Reproductive toxicity of endocrine-disrupting chemicals and the mechanism via peroxisome proliferators-activated receptor in relation to the risk assessment

邻苯二甲酸酯是一种典型的增塑剂，最近被认为是一种干扰内分泌的化学物质。这些化学物质被称为过氧化物酶体增殖物激活受体a （PPARα）的配体。采用相同遗传背景的野生型Sv/129小鼠和ppar α-缺失小鼠，研究邻苯二甲酸二（2-乙基己基）酯（DEHP）的生殖毒性及其作用机制。用市售鼠粮配制0.05% DEHP日粮。DEHP处理增加了野生型小鼠的胎儿分辨率和每对新生幼仔的死亡率，但在ppar α-缺失小鼠中没有。尽管雄性小鼠血清中PPARα与睾酮水平相关，但DEHP也降低了野生型小鼠血清中PPARα-缺失小鼠血清中的睾酮水平。提示DEHP的生殖作用及对血清睾酮水平的影响与PPARα的表达密切相关。邻苯二甲酸酯诱导PPARα依赖于脂溶性。2,4-二氯苯氧乙酸是一种除草剂，可诱导雄性小鼠PPARα并降低睾酮水平，其部分原因是下调胆固醇合成酶。我们还测量了16个人的膳食（包括咖啡或茶）中DEHP的浓度，然后计算出每天的总摄入量。所有样品均检出DEHP，浓度水平为30 ~ 370ug/kg，平均为124ug/kg，估计为70 ~ 1200ug/d（平均320ug/d）。

Phthalic acid esters are typical plasticizer, which is recently noted as an endocrine-disrupting chemical. These chemicals are known as a ligand to peroxisome proliferators-activated receptor a (PPARα). Reproductive toxicity of di(2-ethylhexyl) phthalate (DEHP) and the mechanism were investigated using wild-type Sv/129 mice and PPARα-null mice on the same genetic background. A 0.05% DEHP diet was prepared with commercial rodent chow. DEHP treatment increased the resolution of fetus and mortality of new born pups per pair in wild-type mice, but not in the PPARα-null mice. Although PPARα was related to testosterone level in serum of male mice, DEHP also decreased the level in wild-type mice, not in the PPARα-null mice. These results suggest that the reproductive effect of DEHP and effect on testosterone level in serum are closely related to the expression of PPARα. Phthalic acid esters other than DEHP induced PPARα dependently on the lipid solubility. 2,4-Dichlorophenoxyacetic acid, one of herbicides, induced PPARα and decreased testosterone level in male mice, which is due, in part, to downregulate cholesterol-synthetic enzymes.We also measured DEHP concentration in meals including coffee or tea of 16 persons, and then calculated the total intake per day. DEHP was found in all samples, and the concentration levels were 30〜370ug/kg, and the average was 124ug/kg, which was estimated at 70〜1200ug/day (average 320ug/day).