Aldrich Co. Ltd) in 0.05% ween-20 administered daily by oral gavage. Male foetuses were killed by inhalation of carbon dioxide at birth for ALC analysis PND56. And serum testosterone analysis and realtime-PCR, enzyme assay and 3β-HSD staining were done.
Result:As compared to control, for animals exposed to dose of 10 mg/kg/day, the body and testis weights reduced significantly(P＜0.001). T values were 50% lower in the 5 and 10 mg/kg/day groups. The expression of Cyp11A,oding for P450scc, was markedly reduced at dose of 10 mg/kg/day group (P<0.05). The adult Leydig cell numbers, as compared to control, reduced significantly at dose of 5 and 10 mg/kg groups.
Conclusion:In conclusion, these data, taken together, point out that there are effects on ALC number in lactational rats exposure to PFOS, and steroidogenic capacity is most important. The results suggest that reducing expressions of Cyp11A, P450c17 and 17βHSD might contribute to the reproductive toxicity of PFOS.
4 Structure-dependent inhibition of human and rat 11β-hydroxysteroid dehydrogenase 2 activities by phthalates
Aim:In the present study,12 phthalate diesters and four monoesters for inhibition of human and rat kidney 11 (3-HSD2 were tested. The modes of inhibition and looked for a relationship between potency for inhibition and the chemical structures were examined.
Method:Microsomal preparations of human and rat testes were done according to the author published before, and divided into control and positive group which was treated by DMEM and different phthalates respectively. The activities of 11β-hydroxysteroid dehydrogenase2 (11β-HSD2) in human and rat testes was tested with enzyme assay.
Result:Of the phthalate diesters we tested, dipropyl phthalate (DPrP) and di-n-butyl phthalate (DBP) significantly inhibited both human and rat 11 (3-HSD2 activities. The IC50s were 85.6μmol/L for DPrP and 13.7μmol/L for DBP when calculated for rat 11β-HSD2. However, phthalates could be inhibitors with six carbons in the alcohol moiety if the carbons were cyclized, as in dicyclohexyl phthalate (DCHP), which inhibited rat 11β-HSD2 with an IC50 of 32.64μmol/L. We showed that mono (2-ethylhexyl) phthalate (MEHP) significantly inhibited human (IC50= 110.8±10.9) and rat (121.8±8.5μM) 11(3-HSD2 activity even though its parent compound, di(2-ethylhexyl) phthalate (DEHP) did not. MEHP was a competitive inhibitor of 11β-HSD2 enzymatic activity.
Conclusion:In conclusion, we tested phthalates that varied in size and shape, and found that phthalates that inhibited 11β-HSD2 had alcohol moieties that were intermediate in size to those on the non-inhibitory phthalates. Inhibition was not strictly dependent on the number of carbons in the moieties, but on some aspect of the space-filling conformation of the moiety.
本研究采用多种实验手段观察到,PFOA显著抑制大鼠睾丸微粒体和Leydig细胞中的3β-羟基脱氢酶(3p-HSD) HSD和17β羟基脱氢酶3(17β-HSD3)活性,并抑制Leydig细胞睾丸酮的产生。PFOA抑制这两种酶活性,进而抑制睾丸酮的生成。
PFOS和PFOSK抑制大鼠3β-HSD,而PFHxSK和PFBSK无抑制能力。同时,5种不同的全氟烃基物质对人3β-HSD均无抑制作用。PFOS及PFOSK对人睾丸中17β羟基脱氢酶有显著的抑制作用,而且存在结构和种属的特异性。
PFOS高剂量组大鼠体重及睾丸重量显著性降低。高、低剂量组血清睾丸酮显著性降低。Real-time PCR检测Cypllal表达显著降低。酶学检测P450c17和17βHSD活性显著降低。在高、低剂量组Leydig细胞数目显著降低。PFOS染毒哺乳期大鼠,成年期生殖内分泌功能发生明显改变。
DPrP和DBP明显抑制人和大鼠11βHSD2。DCHP明显抑制大鼠11βHSD2。单体MEHP明显抑制人和大鼠11βHSD2。邻苯二甲酸类化合物对11β-HSD2有明显的抑制作用,且这种抑制作用与邻苯二甲酸类化合物的空间结构有一定的相关性。
本研究结果为政府环保部门制定相应的环保政策、法规提供科学依据,对我国保护环境、提高人口素质具有重要的科学意义。
The term' testicular dysgenesis syndrome'(TDS) refers to a spectrum of reproductive disorders that originate in male fetal life. TDS includes cryptorchidism (undescended testes) and hypospadias (abnormal formation of the urethral meatus) in newborn boys and testicular cancer and reduced fertility in adult males. Environmental endocrine disruptors are suspected contributors to the increase in TDS, perfluorooctane sulfonate (PFOS) is wildly used, and their reproductive toxicity and reproductive endocrine toxicity begun to attract the attention of scientists. The present study was to test the effects of PFOS on male reproductive in Long-Evans rats after exposure to PFOS in lactational. The aim of this study was to test the foetus body weight and testis weight; measure testosterone with radioimmunoassay, enzyme assay and biomarker of Leydig cells with realtime PCR, and evaluate the spectrum of protein of testis with proteinomics. Our objective was to study the effects of PFOS on male reproductive endocrine toxicity and discover the mechanism of affect of PFOS on Leydig stem cells.
1 Inhibition of 3β-and 17β-hydroxysteroid dehydrogenase activities in rat Leydig cells by perfluorooctane acid
Aim:PFOA interferes with Leydig cell steroidogenic enzymes by measuring its effect on 3β-hydroxysteroid dehydrogenase (3β-HSD) and 17(3-hydroxysteroid dehydrogenase 3 (17β-HSD3) activities in rat testis microsomes and Leydig cells.
Method:Testicular microsome and Leydig cells from SD rats were prepared. The experiment was divided into control and positive groups. We incubated DMEM and PFOA with testicular microsome and Leydig cells, enzyme assay for 3β-hydroxysteroid dehydrogenase (3β-HSD) and 17β-hydroxysteroid dehydrogenase 3 (17β-HSD3) activities, and tritium-based radioimmunoassay to test testosterone concentration.
Results:PFOA inhibited microsomal 3β-HSD activity with an IC50 of 53.2±25.9μmol/L and 17β-HSD3 activity with an IC50 17.7±6.8μmol/L. PFOA inhibited intact Leydig cell 3p-HSD activity with an IC50 of 146.1±0.9μmol/L and 17β-HSD3 activity with an IC50 of 194.8±1.0μmol/L. The inhibitions of 3P-HSD and 17p-HSD3 activities by PFOA were competitive for the substrates.
Conclusion:PFOA inhibits 3β-HSD and 17β-HSD3 activities in rat Leydig cells.
2 Comparison of the potencies of perfluoroalkylated substances inhibiting of 3β-and 17β-hydroxysteroid dehydrogenase 3 activities in human and rat testes
Aim:The objective of the present study was to compare the potencies of five different PFASs including PFOA, PFOS, potassium perfluorooctylsulfonate (PFOSK), potassium perfluorohexanesulfonate (PFHxSK) and potassium perfluorobutane sulfonate (PFBSK) in the inhibition of 3β-hydroxysteroid dehydrogenase (βP-HSD) and 17p-hydroxysteroid dehydrogenase 3 (17β-HSD3) in human and rat testes. Human or rat microsomal enzyme was subjected to the exposure to various PFASs.
Method:Microsomal preparations of human and rat testes were done according to the author published before which was treated by DMEM and different perfluoroalkylated substances respectively. The experiment was divided into control and positive groups. The activities of 3β-hydroxysteroid dehydrogenase (3β-HSD) and 17β-hydroxysteroid dehydrogenase 3 (17β-HSD3) in human and rat testes were tested with enzyme assay.
Result:PFOS and PFOSK inhibited rat 3P-HSD activity with IC50 of 1.35±0.05 and 1.77±0.04μmol/L, respectively, and PFHxSK and PFBSK did not inhibit the enzyme at concentrations up to 250μmol/L. However, all of these chemicals weakly inhibited human 3β-HSD activity with IC50s over 250μmol/L. PFOS, PFOSK and PFOA inhibited human 17P-HSD3 activity with IC50s of 6.02±1.02,4.39±0.46 and 127.60±28.52μmol/L, respectively. The potencies of inhibiting 17β-HSD3 activity were PFOSK> PFOS> PFOA> PFHSK= PFBSK for human 17p-HSD3. There was a species difference in the sensitivity to PFAS-mediated inhibition of 17β-HSD3 activity. For example, the IC50s of inhibiting rat 17β-HSD3 activity for PFOS(K) were over 250μmol/L. PFOS(K) showed competitive inhibition of rat 3β-HSD and human 17p-HSD3.
Conclusion:In conclusion, the present study shows that PFOS and PFOSK are the potent inhibitors of human 17β-HSD3 and that there are structure-and species-dependent differences for the potency inhibiting 17β-HSD3 activity.
3 The effects of PFOS on adult Leydig cells in lactational in male Long-Evans rat
Aim:The aims of the present study were to detect whether PFOS exposure results in toxic effects in the adult male reproductive system and determine the mechanism of the PFOS toxicity in the testis when PFOS exposed in lactation.
Method:Adult dams were treated from PND1 to PND8 with 0 (control, n= 6),5 (= 6) or 10(n= 6) mg/kg PFOS (Sigma-Aldrich Co. Ltd) in 0.05% ween-20 administered daily by oral gavage. Male foetuses were killed by inhalation of carbon dioxide at birth for ALC analysis PND56. And serum testosterone analysis and realtime-PCR, enzyme assay and 3β-HSD staining were done.
Result:As compared to control, for animals exposed to dose of 10 mg/kg/day, the body and testis weights reduced significantly(P＜0.001). T values were 50% lower in the 5 and 10 mg/kg/day groups. The expression of Cyp11A,oding for P450scc, was markedly reduced at dose of 10 mg/kg/day group (P<0.05). The adult Leydig cell numbers, as compared to control, reduced significantly at dose of 5 and 10 mg/kg groups.
Conclusion:In conclusion, these data, taken together, point out that there are effects on ALC number in lactational rats exposure to PFOS, and steroidogenic capacity is most important. The results suggest that reducing expressions of Cyp11A, P450c17 and 17βHSD might contribute to the reproductive toxicity of PFOS.
4 Structure-dependent inhibition of human and rat 11β-hydroxysteroid dehydrogenase 2 activities by phthalates
Aim:In the present study,12 phthalate diesters and four monoesters for inhibition of human and rat kidney 11 (3-HSD2 were tested. The modes of inhibition and looked for a relationship between potency for inhibition and the chemical structures were examined.
Method:Microsomal preparations of human and rat testes were done according to the author published before, and divided into control and positive group which was treated by DMEM and different phthalates respectively. The activities of 11β-hydroxysteroid dehydrogenase2 (11β-HSD2) in human and rat testes was tested with enzyme assay.
Result:Of the phthalate diesters we tested, dipropyl phthalate (DPrP) and di-n-butyl phthalate (DBP) significantly inhibited both human and rat 11 (3-HSD2 activities. The IC50s were 85.6μmol/L for DPrP and 13.7μmol/L for DBP when calculated for rat 11β-HSD2. However, phthalates could be inhibitors with six carbons in the alcohol moiety if the carbons were cyclized, as in dicyclohexyl phthalate (DCHP), which inhibited rat 11β-HSD2 with an IC50 of 32.64μmol/L. We showed that mono (2-ethylhexyl) phthalate (MEHP) significantly inhibited human (IC50= 110.8±10.9) and rat (121.8±8.5μM) 11(3-HSD2 activity even though its parent compound, di(2-ethylhexyl) phthalate (DEHP) did not. MEHP was a competitive inhibitor of 11β-HSD2 enzymatic activity.
Conclusion:In conclusion, we tested phthalates that varied in size and shape, and found that phthalates that inhibited 11β-HSD2 had alcohol moieties that were intermediate in size to those on the non-inhibitory phthalates. Inhibition was not strictly dependent on the number of carbons in the moieties, but on some aspect of the space-filling conformation of the moiety.
引文
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