Sharma Rashmi, Kodavanti Prasada Rao S
National Research Council, National Academy of Sciences, Washington, DC, USA.
Toxicol Appl Pharmacol. 2002 Feb 1;178(3):127-36. doi: 10.1006/taap.2001.9328.
Nitric oxide synthases (NOS) play a key role in motor activity in the cerebellum, hormonal regulation in the hypothalamus, and long-term potentiation (LTP), learning, and memory processes in the hippocampus. Developmental exposure to polychlorinated biphenyls (PCBs) has been shown to affect psychomotor functions, learning and memory processes, and to inhibit LTP. We hypothesized that PCBs may disrupt the regulation of such neurological functions by altering NOSs. We have studied the in vitro effects of several PCB congeners and some hydroxy PCBs on NOS activity in cytosolic (presumably neuronal NOS [nNOS]) and membrane (presumably endothelial NOS [eNOS]) fractions in different brain regions of young and adult rats. Among the two selected dichloro PCBs, the ortho-PCB, 2,2'-dichlorobiphenyl (DCB), inhibited both cytosolic and membrane NOS activity at low micromolar concentrations (3-10 microM) in the selected brain regions of all age groups while the non-ortho-PCB, 4,4'-DCB, did not. 2,2'-DCB inhibited cytosolic NOS to a greater extent than membrane NOS. Pentachloro-PCBs (PeCBs) and hexachloro-PCBs (HCBs) did not have a significant effect on adult cerebellar cytosolic or membrane NOS. However, mono- and dihydroxy derivatives of HCBs significantly decreased cytosolic NOS (IC50s: 16.33 +/- 0.47 and 33.65 +/- 4.33 microM, respectively) but resulted in a marginal effect on membrane NOS in the cerebellum. Among three adult rat brain regions, the hypothalamic cytosolic NOS was the most sensitive to 2,2'-DCB. Also, cytosolic NOS in the cerebellum and hypothalamus of young rats was less sensitive than in the older rats. In summary, these results indicate that only di-ortho-PCB inhibited both NOS and hydroxy substitution of one or more chlorine molecules significantly increased the potency of both ortho- and non-ortho-HCBs. The selective sensitivity of NOS to dichloro- ortho-PCB and hydroxy metabolites suggests that the inhibition of NOS could play a role in the neuroendocrine effects as well as learning and memory deficits caused by exposure to PCBs.
一氧化氮合酶（NOS）在小脑的运动活动、下丘脑的激素调节以及海马体的长时程增强（LTP）、学习和记忆过程中发挥着关键作用。已表明，发育期接触多氯联苯（PCBs）会影响精神运动功能、学习和记忆过程，并抑制LTP。我们推测，PCBs可能通过改变NOS来扰乱此类神经功能的调节。我们研究了几种PCB同系物和一些羟基PCB对幼年和成年大鼠不同脑区胞质（可能是神经元型NOS [nNOS]）和膜（可能是内皮型NOS [eNOS]）部分中NOS活性的体外影响。在所选的两种二氯PCB中，邻位PCB，即2,2'-二氯联苯（DCB），在所有年龄组的所选脑区中，在低微摩尔浓度（3 - 10 microM）下均抑制胞质和膜NOS活性，而非邻位PCB，4,4'-DCB则无此作用。2,2'-DCB对胞质NOS的抑制作用比对膜NOS的抑制作用更大。五氯PCB（PeCBs）和六氯PCB（HCBs）对成年小脑的胞质或膜NOS没有显著影响。然而，HCBs的单羟基和二羟基衍生物显著降低了胞质NOS（IC50分别为：16.33 ± 0.47和33.65 ± 4.33 microM），但对小脑的膜NOS产生了轻微影响。在成年大鼠的三个脑区中，下丘脑胞质NOS对2,2'-DCB最为敏感。此外，幼年大鼠小脑和下丘脑的胞质NOS比老年大鼠的敏感性更低。总之，这些结果表明，只有邻位二氯PCB抑制了NOS，并且一个或多个氯分子的羟基取代显著增加了邻位和非邻位HCBs的效力。NOS对二氯邻位PCB和羟基代谢物的选择性敏感性表明，NOS的抑制可能在接触PCBs引起的神经内分泌效应以及学习和记忆缺陷中起作用。
