塑化劑‐鄰苯二甲酸酯類化合物對秀麗隱桿線蟲之 毒性效應評估

Abstract

鄰苯二甲酸酯類化合物，俗稱塑化劑，係存在於環境中類似於環境賀爾蒙的物質，具有類似生物體內激素作用，可改變生物體內免疫、神經與內分泌系統之正常運作，對人類健康與生物造成危害。然而目前對於生物體暴露鄰苯二甲酸酯類之毒性效應及其機制的研究仍不完整，急需更進一步的探討，因此本研究利用活體模式生物－秀麗隱桿線蟲 (Caenorhabditis elegans) 探討鄰苯二甲酸酯類所誘導之發育毒性、生殖毒性與神經毒性，並探討可能的毒性機制。研究結果顯示，C. elegans暴露於特定濃度之鄰苯二甲酸酯類 (DEHP 、DBP及 DIBP) 會引起生殖缺陷與發育異常，並觀察到C. elegans的行為缺陷，包括身體彎曲、頭部擺動、倒轉頻率、趨化及趨熱行為的改變。在神經發育上，鄰苯二甲酸酯類會影響AFD及ASE感覺神經元螢光標記之轉殖C. elegans其神經元細胞體之fluorescent puncta的大小及強度，同時觀察到，暴露於DEHP會導致AFD神經分化相關之TTX-1、 TAX-2、 TAX-4、 CEH-14及ASE神經分化相關之CHE-1、TAX-2、 TAX-4的mRNA表現量下降。我們也發現，C. elegans暴露於特定之鄰苯二甲酸酯類，細胞內之活性氧Reactive oxygen species (ROS) 含量提高，若先將C. elegans暴露於‐抗氧化劑Ascorbic acid ，則可顯著地修復鄰苯二甲酸酯類所誘導之神經毒性效應，因此，推測鄰苯二甲酸酯類對C. elegans造成之神經毒性，氧化壓力扮演重要的關鍵角色。

Phthalate esters, also called plasticizer, are ubiquitous endocrine disrupting chemicals (EDCs) in the environment. They may have adverse consequences for human and ecosystem. Considering the critical, but limited, researches on human neurobehavioral and other healthy outcomes in association with phthalate exposure, we used the nematode Caenorhabditis elegans as an in vivo model to evaluate phthalates-induced developmental toxicity, reproductive toxicity, neurotoxicity, and the possible associated mechanisms. The results showed that exposure to phthalates (DEHP, DBP, and DIBP) at the examined concentrations induced reproductive defects and developmental abnormality. Moreover, exposure to phthalates (DEHP, DBP, and DIBP) at the examined concentrations induced behavioral defects, including changes in body bending, head thrashing, reversal frequency, chemotaxis, and thermotaxis. Furthermore, phthalate (DEHP, DBP, and DIBP) exposure caused toxicity, affecting the relative sizes of cell body fluorescent puncta, and relative intensities of cell bodies in AFD and ASE neurons. The mRNA levels of the majority of the genes (TTX-1, TAX-2, TAX-4, and CEH-14) that are required for the differentiation and function of AFD neurons and the majority of the genes (CHE-1, TAX-2, TAX-4) that are required for the differentiation and function of ASE neurons were both decreased upon DEHP exposure.Moreover, phthalate (DEHP, DBP, and DIBP) exposure at the examined concentrations produced elevated intracellular reactive oxygen species (ROS) in C. elegans. Finally, pretreatment of worms with the antioxidant ascorbic acid significantly ameliorated phthalates-induced neurotoxicity. Our study suggests that oxidative stress may play a critical role in initiating the phthalate ester-induced neurotoxic effects in C. elegans.