具有內分泌干擾性質之物質數目日與俱增，這些物質常隨著未去除完全之污水廠出流、地表逕流以及污水偷排之途徑排放至承受水體中，可能造成水體中生物體產生內分泌系統紊亂或是繁殖力降低等負面影響，甚至可能因其生物累積性而危害人類之健康。
本研究利用基因重組酵母菌檢測臺灣中南部10條河川水相及懸浮固體相之類(抗)雌激素活性、類(抗)雄激素活性以及類(抗)甲狀腺荷爾蒙活性，並搭配液相層析串聯式質譜儀檢測樣本中之內分泌干擾物質，以了解其於河川水體中之流布。由於內分泌干擾物質多以混合物之形式存在於環境當中，為了解其單獨存在與複合狀態之差異，因而配製人工複合樣本進行類雌激素及抗雄激素活性試驗。
生物試驗法結果顯示，水相與懸浮固體相樣本皆無檢測出類雄激素活性以及類甲狀腺荷爾蒙活性。類雌激素活性多於水相樣本中檢出，又以重污染河川樣本最顯著，檢出範圍為ND~344.6 E2-EQ ng/L。抗雌激素活性多於懸浮固體相樣本中檢出，又以中、重污染河川樣本較為顯著，分別為ND~7.4 OHT-EQ μg/L,及ND~7.7 OHT-EQ μg/L。抗雄激素活性多於水相樣本中檢出，以重污染河川樣本最為顯著，檢出範圍為ND~7489.1 FLU-EQ μg/L。抗甲狀腺荷爾蒙活性多於水相樣本中檢出，以重污染河川樣本最為顯著，抑制活性範圍為ND~55%。若以BOD5超過5 mg/L (中度污染)之頻率作為河川分類方式，可大略評估其水體是否具有內分泌干擾活性。
儀器分析結果顯示，水相樣本中普遍存在天然雌激素E1 (ND~236.3 ng/L)，BPA (0.1~611.1 μg/L)、NP (ND~1848.4 ng/L)以及TCS (ND~472.6 ng/L)。以風險商數評估水相中內分泌干擾物質對於生態之危害，其中以E1超標頻率最高 (87.5%)，在三類河川中則以重污染河川超標之物質數目最多，顯示生物體若暴露於重污染河川中可能對其產生負面影響。
根據等效力物質樣本之複合效應，抗雄激素及類雌激素物質於本研究中之基因重組酵母菌中多以相加作用之方式產生活性。
比較河川複合樣本之活性，人工複合樣本之抗雄激素活性與儀器分析之抗雄激素當量濃度 (Flutamide equivalent, FEQ)之值差異大，導因於其抗雄激素活性於人工複合樣本中大多低於方法偵測極限，而與環境樣本之生物活性差異大則可能因為樣本中含有未能於儀器分析中檢測出之抗雄激素物質。人工複合樣本之類雌激素活性則大多與儀器分析之類雌激素當量濃度 (Estradiol equivalent, EEQ)之值相近，但與環境樣本之生物活性EEQ差距甚大，顯示樣本中可能含有非儀器分析目標物質之類雌激素或抗雌激素活性之物質。

SUMMARY
There is a growing concern of organisms exposed to endocrine disrupting chemical (EDCs), which have potential impact on endocrine systems. To understand the occurrence of EDCs in Taiwnese rivers, yeast-based reporter gene assays and liquid chromatography tandem mass spectrometry (LC-MS/MS) were used to analyze EDCs in samples collected from the aquatic environment. Bioassay results showed that (anti-)estrogenic, anti-androgenic, and anti-thyroid hormonal activities were detected in most samples. In addition, natural estrogens, including estrone, 17β-estradiol and estriol, and synthetic compounds, such as bisphenol A, nonylphenol, triclosan, and triclocarban were detected by LC-MS/MS. The results indicated that there was a potential ecological after calculating the risk quotients (RQ) of different compounds. According to the results of combined effects assessment, anti-androgenic and estrogenic compounds showed concentration additive effects in the yeast bioassays, and the the results of iceberg mixture indicated that there were still a lot of unknown EDCs not detected by LC-MS/MS. It is essential to continuously monitor the effects of EDCs on organisms in the aquatic environment
Key words: Endocrine disrupting chemicals (EDCs), Yeast-based reporter gene assays, River water, LC-MS/MS, Combined effects
INTRODUCTION
Emerging Contaminants (ECs) are chemicals that pose potential risk to human and animals associated with their presence, frequency of occurrence, or source may not be known. According to US Environmental Protection Agency, ECs contain pharmaceuticals and personal care products (PPCPs), endocrine disrupting chemicals (EDCs), persistent organic pollutants (POPs), etc. Among ECs, EDCs have been an important concerns for decades because they are widespread in the environment.
EDCs are chemicals which interfere with the endocrine systems of organisms, including synthesis, transport reproduction, etc. A large variety of EDCs have been reported to show estrogenic, androgenic or thyroid hormone disrupting effects. These compounds are introduced into the aquatic environment via industrial, municipal and livestock effluents, and their influence are difficult to evaluate using traditional water qualities, such as pH, DO, BOD5, etc. Many studies have investigated the occurrence of EDCs by using bioassays and chemical analysis. Bioassays, including in vivo and in vitro assays, are used to evaluate the effects on organisms by exposing to EDCs. Chemical analysis using intrument, such as liquid chromatography tandem mass spectrometry (LC-MS/MS), is qualitative and quantitative measurement of known EDCs..
Organisms in environment are often exposed to many EDCs in the same time, therefore, it’s essential to consider the combined effects induced by EDCs.
In this study, both bioassays and chemical analysis were carried out to assess the amount of EDCs in Taiwanses rivers, including water phase and suspended solid (SS) phase samples. In addition, since organisms in environment are often exposed to many EDCs at the same time, the artificial mixtures were also analyzed by bioassays to evaluate the combined effects of EDCs.

MATERIALS AND METHODS
Water grab samples were collected from ten rivers in Taiwan. All water samples (0.5L) were separated into water phase and SS phase by filtration. Water phase samples were extracted by solid phase extraction (SPE) using Oasis HLB Plus cartridge (Waters, USA). Cartridges were activated with 3 mL of 50% methanol and 3 mL of water, and then water phase samples were forced through the cartridges using peristaltic pump. After extraction, the cartridges were washed with 3 mL of 5% methanol and eluted with 1 mL of methanol and 4 mL tert-butylmethylether. SPE extracts were then evaporated by centrifugal vacuum concentrator (EYELA, Japan) and then dissolved in 0.5 mL dimethyl sulfoxide (DMSO) for 1000-fold concentrated samples. SS samples were dried at 105 °C to remove water, and then extracted by Soxhlet extraction using approximately 200 mL of hexane and acetone mixture (1:1, v:v) for 24 h. The extracts were then concentrated to about 3-5 mL by rotary evaporation, and then nitrogen blowing concentrator was used to remove hexane after adding 0.5 mL DMSO for 1000-fold concentrated samples. In this study, yeast-based reporter gene assays used were able to detect estrogenic receptor (ER), androgenic receptor (AR) and thyroid hormone recptor (TR) disrupting activities.
Chemical analysis was carried out using LC-MS/MS to detect the known EDCs. The LC system was Agilent 1260 Infinity (Agilent, USA), and the column was Xbridge BEH C18, 75×2.1 mm i.d., 2.5 μm (Waters, USA).and the mobile phases used in LC were water and methanol. The MS/MS system was Thermo TSQ Quantum Ultra (Thermo, USA) using electrospray ionization (ESI). The mode of detection was multiple reaction monitoring (MRM).
The samples used for combined effect assessment consisted of three parts. The first part was equipotent samples, which were normalized to their effect concentration in yeast-based reporter gene assays so that each EDC should have the same contribution to the mixture effects. The second part was threshold value mixtures, which were based on predicted no-effect concentrations (PNECs) and the values of augmentation of drinking water supplies of Australia. The third part was iceberg mixtures, which were based on the concentrations of EDCs detected in Taiwanese river samples.

RESULTS AND DISCUSSION
Bioassay results demonstrated that high estrogenic activity was detetect in water phase samples in Erren river (ND~346.6 E2-EQ ng/L) and Agodian river (ND~60.5 E2-EQ ng/L). Anti-estrogenic activity was often detected in SS phase samples, especially in Erren river (ND~7.7 OHT-EQ μg/L). Androgenic or thyroid hormonal activities were not detected in all samples. In contrast, high anti-androgenic activity was detected in water phase samples in Erren river (ND~7489.1 FLU-EQ μg/L) and Agodian river (ND~3329.3 FLU-EQ μg/L). Most of water phase samples showed anti-thyroid hormonal activity, especially samples collected from Erren river (ND~47.5%) and Agodian river (30.7~55.1%).
LC-MS/MS results demonstrated that among natural estrogens, estrone was detected most frequently, and the detection frequencies in water phase and SS phase samples were 90.6% and 41.7%, respectively. The highest concentrations of total natural estrogen in water phase samples were detected in Erren river (ND~455.8 ng/L), following by Agodian river (7.3~327.7 ng/L). The detection frequencies of bisphenol A (BPA) were 100% both in water phase and SS phase samples, and the highest concentrations in water phase samples were detected in Erren river (775.3~613258.3 ng/L). The detection frequencies of nonylphenol (NP) were 91.7% and 45.8% in water phase and SS phase samples, respectively, and the highest concentrations in water phase samples were detected in Agodian river (74.6~2086.7 ng/L). The detection frequencies of triclosan (TCS) were 68.8% and 18.8% in water phase and SS phase samples, respectively, and the highest concentrations in water phase samples were detected in Erren river (ND~509.7 ng/L). The detection frequencies of triclocarban (TCC) were 7.3% and 45.8% in water phase and SS phase samples, respectively, and the highest concentrations in SS phase samples were detected in Tsengwen river (ND~1192.2 ng/L).
To evaluate the potential effects of target EDCs measured by LC-MS/MS on organisms, risk quotient (RQ), which represents the ratio of measured environment concentrations of target compounds in water samples and their PNECs was calculated. The results showed that the concentrations of estrone, TCS and BPA had potential ecological risk to the aquatic environment of Taiwan.
In order to clarify the relation between yeast-based reporter gene assays and chemical analysis, the target EDCs were analyzed by using bioassays to determine their estrogenic or anti-androgenic activities relative to 17β-estradiol or flutamide, respectively, and then the EEQLC-MS/MS and FEQLC-MS/MS were obtain to compared with the EEQbioassay and FEQbioassay. The results showed that EEQLC-MS/MS and FEQLC-MS/MS of most samples were lower than EEQbioassay and FEQbioassay, indicating that there were still a large amount of EDCs not detected by LC-MS/MS analysis.
Bioassay results of equipotent samples showed that EDCs exhibited concentration additive estrogenic and anti-androgenic activities in yeast-based reporter gene assays. The results of threshold value mixtures showed that mixture samples may produce significant effects even all concentrations of EDCs were under PNECs via concentration addition. The iceberg mixtures were also analyzed by bioassays after LC-MS/MS analysis, and the results worked in concert with the relation between bioassay and chemical analysis, which indicated that there were some unknown EDCs in the environmental samples.
CONCLUSION
The yeast-based in reporter gene assay adopted in the present study were used to estimate the (anti-)estrogenic, (anti-)androgenic and (anti-)thyroid hormonal activities in Taiwanese rivers. The results showed that estrogenic and anti-androgenic activities were detected in water phase samples, while anti-estrogenic activities were present in SS phase samples. In addition, TR agonist and antagonist activities were also detected both in water phase and SS phase samples . Among these samples, Erren river and Agodian river showed higher endocrine disrupting activities. By using LC-MS/MS, natural estrogens, BPA, NP, TCS and TCC were detected in samples, and the results of RQ posed potential risk of EDCs to local aquatic organisms. The combined effects assessment conducted in this study indicated that EDCs showed concentration additive effects in yeast assay, which meant that even the chemical concentrations under PNEC might also induce significant effects. Therefore, the combined effects must be considered when evaluating the effects of EDCs on organisms.

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