6.1 Ag concentrations of cetacean liver and kidney tissues estimated by cetacean histological Ag assay (CHAA)
The CHAA was developed based on the autometallography (AMG) positivity values and regression model, which is statistically validated by the extra sum-of-squares F test and Akaike's information criterion. The adjusted R2 of the CHAA for livers (0.74) and kidneys (0.69) indicates that most of the response is attributed to Ag concentration, but some undetermined factors still influence the CHAA for the liver and kidney tissues of cetaceans. Possible factors influencing the accuracy and precision of CHAA for the liver and kidney tissues of cetaceans are animal species (i.e. different animal species have different habitats, prey, and physiological characteristics) and relatively small sample size with known Ag concentrations determined by ICP-MS. If the sample sizes for each animal species and samples with known Ag concentrations are large enough, a more accurate model for estimating the Ag concentration can be developed for each cetacean species.
The tissues of cetaceans in this study were from 7 different species that have different habitats and prey, but no significant difference in Ag concentrations between different cetacean species was found, suggesting that the Ag contamination may have existed in all aspects of the marine ecosystem. Furthermore, our results suggest that Ag contamination is more severe in cetaceans living in the North-western Pacific Ocean than in cetaceans living in other marine regions of the world and may have caused detrimental effects on their health condition. Therefore, it is necessary to raise the public awareness and encourage more studies on the issue of Ag contamination.
6.2 Metabolic pathway of Ag in cetaceans
The AMG positive signals were variably sized brown to black granules in the cytoplasm of proximal renal tubular epithelium, hepatocytes, and Kupffer cells.
Occasionally, amorphous golden yellow to brown AMG positive signals were noted in the lumen and basement membrane of some proximal renal tubules. In contrast, AMG positive signals were commonly found in the basement membranes of various tissues in rats exposed to AgNPs (60 nm in diameter) or silver lactate (Danscher, 1981; Kim et al., 2009b), suggesting that the metabolic profile of Ag in cetaceans may be different from that in laboratory rats. The underlying mechanisms that cause the different metabolic profile of Ag in cetaceans are still undetermined, but several possibilities should be considered, including 1) cetaceans may have different physiological characteristics, such as different composition of the basement membrane, 2) cetaceans may be exposed to different types/concentration/time period of Ag/Ag compounds, 3) cetaceans may be exposed to varieties of contaminants; thus, the interactions between Ag and other contaminants may affect the process of Ag deposition. The current study has found a significant age-dependent increase in the Ag concentration of cetacean liver and kidney tissue, and it is suggested that the Ag deposition in cetaceans aggravates with time, and thus the source of Ag deposition is most likely from their prey. Considering the relatively high Ag concentrations in the liver rather than kidney, it is presumed that the liver is the main storage organ for Ag/Ag compounds, but the kidneys may be a transit station for the metabolism of Ag/Ag compounds in cetaceans (or just means that majority of the uptaken Ag/Ag compounds will store in the liver while only a small proportion will excrete from kidney prior to reaching the limit of liver storage capacity). The presumptive metabolic pathway of Ag in cetaceans is illustrated in Chapter 2, figure 5. However, a more comprehensive investigation by AMG method to determine the Ag distribution in cetaceans is warranted.
6.3 Histopathological lesions possibly caused by the Ag in cetaceans
In our study, Ag concentrations of the liver (kidney) tissues in approximate 50%
(30%) of the individuals were higher than the unhealthy Ag concentration, but no statistically significant correlation between the observed lesions and the Ag concentrations were noted in the liver and kidney tissues. This finding suggests that the toxicity caused by Ag, as non-essential/non-toxic metals, may be different from other non-essential toxic metals, which are usually organ targeting, such as the neurotoxicity caused by mercury and renal toxicity caused by cadmium. In other words, the negative health effects caused by Ag in cetaceans may be systemic rather than organ targeting.
Therefore, the negative health effects caused by Ag in cetaceans should be further investigated.
6.4 The immunotoxicity of AgNPs on the leukocytes of cetaceans
Only one study on the functional activity of human leukocytes exposed to AgNPs was reported, and it revealed that functional activity was not affected by AgNPs (Haase et al., 2014). However, our study demonstrated that AgNPs at the sub-lethal doses (0.1 and 1 μg/ml) could negatively affect the functional activities of cPMNs (phagocytosis and respiratory burst) and cPBMCs (proliferative activity) and induce Th2 cytokine bias of cPBMCs. Comparing to previous human studies, our results suggest that the leukocytes of cetaceans are more vulnerable than those of humans to the negative effects of AgNPs.
This result also reminds us of “when we constantly generate new substances for our convenience as humans, these new substances may have negative health impacts on the environment and wildlife”. Furthermore, the immunotoxicity caused by AgNPs found in the present study is an important warning signal for human medicine. There are many studies on the application of AgNPs (as adjuvant for chemotherapy and target therapy) for the cancer therapy. Therefore, our study not only benefits the environmental medicine/conservation but also reminds human medicine of the possible negative health effects of AgNPs. The in vitro toxicity test by using cetacean leukocytes can be applied
to investigate the toxicity mechanism of emerging contaminants and thereby facilitates the establishment of regulations for emerging contaminants in the future.
6.5 Summary and suggestions of future study
The current study has developed an adjuvant method to localize the Ag distribution at suborgan levels (Chapter II), has estimated the Ag concentrations of cetacean tissues by CHAA (Chapters II and III), has provided a presumptive metabolic pathway of Ag in cetaceans (Chapter III), has demonstrated the possible systemic rather than organ-targeting negative health effects caused by Ag in cetaceans (Chapter III), and has revealed the cytotoxicity and immunotoxicity caused by AgNPs on the leukocytes of cetaceans (Chapters IV and V). All the data have demonstrated the negative impacts of Ag/Ag compounds and AgNPs on the health of cetaceans and its potential ecotoxicity in marine environment.
There are several suggestions for the future studies, including 1) investigations on the systemic Ag distribution is warranted, which may provide a more comprehensive Ag metabolic pathway in cetaceans; 2) the causes of death/stranding, pathological findings, and infectious diseases in stranded cetaceans with different Ag concentrations are worth to be investigated for evaluating the negative health effects caused by Ag in cetaceans; 3) experiments on the molecular mechanism of phagocytosis of cPMNs is necessary to expand the knowledge on the phagocytosis of cPMNs as well as to determine the interactions between AgNPs and phagocytosis of cPMNs; and 4) the differences of AgNP-induced toxicity in different cells/animals may be associated with the different state (such as coating, sizes, and the intracellular Ag ions release) of the AgNPs; thus, investigations on the underlying cytotoxic/immunotoxic mechanisms of AgNPs in the leukocytes of cetaceans with comprehensive AgNPs characterization and a suitable reference of Ag ions are warranted.
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