近年來研究顯示，在所有不孕症案例中，男性因素約佔三成的比例，且不孕症患者中男性的精液品質有下降的趨勢。相關影響因素除先天的基因缺陷外，其他的影響因素包括不良生活習慣、壓力、環境因子等，而外源性的環境因子，如環境中的環境荷爾蒙暴露無法完全避免。由於鄰苯二甲酸酯(Phthalates，PAEs)廣泛用於人類日常用品製造，且其使用過程缺乏完善的管控而導致環境污染，進而使 PAEs 經由空氣、水、食物等途徑，進入人體使使得人體暴露PAEs 的機會大增。
PAEs 可能存在於個人護理用品、食品、食品包裝材、玩具、醫療用品、裝潢建材等，由於 PAEs 具親脂性且容易揮發、滲出並釋放於環境，進而經由食入、吸入、皮膚接觸等途徑進入人體內。人體流行病學研究指出，由於日常生活中難以避免暴露到 PAEs，因此可能會導致體內生殖荷爾蒙的改變，並對生殖系統及精液品質產生不利的影響。本研究假設不孕症男性暴露 PAEs 後可能影響 HPG 軸促使 FSH、LH 分泌減少，並對睪丸的Sertoli cell 及 Leydig cell 產生干擾，從而降低睪固酮、INSL 3 濃度並影響男性精液品質，造成男性生殖功能降低。
本研究為橫斷性研究，以男性不孕症患者為研究族群，自國立成功大學附設醫院婦產科門診招募 61 位不孕症男性（依 WHO 2024 年定義在沒有避孕情況下至少一年規律性生活而沒有受孕）為研究對象，於簽署人體試驗同意書後，收集受試者尿液、血液、精液及進行標準化問卷訪談，透過問卷了解受試者基本資料，包括人口特徵、疾病史、飲食問卷、生活品質及習慣等。尿液樣本用以檢測 12 種 PAEs 代謝物(MMP、MEP、MiBP、MnBP、MEHHP、MECPP、MEOHP、MBzP、MEHP、MnOP、MINP、MIDP)及肌酐酸(Creatinine)濃度，PAEs 代謝物以液相層析串聯質譜儀(LC-MS/MS)進行分析，Creatinine 則委由邱內科暨立人醫學檢驗所進行分析；血液樣本用於生殖荷爾蒙(Albumin、SHBG、Free testosterone、Testosterone、Bioavailable-Testosterone、LH、FSH、E2、DHEA-Sulfate、Androstenedione、5α-Dihydrotestosterone、Aromatase、E1、Inhibin B) 及類胰島素3 (INSL3)的檢測，亦委由邱內科暨立人醫學檢驗所進行分析；精 液 檢 體 則 委 由 國 立 成 功大 學 生殖 醫 學中 心進 行 一般 常 規精液檢測及CASA(Computer-aided sperm analysis)電腦輔助分析。整合所有資訊，以瞭解尿液中PAEs 代謝物濃度、血清生殖荷爾蒙濃度與精液品質之分布情形，再以各 PAEs 代謝物中位數濃度區分高低濃度組別，探討高低濃度組別生殖荷爾蒙、精液參數的濃度差異，最後以迴歸分析，評估 PAEs 代謝物與生殖荷爾蒙、INSL3、精液品質參數之間的關係，並了解其對男性生殖功能所產生的影響。
研究結果顯示本研究男性尿液中 PAEs 代謝物檢測結果顯示，12 種 PAEs 代謝物以平均濃度及標準差表示，其中MEP(40.10±131.59 ppb)濃度為最高，其次則是MnBP(15.48±13.83 ppb)、MiBP(8.58±8.67 ppb )和 MECPP(6.96±5.67 ppb)，最低為MIDP(0.25±0.28 ppb)。比較本研究各 PAEs 代謝物中位數濃度與其他各國不孕症男性尿液中 PAEs 代謝物濃度，本研究中MEP 濃度相較其他國家低，原因可能為歐美、沙烏地阿拉伯地區由於使用體香劑亦或是香水等個人用品較為普遍，因此其暴露量相較於我國男性濃度而偏高，而導致MEP 濃度較高。 MiBP、MEOHP、MECPP 及 MBzP等代謝物濃度多低於中國、沙烏地阿拉伯、德國、波蘭之研究，並與日本研究結果較為接近。其中中國較高之 MEHP 與 MiBP 相關代謝物濃度可能反映其塑化劑生產、使用量較高，而沙烏地阿拉伯較高之 MEP、MnBP、MiBP 濃度則可能與香水及個人護理用品中暴露有關。
生殖荷爾蒙濃度分布情形，根據臨床上之參考值評估受試者男性生殖荷爾蒙異常率，結果顯示受試者異常率如下：SHBG(11.5%)、FT (8.2%)、Testosterone (3.3%)、Bio-T (6.6%)、Androstenedione(24.6%)、5α-DHT (6.6%)、E1(24.6%)，上述項目的測值均為異常偏低；而 LH (1.6%)、 FSH (1.6%)、DHEA-S (1.6%)、E2 (9.8%)四者的的測值均為異常偏高。
進一步分析生殖荷爾蒙之相關性，LH、FSH 呈統計上顯著正相關(R=0.441,P<0.01)。Testosterone 與 SHBG、FT、Bio-T 三者為正相關(R=0.552, 0.738, 0.984, P<0.01)。Androstenedione 與 Testosterone 呈顯著正相關(R=0.446, P<0.01)。5α-DHT 與Testosterone、FT 呈顯著正相關(R=0.676, 0.532, P<0.01)；5α-DHT 也與 DHEA-S、Androstenedione 呈顯著正相關(R=0.386, 0.488, P<0.01)，根據上述相關性分析其大致符合生理學意義。
精液檢查結果依 WHO 2021 年之精液品質參數評估標準，本研究男性精液品質參數異常率依序如下：精液量(9.8%) 、濃度(11.4%) 、精子總數(14.7%) 、總活動力(34.4%)、前向運動(22.9%) 、非前向運動(14.7%) 、不活動(31.1%) 、正常形態率(31.1%)。在 61 位受試者中，有41 位精液品質異常，僅 20 位精液品質正常。
關於問卷資料分析，結果顯示有使用塑膠瓶冷藏或加熱的習慣者，尿中 MMP 濃度高於無此習慣者(5.9027 vs. 3.2919, P = 0.088)，MECPP 濃度亦呈現邊緣顯著升高的情形(9.2190 vs. 6.3399, P = 0.07)，而 MBzP 濃度在有此習慣者顯著高於無此習慣者(0.3748 vs. 0.2909, P = 0.027)。採樣前一天飲食容器使用塑膠容器之調查，僅 MiBP在有使用塑膠容器者的濃度，呈現邊緣顯著升高的趨勢(11.6480 vs. 9.8259, P = 0.097)。在紙杯裝熱飲的部分，有使用者其尿液中 MECPP 濃度(7.703 vs. 6.459, P = 0.048)與MINP 濃度(1.367 vs. 0.718, P = 0.004)呈現顯著較高的情形。在保麗龍杯裝冷飲的使用量，有此習慣者其尿液中多項特定代謝物濃度皆顯著高於無此習慣者，包括 MiBP濃度(21.066 vs. 9.81, P = 0.049)、MnBP 濃度(28.988 vs. 15.882, P = 0.039)、MEOHP濃度(5.344 vs. 3.47, P = 0.045)、MBzP 濃度(0.617 vs. 0.287, P = 0.028)以及 ΣDBPm(0.225 vs. 0.116, P = 0.020)。然其餘針對各類飲食攝取進行分析，大部分未發現與尿液中各項 PAEs 代謝物有顯著差異。
根據尿液中各PAEs 代謝物濃度以中位數區分為高低濃度組，進一步比較兩組間生殖荷爾蒙濃度之差異。結果顯示MMP、MIDP 高濃度組的 FSH/Inhibin B 有低於低濃度組之情形，呈邊緣顯著差異(p<0.1) ；而 MEP、MiBP、MnBP、MEHHP、MECPP、MEOHP 高濃度組於 FSH/Inhibin B 顯著低於低濃度組 (p<0.05)。此外， MEHHP、MEOHP 高濃度組的 FSH 濃度低於低濃度組，呈邊緣顯著差異(p<0.1)；而 MnBP、MECPP 高濃度組於FSH 顯著低於低濃度組(p<0.05)。以 MMP、%MEHP 濃度分為高低濃度組，結果顯示高濃度組的 INSL 3 較低濃度組低(4.98±4.36 vs.5.61±3.03)、(4.14±1.61 vs.6.46±4.88)，兩者分別呈現顯著差異(p<0.05)、邊緣顯著差異(p<0.1)。分析 PAEs 代謝物濃度與生殖荷爾蒙相關性，尿液中 MnBP、MEHHP、MECPP、MEHP、MINP、ΣDBPm 與 FSH 均呈現為負相關，進一步校正年齡、BMI 、吸菸、抽血季節、抽血時間等因子後進行線性迴歸分析發現，在 MECPP、MINP 與 FSH 呈負相關(P<0.01) 。本研究亦以 FSH/Inhibin B 的比值為指標，用以判斷 Sertoli cell 的功能，結果顯示，經校正年齡、BMI、吸菸、抽血季節、抽血時間等相關因子後進行迴歸分析，發現 MEP、MiBP、MnBP、MEHHP、MECPP、MEOHP、MBzP、MINP、ΣDEHPm 、ΣDBPm 、ΣmPAEs 皆與FSH/Inhibin B 呈現負相關(P<0.05)，可能會干擾 Sertoli cell 功能，進而影響後續精子生成作用。在精液品質部分，MMP與精子活動力、前向運動、前向運動-慢速前進呈現負相關(r = -0.240,-0.263, -0.256,P<0.05) ；而 MMP 與不活動精子、精子中段異常率呈正相關(r = 0.253, 0.393, P<0.05)。在校正年齡、BMI 和吸菸等因子後進行線性迴歸分析，然未達到統計上顯著相關，惟上述MMP 與精子活動力、前向運動、前向運動-慢速前進皆顯示呈現負相關；與不活動精子、精子中段異常率呈正相關，表示 MMP 濃度越高在精子活動力及運動能力、方向相對降低。此外，PAEs 濃度與INSL3 的關係，僅在%MEHP 中發現與INSL3 呈現邊緣顯著負相關(r = -0.219, P<0.1)，然校正年齡、BMI、吸菸和抽血季節等因子後進行線性迴歸分析，%MEHP 未達到統計上顯著相關，反而在MiBP、MEHHP、MEOHP、ΣDBPm 卻與INSL3 呈現正相關(P<0.05) ，相較於過去其他研究結果，大多發現PAEs代謝物與 INSL 3 呈現負相關，推測可能與樣本數較少、研究族群特性不同、PAEs 暴露濃度較低，以及個體 DEHP 代謝能力差異有關。
本研究結果顯示，PAEs 暴露可對男性體內生殖荷爾蒙濃度產生干擾，進而影響其睪丸之功能以及精子活動力等，後續仍需招募更多受試者，以釐清 PAEs 暴露對男性生殖荷爾蒙、INSL3 及精液品質之影響性。

The aim of the present study is to investigate the relationship between phthalate ester(PAEs) exposure, reproductive hormones, insulin-like factor 3 (INSL3), and semen quality in infertility male . PAEs are common environmental endocrine-disrupting chemicals found in personal care products, food packaging, toys, medical supplies, and building materials.Due to PAEs easily enter the human body through ingestion, inhalation, and skin contact, long-term daily exposure may affect male reproductive function.
This cross-sectional study recruited 61 infertile men. After signed inform consent, urine samples were collected to measure 12 PAEs metabolites and creatinine, blood samples were used to examine reproductive hormones and INSL3. Semen samples and questionnaire data were also collected. All the data were integrated to investigate the associations between PAEs metabolites, reproductive hormones, INSL3, and semen quality.
The results showed that MEP had the highest urinary concentration among PAEs metabolites, followed by MnBP, MECPP, and MEHHP. MEP、MiBP、MnBP、MEHHP、MECPP、MEOHP、ΣDEHPm 、ΣDBPm 、ΣmPAEs、MBzP、MEHP、MINP were negatively associated with FSH and the FSH/Inhibin B ratio(P<0.05), suggesting possible impairment of Sertoli cell function and spermatogenesis. In addition, MMP was negatively correlated with sperm motility and progressive motility, and positively correlated with immotile sperm(P<0.05).
PAEs exposure may interfere with male reproductive hormone levels, testicular function, and sperm motility. Further studies with larger sample sizes are needed to confirm the effects of PAEs exposure on male reproductive health.

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