Research paperSex-specific accumulation of silver nanoparticles in rat kidneys is not ovarian hormone regulated but elimination limited
Introduction
AgNP has been known to distribute many major organs such as liver, kidneys, adrenals, brain, olfactory bulbs, eyes, lungs and blood after oral, inhalation or intravenous exposure (Kim et al., 2008; van der Zande et al., 2012; Sung et al., 2009; Song et al., 2013; Lee et al., 2013; Boudreau et al., 2016). A sex difference in Ag accumulation in the kidneys was first reported by Kim et al. (Kim et al., 2008) in a 28-day AgNP (60 nm) oral administration study, where 2–3 times more silver accumulated in female kidneys than in male kidneys. This observation was also confirmed by subchronic and subacute oral administration studies (van der Zande et al., 2012; Lee et al., 2013; Kim et al., 2010). Ninety-day and 12-week AgNP inhalation studies reported 3–4 times more silver accumulation in female kidneys than in male kidneys (Sung et al., 2009; Song et al., 2013). From these studies, it appears that orally ingested, inhaled or intravenously exposed AgNPs are translocated to the kidneys, where some Ag is excreted and some accumulate. In a follow-up histological study using silver enhancement staining, female rats also showed a higher accumulation of Ag nanoparticles in all kidney regions, including the cortex, outer medulla, and inner medulla, and particularly the glomerulus in the cortex. Ag nanoparticles were also preferentially accumulated in the basement membranes of the renal tubules in the cortex, middle, and terminal parts of the inner medulla and outer medulla. Plus, Ag nanoparticles were detected in the cytoplasm and nuclei of interstitial cells in the inner medulla. Sex-specific accumulation differences have also been reported in the urinary bladder and adrenal glands (Supplement 1) (Kim et al., 2009). In addition, a recent 13-week oral gavage study using AgNPs and silver acetate reported sex-specific accumulation differences in the kidneys, as well as the liver, jejunum, and colon (Boudreau et al., 2016). A sex difference has also been observed in lung function after AgNP subchronic inhalation. After 90-day AgNP (19 nm) exposure, male rats showed a larger decrease in the tidal volume when compared with female rats (Sung et al., 2008). This result was confirmed in a 12-week AgNP (14–15 nm) inhalation and 12-week recovery study, where an exposure-related lung function decreased after the 12-week exposure period and during the 12-week recovery period was observed in male rats. In contrast, female rats did not show a consistent lung function decrease during either the exposure or recovery period. Histopathology of the lung showed a gradual recovery from lung inflammation in the female rats, whereas the male rats in the high-dose group showed persistent inflammation throughout the 12-week recovery period (Song et al., 2013). These results indicate that AgNP exposure affects not only Ag deposition in specific tissues, but also influences the functional capacity in animals.
This study investigated whether sex-specific silver accumulation differences in the kidneys are dependent on sex-dependent hormonal regulation. AgNPs were orally administered to female rats with and without ovaries (ovariectomized), and the Ag accumulation in the kidneys then compared.
Section snippets
Test materials
Silver nanoparticle (AgNP) powder (purity 99.98%) was purchased from NAMATECH Co., Ltd. (Daejeon, Korea), and carboxymethylcellulose (CMC) was purchased from Sigma-Aldrich (St. Louis, USA) as the vehicle. The average particle size of the AgNPs was 60 nm (52.7–70.9 nm), plus the count median diameter and geometric standard deviation of AgNPs in 0.5% aqueous CMC were previously confirmed as 56 nm and 1.46, respectively (Supplement 2) (Kim et al., 2010).
Test animals and ovariectomy
Five-week-old male and female,
Animal observation, food consumption, and effect on body weight
No significant differences were noted in food consumption or water intake among the treated male and female rats and the control group (data not shown). While no significant treatment-related changes were noted in the body weights of the male rats (Fig. 1 A), significant (P < 0.01) operation-related increases were noted in the body weights of ovariectomized rats from 2 weeks to the conclusion of the study at 4 weeks (Fig. 1 B).
Ag distribution in tissues
No statistical differences in the silver concentrations were noted
Discussion
The AgNP used in this study were the same AgNP (58–60 nm) previously characterized and used for the 28-day and 90-day oral toxicity (Kim et al., 2008; Kim et al., 2010). The AgNP, re-analyzed for the clearance kinetics, were the same particle described in the previous 28-day oral administration and 4-month recovery (Lee et al., 2013). One potential explanation for sex-specific differences in the distribution of silver in rat kidneys may be hormonal regulation, as suggested by several papers (
Conclusions
To study preferential Ag deposition in female kidneys reported in subacute and subchronic oral gavage and inhalation studies of various sizes of silver nanoparticles (AgNPs), AgNPs were orally administered to female rats with and without ovaries (ovariectomized). Ag accumulation in the kidneys of female rats with and without ovaries was then compared to investigate whether sex-specific silver accumulation differences in the kidneys are dependent on sex-dependent hormonal regulation.
There was no
Ethics approval and consent to participate
The study was carried out in accordance with the Korean Animal Welfare Act. The study was also approved by the KCL Institutional Animal Care and Use Committee.
Consent for Publication
Not applicable.
Availability of supporting data
All data and materials are included in the manuscript, tables, figures, and supplements.
Funding
This study was supported by the Global Top Environment Technology Development project (No. 2018001860004) funded by the Ministry of Environment, Republic of Korea
Authors' contributions
JHL, experimental preparation, silver analysis in tissues and manuscript preparation; YSK, experimental and manuscript preparation; JHS, experimental preparation and manuscript preparation; JKK, silver clearance kinetic analysis; CJS, manuscript review; JDP, tissue analysis of silver; EMF, manuscript review and statistical review; BK, manuscript preparation and review; IJY, experimental planning, manuscript preparation and review. All authors have read and approved the final manuscript.
Declaration of Competing Interest
The authors declare no competing interests.
References (29)
- et al.
Differences in cadmium and mercury uptakes by hepatocytes: role of calcium channels
Toxicol. Appl. Pharmacol.
(1991) - et al.
Postnatal development of sex differences in renal tubular transport of p-aminohippurate (PAH) in rats
Exp. Toxicol. Pathol.
(1993) - et al.
Biopersistence of silver nanoparticles in tissues from Sprague-Dawley rats
Particle Fibre Toxicol.
(2013) - et al.
Gender differences in expression of organic cation transporter OCT2 in rat kidney
FEBS Lett.
(1999) - et al.
Interactions between thyroid disorders and kidney disease
Indian J Endocrinol Metab.
(2012) - et al.
Sex differences in hepatic and renal cadmium accumulation and metallothionein induction: role of estradiol
Biochem. Pharmacol.
(1991) - et al.
Developmental and sex differences in cadmium distribution and metallothionein induction and localization
J. Appl. Toxicol.
(1988) - et al.
Differential effects of silver nanoparticles and silver ions on tissue accumulation, distribution, and toxicity in the Sprague Dawley rat following daily Oral gavage administration for 13 weeks
Toxicol. Sci.
(2016) - et al.
Gene expression profiling of kidneys from Sprague-Dawley rats following 12-week inhalation exposure to silver nanoparticles
Toxicol Mech Methods
(2013) - et al.
The physiology of massive zinc accumulation in the liver of female squirrelfish and its relationship to reproduction
J. Exp. Biol.
(1996)