Elsevier

NanoImpact

Volume 20, October 2020, 100255
NanoImpact

Research paper
Sex-specific accumulation of silver nanoparticles in rat kidneys is not ovarian hormone regulated but elimination limited

https://doi.org/10.1016/j.impact.2020.100255Get rights and content

Highlights

  • Ovarian hormonal effects on preferential silver deposition in female kidneys were studied in the ovariectomized rats

  • No significant difference in Ag content in the kidneys among the control, sham, and ovariectomized rats after 28-day study

  • The clearance of Ag in the kidneys showed 2 different phases (fast and slow), showing clearances for females than males

  • The preferential silver accumulation in female kidneys is not regulated by ovarian hormones, but by elimination rate.

Abstract

Preferential Ag deposition in female kidneys has been reported in subacute and subchronic oral gavage and inhalation studies of various sizes of silver nanoparticles (AgNPs). In these in vivo animal studies, female kidneys were shown to accumulate 3–4 times more silver than male kidneys. The current 28-day oral gavage study of AgNPs administered to ovariectomized female rats investigated the effect of sex-dependent hormones. Ovariectomized rats were allowed to recover for 14 days, then AgNPs (60 nm) were administered by gavage for 28 days based on 500 mg/kg body weight. After this subacute oral exposure, the rats were sacrificed and the Ag content in the kidneys was measured using an atomic absorption spectrophotometer. No statistically significant difference was noted in the Ag content in the kidneys among the AgNP administered, AgNP administered sham, and AgNP administered ovariectomized rats, although the female kidneys showed a statistically significant higher accumulation of Ag than the male kidneys. Reanalysis of the clearance of Ag accumulated in the kidneys showed 2 different phases; fast (T1/210.4 days) and slow (T1/2 61.9 days) for males, while the clearance of females showed (T1/2 20.8 days) and slow (T1/2 154 days). The higher accumulation of Ag in female kidneys is due to slower clearance of Ag in female kidneys than those of males. Therefore, the current results indicate that the preferential silver accumulation in female kidneys is not regulated by ovarian hormones, but by elimination rate differences between males and females.

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.

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