Alterations in the endometrium of rats, rabbits, and Macaca mulatta that received an implantation of copper/low-density polyethylene nanocomposite

Hu, Li-Xia; Wang, Hong; Rao, Meng; Zhao, Xiaoling; Yang, Jing; Hu, Song; He, Jing; Xia, Wei; Liu, He-fang; Zhen, Bo; Di, Haihong; Xie, Changsheng; Xia, Xianping; Zhu, Changhong

doi:10.2147/ijn.s56756

Cited by 8 publications

(5 citation statements)

References 55 publications

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“…Recently, Cu NP has shown great promise as an antibacterial material [4][5][6][7] and even been used as intrauterine contraceptive device (IUD). [8][9][10][11][12][13][14] Recently, a new type of nano-Cu IUD was invented by However, numerous studies have unequivocally indicated that exposure to Cu NPs can result in adverse effects in vivo and in vitro. [16][17][18][19][20] For instance, a previous study demonstrated that the exposure of mice to Cu NPs resulted in severe kidney, liver, and spleen impairment.…”

Section: Introductionmentioning

confidence: 99%

Copper nanoparticle-induced ovarian injury, follicular atresia, apoptosis, and gene expression alterations in female rats

Yang¹,

Hu²,

Rao³

et al. 2017

IJN

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Numerous studies have reported the accumulation of copper nanoparticles (Cu NPs) in organs and the corresponding damage, although whether Cu NPs can be translocated to the ovaries and their ovarian toxicity are still unknown. In this study, three groups of female rats were injected with 3.12, 6.25, or 12.5 mg/kg Cu NPs for 14 consecutive days. The pathological changes, hormone levels, apoptosis and apoptotic proteins, oxidative stress, and gene expression characteristics in the ovaries were then investigated. The results demonstrated that the Cu NPs exhibited obvious accumulation in the rat ovaries, leading to ovarian injury, an imbalance of sex hormones, and ovarian cell apoptosis. Cu NP exposure activated caspase 3, caspase 8, caspase 9, and tBid, decreased the protein levels of Bcl-2, increased the expression levels of the proteins Bax and cytochrome c , and promoted malondialdehyde (MDA) accumulation and superoxide dismutase (SOD) reduction. Furthermore, gene microarray analysis showed that Cu NPs (12.5 mg/kg/d) caused 321 differentially expressed genes. Of these, 180 and 141 genes were upregulated and downregulated, respectively. Hsd17b1 , Hsd3b1 , Hsd3b6 , and Hsd3b were involved in steroid and hormone metabolism, whereas Mt3 and Cebpb were associated with apoptosis. Overall, these findings provide strong evidence that Cu NPs trigger both intrinsic and extrinsic apoptotic pathways and regulate key ovarian genes in oxidative stress-mediated ovarian dysfunction.

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Section: Introductionmentioning

confidence: 99%

Copper nanoparticle-induced ovarian injury, follicular atresia, apoptosis, and gene expression alterations in female rats

Yang¹,

Hu²,

Rao³

et al. 2017

IJN

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“…Our previous in vivo studies demonstrated that exposure to 12.5 mg/kg/d Cu‐NPs for 14 days led to an obvious accumulation in the ovaries, resulting in ovarian injury, an imbalance in sex hormone levels, and ovarian cell apoptosis . In previous studies, our research team successfully applied Cu‐NPs to develop a novel copper/low‐density polyethylene nanocomposite material for intrauterine devices (IUDs) . Our experiments revealed that this material had a high contraceptive efficacy and reliable safety, with low rates of side effects.…”

Section: Introductionmentioning

confidence: 87%

Copper nanoparticle‐induced uterine injury in female rats

Yang

Rao

et al. 2018

Environmental Toxicology

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Copper nanoparticles (Cu-NPs) have been used increasingly in various products and applications.Although recent studies have reported that exposure to Cu-NPs leads to organ accumulation and obvious toxicity, it remains unclear whether Cu-NPs can be translocated to and cause damage in the uterus. In this study, we investigated the potential for uterine injury and gene expression patterns in female rats exposed to 3.12, 6.25, or 12.5 mg/kg/d Cu-NPs via intraperitoneal injection for 14 consecutive days. The results indicated that exposure to Cu-NPs led to significant decreases in the relative uterine weight coefficients and increases in inflammatory cell infiltration, mitochondrial swelling and vacuolization, shortened and reduced endometrial epithelial cell microvilli, and apoptosis. Furthermore, exposure to Cu-NPs increased malondialdehyde (MDA) accumulation and decreased superoxide dismutase (SOD) levels. Signal transduction mechanism studies indicated that exposure to Cu-NPs activated caspases 3, 8, and 9 and BH3 interacting domain death agonist (tBid), reduced B cell leukemia/lymphoma 2 (Bcl-2) expression, and increased the expression of apoptotic peptidase activating factor 1 (Apaf-1), BCL2-associated X, apoptosis regulator (Bax), and cytochrome c. A microarray analysis revealed significant alterations in the expression of 963 genes; of these, 622 were upregulated and 341 were downregulated. The results of further evaluations of some altered genes, including matrix metallopeptidase 12 (Mmp12), using quantitative RT-PCR agreed with the microarray findings. These results provide strong evidence that Cu-NPs can trigger both intrinsic and extrinsic apoptotic pathways to mediate uterine injury, resulting in oxidative stressrelated changes in gene expression. K E Y W O R D Sapoptosis, Cu-NPs, microarray, rat, uterus

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“…The process used to prepare the nano-Cu/LDPE IUD was introduced in our previous work (Figure 3). 8 The nano-Cu/LDPE IUD comprises a pair of symmetrical transverse arms with a total length of 28 mm and a longitudinal stem with a total height of 30 mm. Both the transverse arms and the longitudinal stem have a diameter of 2.0 mm.…”

Section: Methodsmentioning

confidence: 99%

“…Therefore, controlling the process of cupric ion release and thus preventing such a burst initially after insertion should be considered to maximize contraceptive efficacy and minimize adverse effects. 8 Recent decades have seen rapid advances in nanotechnology in many scientific fields ( Figure 2). The characteristics of nanomaterials have contributed to notable biomedical achievements.…”

Section: Introductionmentioning

confidence: 99%

“…11,12 Additionally, experiments to determine the contraceptive effectiveness, side effects, and safety of the nano-Cu IUD in rats, mice, rabbits, and rhesus monkeys demonstrated a high level of efficacy with low side effects and relative safety. 8,[13][14][15][16][17] In summary, previous studies of this novel composite IUD material indicate that it can greatly improve the performance of IUDs.…”

Section: Introductionmentioning

confidence: 99%

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Studies of acute and subchronic systemic toxicity associated with a copper/low-density polyethylene nanocomposite intrauterine device

Hu¹,

Hu²,

Rao³

et al. 2018

IJN

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IntroductionThe physiologic safety of devices and materials intended for clinical implantation should be evaluated. This study, a logical extension of our previous work, aimed to investigate the safety of a novel contraceptive device, the copper/low-density polyethylene nanocomposite intrauterine device (nano-Cu/LDPE IUD), through studies of its potential toxicity after acute and subchronic administration in mice and rats.MethodsFor the acute toxicity study, single 50 mL/kg doses of nano-Cu/LDPE IUD extracts were administered to mice via intravenous or intraperitoneal injection. General behavioral adverse effects, mortality, and body weights were evaluated for up to 72 hours. In the 13-week subchronic toxicity study, the nano-Cu/LDPE composite with 10-fold higher than the standard clinical dose was implanted subcutaneously into the dorsal skin of Wistar rats. The control group underwent a sham procedure without material insertion.ResultsDuring all acute study observation times, the biologic reactions of the mice in the nano-Cu/LDPE group did not differ from those observed in the control group. The groups did not differ statistically in terms of body weight gain, and no macroscopic changes were observed in any organs. In the subchronic study, no clinical signs of toxicity or mortality were observed in either the nano-Cu/LDPE or control group during the 13-week period. The nano-Cu/LDPE composite did not cause any alterations in body weight, food consumption, hematologic and biochemical parameters, or organ weight relative to the control for any observed sample group. Histopathologic examinations of the organs revealed normal architecture, indicating that the inserted material did not cause morphologic disturbances in the rats.ConclusionOverall, the results indicate that the nano-Cu/LDPE IUD did not induce systemic toxicity under experimental conditions of the recommended standard practices, suggesting that the novel material IUD is safe and feasible for future contraceptive applications.

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Alterations in the endometrium of rats, rabbits, and Macaca mulatta that received an implantation of copper/low-density polyethylene nanocomposite

Cited by 8 publications

References 55 publications

Copper nanoparticle-induced ovarian injury, follicular atresia, apoptosis, and gene expression alterations in female rats

Copper nanoparticle-induced ovarian injury, follicular atresia, apoptosis, and gene expression alterations in female rats

Copper nanoparticle‐induced uterine injury in female rats

Studies of acute and subchronic systemic toxicity associated with a copper/low-density polyethylene nanocomposite intrauterine device

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