Effects of silver nanoparticles prenatal exposure on rat offspring development
Introduction
Silver nanoparticles (AgNP) are one of the most commonly employed nanomaterials (Silva et al., 2017; Adepu and Khandelwal, 2018) for a variety of applications including as additive for food packaging due to their strong antibacterial properties (Hebeish et al., 2013; Kanmani e Rhim, 2014; Artiaga et al., 2015; Popov et al., 2015; Hoseinnejad et al., 2018). For instance, polymers added with silver nanoparticles have been employed in food packaging applications, allowing physical protection combined with antimicrobial activity, which can improve food conservation (Becaro et al., 2016; Kernberger-Fischer et al., 2017; Narayanan and Han, 2017) by limiting spoilage and harmful microflora.
The microbial inhibitory effectiveness of nanomaterials-containing packaging is determined by the migration of the antimicrobial agent towards the package inner part, or directly onto the food surface. Thus, it is important to investigate the level of migration experienced for the nanomaterial contained in the food packaging as well as its toxicity, once data relating all aspects of risk assessment are still scarce in the literature (Jokar et al., 2017).
Previous study demonstrated that the release of nanosilver from film to the food samples after storage was around 4.3–4.5 μg L−1 after two weeks (Krasniewska et al., 2020). Additionally, 0.1 mg/L (100 ppb) of silver is the standard recommended level by the United States Environmental Protection Agency – US/EPA for drinking water (Scenihr, 2014). Besides, the overuse of AgNP raises some concerns regarding the potential risks for humans and the environment, combined to the lack of sufficient information about their effects (Zhang et al., 2013; Becaro et al., 2015; McGillicuddy et al., 2017; Abramenko et al., 2018; Ellis et al., 2018; Kataoka et al., 2018; Zhang et al., 2018). Some studies have addressed adverse effects caused by AgNP at different levels of biological integration (Pulit et al., 2011; Zhang et al., 2013; Strużyński et al., 2014; Vazquez-Muñoz et al., 2017), with implications, for instance, in reactive oxygen species (ROS) generation (Gaillet and Rouanet, 2015; McGillicuddy et al., 2017; Ale et al., 2018). Additionally, silver nanoparticles, regardless of their size and dose, can disrupt hormonal control of reproductive processes by changing the hormonal balance and steroid metabolism in male gonads (Dziendzikowska et al., 2016), which requires reproductive and developmental evaluation of AgNP toxicity in greater detail (Wijnhoven et al., 2009). However, the developmental toxicity of nanoparticles has not been deeply studied until very recently. AgNP can induce behavioral changes in rats in the first days of life (Ema et al., 2017). Nevertheless, spatial cognition or hippocampal neurogenesis were not impaired in male mice that received intraperitoneal administration of AgNP (0 till 50 mg/kg body weight) daily for 7 days (Liu et al., 2012). Moreover, nanoparticles can pass the placenta and accumulate in the brain before the blood–brain barrier is developed (Lee et al., 2012). In another work, Wang et al. (2013) treated mice intraperitoneally with AgNP and Ag ions (from AgNO3) three times a week for 30 days. After the treatment, mice were immediately mated and embryos were dissected from uteri and weighed on day 14.5 of pregnancy. The exposure caused anemia in the embryos and the average number of viable pups per litter was significantly reduced. On the other hand, Charehsaz et al. (2016) did not observed developmental toxicity at dose levels of up to 20 mg/kg/day of AgNP during pregnancy measured by traditional parameters as pregnancy length, number of implantations, resorptions, birth weight and litter size. Also, AgNP exposure during pregnancy can induce adverse influence on neurobehavioral development of adult offspring. It seems that some impairments are sex dependent, with greater susceptibility of female offspring. Despite of these studies, the potential negative effects of AgNPs on development and reproduction have yet to be fully clarified and further investigations are required (Ghaderi et al., 2015).
The toxicity of silver can arise from AgNP, silver ions or a combination of both (Wijnhoven et al., 2009; Charehsaz et al., 2016). Therefore, bioavailability, morphology and toxicity of AgNP are critical factors and should be considered for the complete environmental risk assessment (Zhang et al., 2018). Here we investigate the impact of AgNP exposure to dams and their pups by evaluation of some features. The parameters evaluated were gestation length (days), litter size on birth (pups born), number of stillborn pups and number of dead pups during lactation period, in addition to mean body weight gain of dams per dose of AgNP during gestational period, in order to gain insights on its reproductive and developmental effects. The low AgNPs daily doses (0, 1, 3 and 5 μg/kg/day) employed were based on previous investigation of silver migration from food package. Our findings will add to other results already reported in the literature concerning AgNPs toxic effects (including those dealing with hepatic, renal and hematological functions) in order to provide safer protocols for AgNPs use.
Section snippets
Silver nanoparticles (AgNP) synthesis
Silver nanoparticles were synthesized using a methodology fully described in Becaro et al. (2015). Initially, 60 mM PVA (stabilizing agent) was added in 10 mL of a 5 mM silver nitrate solution (silver precursor) and stirred for 5 min. After, 5 mL of a freshly prepared NaBH4 solution (reducing agent) was added and stirred for 15 min using a magnetic stirrer. All solutions were prepared with distilled water. At the end of the synthesis, a yellow solution was obtained confirming the formation of
AgNP characterization
Fig. 1 shows the TEM images of AgNP obtained with the synthesis described in the experimental section. The nanoparticles present spherical morphology, and are well dispersed, with size range from 2 to 20 nm. Additionally, UV–vis absorption spectrum of AgNP (not shown) revealed they present absorption band around 400 nm, related to the surface plasmon absorption band of AgNP (Becaro et al., 2015).
Ag concentration analysis in dams’ tissue
There were no deaths observed for the animals exposed to AgNP. Daily observations on the appearance
Discussion
Due to the fact that issues concerning the health and safety of nanomaterials utilization are not fully understood, especially during developmental period, we tried to establish some initial parameters that could link low concentrations of AgNP ingestion (representing the ingestion of AgNP due to its migration from nanocomposite film to food) to possible toxicological effects.
According to the literature, the highly dynamic properties of AgNP can lead to coexposure to nanoparticulate and ionic
Conclusion
The effects of prenatal exposure of AgNP on the pregnancy outcomes of dams and postnatal development of their offspring were investigated. For this purpose, pregnant Wistar rats were exposed to AgNP concentrations of 0, 1, 3 and 5 μg/kg/day from beginning to the end of pregnancy. Our results revealed that AgNP may have an apparent effect on sexual maturation even at concentrations that do not cause changes in developmental and reproductive landmarks such as organs weight, indicating that
CRediT authorship contribution statement
Aline A. Becaro: Investigation, Data curation, Formal analysis, Writing - original draft. Luzia P. de Oliveira: Investigation, Data curation, Formal analysis, Writing - review & editing. Vera L.S. de Castro: Methodology, Visualization, Investigation, Writing - review & editing, Resources. Maria C. Siqueira: Investigation. Humberto M. Brandão: Conceptualization, Formal analysis, Writing - review & editing. Daniel S. Correa: Conceptualization, Supervision, Resources, Writing - review & editing.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgments
The authors thank the financial support from financial support from Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), MCTI-SisNano (CNPq/402.287/2013-4), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brasil (CAPES)- Código de Financiamento 001 and Rede Agronano (EMBRAPA) from Brazil.
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These authors contributed equally to this work.