Khan I A, Thomas P
The University of Texas at Austin, Marine Science Institute, Port Aransas, Texas 78373, USA.
Biol Reprod. 2001 Mar;64(3):955-64. doi: 10.1095/biolreprod64.3.955.
Mechanisms governing the effect of polychlorinated biphenyl (PCB) toxicity on hypothalamic serotonergic function and the neuroendocrine system controlling LH secretion were investigated in Atlantic croaker (Micropogonias unulatus) exposed to the PCB mixture Aroclor 1254 (1 microg x g body weight(-1) x day(-1)) in the diet for 30 days. PCB treatment caused a decrease in hypothalamic 5-hydroxytryptamine (5-HT) concentrations and significant inhibition of hypothalamic tryptophan hydroxylase (TPH), the rate-limiting enzyme in 5-HT synthesis, but did not alter the activity of monoamine oxidase, the catabolic enzyme. Further, PCB treatment caused significant decreases in GnRH content in the preoptic-anterior hypothalamic area. Significant decreases in pituitary GnRH receptor concentrations and the LH response to the GnRH analogue (GnRHa) were also observed in PCB-exposed fish, possibly as a consequence of a decline in GnRH release. The possible association between impaired serotonergic and neuroendocrine functions after PCB treatment was explored using serotonergic drugs. Treatment of croaker with p-chlorophenylalanine, an irreversible TPH inhibitor, mimicked the effects of PCB on the GnRH system and the LH response to GnRHa. Bypassing the TPH-dependent hydroxylation step with the administration of 5-hydroxytryptophan restored 5-HT to control levels and prevented the deleterious effects of PCB on the neuroendocrine parameters. Moreover, slow-release GnRH implants prevented the PCB-induced decline in GnRH receptors and restored the LH response to GnRHa, suggesting that GnRH therapy can reverse PCB-induced disruption of LH secretion. These results demonstrate that TPH is one of the targets of PCB neurotoxicity and indicate that a decrease in 5-HT availability in PCB-exposed croaker results in disruption of the stimulatory 5-HT/GnRH pathway controlling LH secretion.
研究了多氯联苯（PCB）毒性对下丘脑5-羟色胺能功能以及控制促黄体生成素（LH）分泌的神经内分泌系统的影响机制，实验用大西洋鲳（Micropogonias unulatus），在饲料中添加PCB混合物Aroclor 1254（1微克×克体重-1×天-1），持续投喂30天。PCB处理导致下丘脑5-羟色胺（5-HT）浓度降低，并显著抑制下丘脑色氨酸羟化酶（TPH），即5-HT合成中的限速酶，但未改变分解代谢酶单胺氧化酶的活性。此外，PCB处理导致视前区-下丘脑前部GnRH含量显著降低。在暴露于PCB的鱼中还观察到垂体GnRH受体浓度和LH对GnRH类似物（GnRHa）反应的显著降低，这可能是GnRH释放减少的结果。使用5-羟色胺能药物探讨了PCB处理后5-羟色胺能和神经内分泌功能受损之间的可能关联。用不可逆TPH抑制剂对氯苯丙氨酸处理鲳鱼，模拟了PCB对GnRH系统和LH对GnRHa反应的影响。通过给予5-羟色氨酸绕过TPH依赖的羟化步骤，使5-HT恢复到对照水平，并防止了PCB对神经内分泌参数的有害影响。此外，缓释GnRH植入物可防止PCB诱导的GnRH受体下降，并恢复LH对GnRHa的反应，表明GnRH疗法可逆转PCB诱导的LH分泌紊乱。这些结果表明TPH是PCB神经毒性的靶点之一，并表明暴露于PCB的鲳鱼中5-HT可用性的降低导致控制LH分泌的刺激性5-HT/GnRH途径的破坏。
