Martin-Diaz Laura, Franzellitti Silvia, Buratti Sara, Valbonesi Paola, Capuzzo Antonio, Fabbri Elena
University of Cadiz, Department of Physical Chemistry, Polígono Río San Pedro s/n, 11510 Puerto Real, Spain.
Aquat Toxicol. 2009 Sep 14;94(3):177-85. doi: 10.1016/j.aquatox.2009.06.015. Epub 2009 Jul 7.
Pharmaceuticals represent a diverse collection of thousands of bioactive chemicals used in human and veterinary medicine. The increased consumption, together with the recent development of more sensitive analytical techniques, has identified these as emerging contaminants in the aquatic environment. According to many investigations pharmaceuticals do not cause acute toxic effects in organisms when released in the environment. However, many independent studies agree that chronic exposure and more specific endpoints should be used in risk assessment of these compounds. We thus investigated the effects of exposure to environmentally relevant concentrations of the antiepileptic drug carbamazepine (CBZ) on Mediterranean mussels (Mytilus galloprovincialis) by considering the existing knowledge about the therapeutic and side effects of this drug on humans. To do so we analysed: (a) six consolidated biomarkers related primarily to oxidative stress; (b) cAMP levels and protein kinase A (PKA) activities; (c) mRNA expression of MXR-related genes. MXR proteins are involved both in the cAMP pathway and in the protective response of organisms towards xenobiotics. Mussels exposed to 0.1 or 10microg CBZ per liter water for 7 days showed a 60% and 80% reduction in haemocyte lysosome membrane stability, respectively. Moreover, increased neutral lipid and lipofuscin accumulation in the digestive gland, and lipid peroxidation in gills and mantle/gonads were observed. Also glutathione S-tranferase and catalase activities were increased in digestive gland and mantle, while no increase in primary DNA damage was observed. In agreement with the mode of action of CBZ in humans, exposure resulted in a significant reduction in cAMP levels and PKA activities in digestive gland, gills and mantle/gonads of mussels, and lowered the mRNA expression of genes encoding three different MXR-related transporters in the same tissues. Our data indicate that CBZ, at concentrations found in the environment, affects the Mediterranean mussel by acting on specific biochemical pathways that are evolutionarily conserved.
药物是用于人类和兽医学的数千种生物活性化学物质的多样化集合。随着消费量的增加，以及最近更灵敏分析技术的发展，这些物质已被确定为水环境中的新兴污染物。根据许多调查，药物在环境中释放时不会对生物体造成急性毒性作用。然而，许多独立研究一致认为，在这些化合物的风险评估中应采用慢性暴露和更具体的终点指标。因此，我们通过考虑关于这种药物对人类的治疗作用和副作用的现有知识，研究了暴露于环境相关浓度的抗癫痫药物卡马西平（CBZ）对地中海贻贝（Mytilus galloprovincialis）的影响。为此，我们分析了：（a）六个主要与氧化应激相关的成熟生物标志物；（b）环磷酸腺苷（cAMP）水平和蛋白激酶A（PKA）活性；（c）多药耐药相关基因的mRNA表达。多药耐药蛋白既参与cAMP途径，也参与生物体对外源生物的保护反应。暴露于每升水0.1或10微克CBZ 7天的贻贝，其血细胞溶酶体膜稳定性分别降低了60%和80%。此外，观察到消化腺中中性脂质和脂褐素积累增加，鳃和外套膜/性腺中脂质过氧化增加。消化腺和外套膜中的谷胱甘肽S-转移酶和过氧化氢酶活性也增加，而未观察到原发性DNA损伤增加。与CBZ在人类中的作用方式一致，暴露导致贻贝消化腺、鳃和外套膜/性腺中的cAMP水平和PKA活性显著降低，并降低了同一组织中编码三种不同多药耐药相关转运蛋白的基因的mRNA表达。我们的数据表明，环境中发现的浓度的CBZ通过作用于进化上保守的特定生化途径来影响地中海贻贝。
