Ladefoged O, Lam H R, Ostergaard G, Hansen E V, Hass U, Lund S P, Simonsen L
Institute of Food Safety and Toxicology, Danish Veterinary and Food Administration, Søborg.
Neurotoxicology. 1998 Aug-Oct;19(4-5):721-37.
Male Wistar rats were dosed with 0, 1250, 3750 or 5000 mg/l of phenylglyoxylic acid (PGA) (CAS no. 611-73-4) in the drinking water ad libitum for 3 months. During the entire treatment period, there were no gross signs of toxicity related to PGA. No changes in neurobehavior were found after using a functional observational battery or radial arm maze. An increased relative kidney weight was seen in the highest dose-group (Controls: 0.504 +/- 0.031 g/100 g b.wt.; 5000 mg PGA/l: 0.579 +/- 0.033 g/100 g b.wt.; p<0.01). No other organ weights were affected. Histopathology revealed no change in kidney structure. No changes in clinical biochemistry. In the highest dose-group three animals out of ten showed reduction in peripheral nerve myelin sheath thickness. No such changes were seen in the control group. The study revealed no changes in auditory brain stem response but minor changes in electroretinography. The noradrenaline (NA) concentration decreased in pons and thalamus whereas it increased in medulla oblongata and whole brain. The dopamine (DA) concentration increased in cerebellum, hippocampus, pons, and whole brain. The most marked DA increase was seen in hippocampus (Controls: 0.56 +/- 0.10 nmol/g tissue; 5000 mg/l: 1.04 +/- 0.11 nmol/g tissue; p<0.001). The 5-hydroxytryptamine (5-HT) concentration decreased in cerebellum, cerebral cortex, hippocampus, and medulla oblongata, whereas it increased in thalamus. The yield of synaptosomal protein, synaptosomal NA, DA, and 5-HT concentrations, and DA uptake rate were not affected. When dosed males were mated with naive females, there were no differences between groups in the pregnancy rate, number of corpora luteae, implantations, live or dead fetuses, resorptions, preimplantation loss, or postimplantation loss. It is concluded that a part of the effects on kidney, peripheral nerves, and vision, which have previously been reported after exposure to styrene, might be induced by the styrene metabolite, PGA. If PGA has ototoxic effects in rats, the dosing in the present study is not sufficient to induce the necessary ototoxic concentration in blood. Alternatively, the ototoxicity of styrene, like toluene, may be caused the parent compound itself and not by a metabolite like PGA.
将雄性Wistar大鼠随意饮用含0、1250、3750或5000mg/L苯甲酰甲酸（PGA）（化学物质登记号：611 - 73 - 4）的饮用水3个月。在整个治疗期间，未发现与PGA相关的明显毒性迹象。使用功能观察组合或放射状臂迷宫后，未发现神经行为有变化。最高剂量组的相对肾重增加（对照组：0.504±0.031g/100g体重；5000mg PGA/L组：0.579±0.033g/100g体重；p<0.01）。其他器官重量未受影响。组织病理学检查显示肾脏结构无变化。临床生化指标无变化。最高剂量组的十只动物中有三只出现外周神经髓鞘厚度降低，对照组未出现此类变化。该研究显示听性脑干反应无变化，但视网膜电图有轻微变化。去甲肾上腺素（NA）浓度在脑桥和丘脑降低，而在延髓和全脑升高。多巴胺（DA）浓度在小脑、海马、脑桥和全脑升高。海马中DA升高最为明显（对照组：0.56±0.10nmol/g组织；5000mg/L组：1.04±0.11nmol/g组织；p<0.001）。5 - 羟色胺（5 - HT）浓度在小脑、大脑皮层、海马和延髓降低，而在丘脑中升高。突触体蛋白产量、突触体NA、DA和5 - HT浓度以及DA摄取率未受影响。当给药的雄性大鼠与未接触过药物的雌性大鼠交配时，各组在妊娠率、黄体数、着床数、活胎或死胎数、吸收数、着床前损失或着床后损失方面无差异。得出的结论是，先前报道的接触苯乙烯后对肾脏、外周神经和视觉的部分影响可能由苯乙烯代谢产物PGA诱导。如果PGA对大鼠有耳毒性作用，本研究中的给药剂量不足以在血液中诱导出必要的耳毒性浓度。或者，苯乙烯的耳毒性可能像甲苯一样，是由母体化合物本身引起的，而不是由像PGA这样的代谢产物引起的。
