diclofenac and naproxen at 0.1, 1, 10, 100, and 1,000 μg/L throughout the developmental period. Morphological endpoints were associated with significantly altered
levels of hepatic triglycerides, which in turn were correlated with increased peroxidase activity at the highest concentration (1,000 μg/L) [49]. On the other hand,
Veldhoen et al. [50] assessed the ability of sub-lethal and environmentally relevant
concentrations (13.7 μg/L) of ibuprofen to function as a disruptor of endocrinemediated post-embryonic development of the Rana catesbeiana tadpoles; the results
indicated that the exposure caused subsequent disruption of thyroid hormonemediated reprogramming in the liver transcriptome affecting constituents of several
metabolic, developmental, and signaling pathways and raised the possibility that
ibuprofen may alter the post-embryonic development of anuran species in freshwater
environs [50].
Studies about the metabolism of ibuprofen were carried out by Jones and collaborators, in 2012, through the exposition of zebrafish larvae to 100 μg/L of ibuprofen;
the results provide strong evidence that zebrafish larvae can metabolize and excrete
ibuprofen in a manner known to be cytochrome P450-dependent in mammals
[51]. Exposure of trout fry to a range of salicylate or ibuprofen concentrations
(1, 10, 100, or 1,000 μ/L) for 4 d caused an increment on heat-shock protein
70 (mRNA and protein levels), in the liver; also, liver glucose levels and the
activities of hexokinase, pyruvate kinase, and lactate dehydrogenase were elevated
by NSAIDs suggesting enhanced tissue glycolytic capacity [24].
Due to the fact that paracetamol induces oxidative stress in mammals, Bebianno
et al. [52] evaluated if similar effects were observed in oysters Crassostrea gigas,
through the exposition for 1, 4, and 7 days to two different sub-lethal concentrations
(0.1 and 100 μg/L). The results showed that no changes in cell viability and DNA
damage were observed in oysters exposed to both concentrations. Similarly, no
significant changes were detected in the major antioxidant enzymes (except for
glutathione reductase) in oyster gills, suggesting that changes in glutathione reductase activity are enough to counteract a potential oxidative stress in C. gigas gills
under these experimental conditions [52]. On the other hand, the ecotoxicity of
naproxen in aquatic organisms is limited primarily to acute lethal effects. In 2018,
Kwak and colleagues demonstrated that the chronic no observed effect concentrations (NOECs) of naproxen for reproduction were determined to be 10 mg/L in
Daphnia magna and 0.3 mg/L in Moina macrocopa. At concentrations of 0.5 mg/L,
the survival of juvenile medaka fish was significantly decreased and transcription of
erβ2 gene was significantly increased [53].
Finally, the evaluation of a drug mix composed of different medication classes
(antibiotic, NSAIDs, antidepressant, anxiolytic, analgesic, and antacid drugs), at
environmentally relevant concentrations, was carried out by do Amaral et al. [54]
in Lithobates casteibeianus tadpoles, finding that drug mix promoted changes in
mandibular sheath pigmentation, dentition, and swimming activity, as well as
atypical behavior in the social aggregation test; besides, the mutagenic analysis
revealed higher frequency of nuclear abnormalities in the erythrocytes of tadpoles
that were exposed [54].
Overview of Non-steroidal Anti-inflammatory Drugs as Emerging Contaminants
49
levels of hepatic triglycerides, which in turn were correlated with increased peroxidase activity at the highest concentration (1,000 μg/L) [49]. On the other hand,
Veldhoen et al. [50] assessed the ability of sub-lethal and environmentally relevant
concentrations (13.7 μg/L) of ibuprofen to function as a disruptor of endocrinemediated post-embryonic development of the Rana catesbeiana tadpoles; the results
indicated that the exposure caused subsequent disruption of thyroid hormonemediated reprogramming in the liver transcriptome affecting constituents of several
metabolic, developmental, and signaling pathways and raised the possibility that
ibuprofen may alter the post-embryonic development of anuran species in freshwater
environs [50].
Studies about the metabolism of ibuprofen were carried out by Jones and collaborators, in 2012, through the exposition of zebrafish larvae to 100 μg/L of ibuprofen;
the results provide strong evidence that zebrafish larvae can metabolize and excrete
ibuprofen in a manner known to be cytochrome P450-dependent in mammals
[51]. Exposure of trout fry to a range of salicylate or ibuprofen concentrations
(1, 10, 100, or 1,000 μ/L) for 4 d caused an increment on heat-shock protein
70 (mRNA and protein levels), in the liver; also, liver glucose levels and the
activities of hexokinase, pyruvate kinase, and lactate dehydrogenase were elevated
by NSAIDs suggesting enhanced tissue glycolytic capacity [24].
Due to the fact that paracetamol induces oxidative stress in mammals, Bebianno
et al. [52] evaluated if similar effects were observed in oysters Crassostrea gigas,
through the exposition for 1, 4, and 7 days to two different sub-lethal concentrations
(0.1 and 100 μg/L). The results showed that no changes in cell viability and DNA
damage were observed in oysters exposed to both concentrations. Similarly, no
significant changes were detected in the major antioxidant enzymes (except for
glutathione reductase) in oyster gills, suggesting that changes in glutathione reductase activity are enough to counteract a potential oxidative stress in C. gigas gills
under these experimental conditions [52]. On the other hand, the ecotoxicity of
naproxen in aquatic organisms is limited primarily to acute lethal effects. In 2018,
Kwak and colleagues demonstrated that the chronic no observed effect concentrations (NOECs) of naproxen for reproduction were determined to be 10 mg/L in
Daphnia magna and 0.3 mg/L in Moina macrocopa. At concentrations of 0.5 mg/L,
the survival of juvenile medaka fish was significantly decreased and transcription of
erβ2 gene was significantly increased [53].
Finally, the evaluation of a drug mix composed of different medication classes
(antibiotic, NSAIDs, antidepressant, anxiolytic, analgesic, and antacid drugs), at
environmentally relevant concentrations, was carried out by do Amaral et al. [54]
in Lithobates casteibeianus tadpoles, finding that drug mix promoted changes in
mandibular sheath pigmentation, dentition, and swimming activity, as well as
atypical behavior in the social aggregation test; besides, the mutagenic analysis
revealed higher frequency of nuclear abnormalities in the erythrocytes of tadpoles
that were exposed [54].
Overview of Non-steroidal Anti-inflammatory Drugs as Emerging Contaminants
49