研究顯示鄰苯二甲酸酯透過抗雄性激素及弱雌激素作用影響雄性動物生殖功能（包括生殖荷爾蒙調控及精子生成），然而是否同樣影響人類男性生殖，目前尚無定論且鮮少研究探討其影響機制。本研究同時探討尿液及精液中鄰苯二甲酸酯代謝物與男性成人生殖荷爾蒙調控、類胰島素因子-3與精液品質之相關性與可能機制。2010至2014年自南部地區不孕門診招募253位不孕夫妻之男性配偶及媽媽教室招募37位懷孕夫妻之男性配偶為研究族群，簽署同意書後，收集其尿液、血液及精液樣本，樣本採集與保存時均以玻璃容器進行，隨後分析血漿中類胰島素因子-3、血清中生殖荷爾蒙濃度、精液品質及11種尿液中與精液中鄰苯二甲酸酯代謝物濃度。精液與尿液中鄰苯二甲酸乙酯（MEP）及鄰苯二甲酸二(2-乙基己基)酯（DEHP）代謝物分布具顯著相關。校正干擾因子後，尿中鄰苯二甲酸酯代謝物增加，與睪固酮（DEHP代謝物）、睪固酮與促黃體生成素比值（DEHP代謝物）、類胰島素因子-3（鄰苯二甲酸苯甲酯[MBzP]、鄰苯二甲酸己基乙酯[MEHP]及MEHP%）、精子濃度（MBzP、MEHP及MEHP%）、精子活動力（MBzP及MEHP）及正常型態精子（MEHP%）成顯著負相關；然而與雌二醇（DEHP代謝物）、雌二醇與睪固酮比值（鄰苯二甲酸甲酯[MMP]、MEP及DEHP代謝物）及性激素結合球蛋白（DEHP代謝物）成顯著正相關（all p<0.05）。同樣校正干擾因子後，精液中鄰苯二甲酸酯代謝物增加，則與促黃體生成素（MEHP）、性激素結合球蛋白（MEHP）、抑制素B（MBzP）、雌二醇與睪固酮比值（鄰苯乙基氫氧己基酯）成顯著正相關；然而與抑制素B與促卵泡激素比值（鄰苯二甲酸異丁酯及鄰苯羧基乙基戊基酯）、精子濃度（MMP及DEHP代謝物）、精子活動力（MEP及DEHP代謝物）、正常型態精子（MEP）及類胰島素因子-3（MMP及MEP）成顯著負相關（all p<0.05）。而精液量、精子濃度及活動力會隨類胰島素因子-3成顯著正相關（all ptrend< 0.001）。因此本研究證實鄰苯二甲酸酯暴露（如鄰苯二甲酸丁基苯酯及DEHP）增加時，確實會干擾類胰島素因子-3表現及生殖荷爾蒙平衡（尤其是睪固酮及雌二醇），也同時影響精子生成及品質。本研究結果提供目前探討內分泌干擾物質對男性成人生殖功能影響機制更進一步的證據。

Certain phthalates have adverse effects on male reproductive functions in animals, and they potentially affect human testicular function, including steroidogenesis and spermatogenesis, but the results debated yet and little is known about the active mechanisms in adult males. We measured the biomarkers of phthalate exposures and explored the associations between reproductive hormones balance, insulin-like factor 3 (INSL3) secretion and semen quality in adult men. Urine, blood, and semen samples were collected from the male partners of infertile (n = 253) and fertile (n = 37) couples who presented to a reproductive center in southern Taiwan between 2010 and 2014. Plasma levels of INSL3, reproductive hormones, semen-quality parameters, and 11 phthalate metabolites in urine and semen were measured. There were significant correlations in the distribution pattern of phthalate metabolites (mono-ethyl phthalate [MEP] and di-2-ethylhexyl phthalate [DEHP] metabolites) in urine and semen. In adjusted regression models, increases in urinary phthalate metabolites levels were adversely associated with TT (DEHP metabolites), the TT: LH ratio (DEHP metabolites), INSL3 (monobenzyl phthalate [MBzP], mono-2-ethylhexyl phthalate [MEHP] and MEHP%), sperm concentration (MBzP, MEHP and MEHP%) , motility (MBzP and MEHP) and normal morphology (MEHP%); but were positively associated with estradiol (E2, DEHP metabolites), the E2: TT ratio (mono-methyl phthalate [MMP], MEP and DEHP metabolites) and SHBG (DEHP metabolites) (all p < 0.05). Higher seminal phthalate metabolite levels were associated with increases in LH (MEHP), SHBG (Mono-2-ethyl-5-hydroxyhexyl phthalate), inhibin B (MBzP) and the E2: TT ratio (MEHHP) as well as decreases in the Inhibin B: FSH ratio (mono-iso-butyl phthalate and mono-2-ethyl-5-carboxypentyl phthalate), sperm concentration (MMP and DEHP metabolites), motility (MEP and DEHP metabolites), normal morphology (MEP) and INSL3 (MMP and MEP) (all p< 0.05).The significant and monotonic trends in semen volume, sperm concentration, and sperm motility were also associated with increasing quartiles of INSL3 levels (all Ptrend< 0.001). Our data suggest that INSL3 secretion, reproductive hormone balance (especially TT and E2), and sperm production and quality might be simultaneously adversely affected in individuals excreting increasing levels of phthalates metabolites (especially butyl benzyl phthalate and DEHP) in urine and semen samples. Therefore, our findings support the need for additional research on the reproductive effects of endocrine disruptors in adult males.

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