Association between titanium and silver concentrations in maternal hair and risk of neural tube defects in offspring: A case-control study in north China
Graphical abstract
Introduction
Neural tube defects (NTDs) are a group of birth defects with multifactorial aetiology. They result from failure of the neural tube to complete closure, which normally occurs by post-conception day 28 [1]. NTDs usually lead to abortion, still-birth, or the permanent disability of newborns [2], which, in turn, leads to economic burdens for and psychological pressure on NTD-affected families [3]. The incidence of NTDs varies from 1 to 10/1000 births worldwide [4]. Risk factors of NTDs include environmental and genetic aspects, as well as their interaction effects. Folic acid supplement, as a main factor, could decrease about 46%–70% NTD incidence [5]. In addition, socioeconomic status [1], nutritional deficiency [6], and environmental exposures such as persistent organic pollutants [7], [8], or heavy metals [9] are reported as risk factors.
Titanium (Ti) is a nonessential element for humans and the ninth most abundant element in the Earth’s crust. Ti can be detected in the blood, brain, parenchymatous organs, and hair of individuals in the general population [10], [11], [12]. About 95% of Ti used worldwide is in the form of titanium(IV) oxide (TiO2), and its microparticles and nanoparticles (NPs) are widely used in consumer goods, including foods and cosmetics available to the general population [13], [14]. Widespread use of these particles raised concerns of their impact on the environment and human [15]. Studies on areas polluted by metal contaminations indicated that hair samples of children living in such areas contained higher Ti concentration than those who lived in non- or less exposed sites, and food consumption and exposure to metal rich soils might be responsible for this difference [16], [17]. Ti can be detected in the brains of experimental mice maternally exposed to TiO2 [18]. In vivo and in vitro studies have revealed that TiO2 NPs are toxic because they induce oxidative stress [19], [20], DNA damage [21], [22], apoptosis [23], [24], and external morphological defects in offspring [25]. In vivo mouse models, TiO2 was found to cause oxidative stress at the level of 5 mg/kg (body weight)/day for 60 days administration [20], DNA damage at 50 mg/kg (body weight)/day for 5 days [21], and external morphological defects in offspring beyond 100 mg/kg (body weight)/day for 10 days [25]. However, the relationship between maternal Ti intake and NTD risk is poorly understood.
Silver (Ag) is a nonessential element with well-known antimicrobial effects [26]. Ag and Ag-containing compounds are absorbed in the human body through inhalation, ingestion, and dermal absorption [27]. Ag ions induce apoptosis and necrosis mediated by generating reactive oxygen species (ROS) [28]. Ag ions are also cytotoxic, as they inhibit DNA synthesis and fibroblast proliferation [29]. Ag NPs are one of the most commercialized NPs and are used widely in commercial products, such as medical devices and food packaging [30], [31]. Some studies on non-mammals indicate that Ag NPs cause reproductive failure, embryonic death, and morphological abnormalities [32], [33], [34], whereas the evidence on mammals is inconsistent. Fourteen-day prenatal exposure to Ag NPs induces oxidative stress in maternal hepatic tissues of rats, but they have no reproductive or developmental effects even at a dose of 1000 mg/kg/day [35]. On the other hand, another study reported increased mortality of fetal mice maternally exposed to 10 mg/kg Ag NPs on gestation day 9 [25]. A case-control study in Mexico found significantly higher Ag concentrations (1.45 ± 0.76 μg/g (mean ± standard deviation)) in hair samples of 8 newborn infants with neural tube pathology than those (0.25 ± 0.53 μg/g (mean ± standard deviation)) of 15 healthy newborns [36]. Hence, the relationship between Ag and NTD risk in offspring remains controversial.
Analysis of hair samples is a noninvasive technique that is widely used to monitor internally accumulated levels of metals [37], [38]. To the best of our knowledge, the hair contents of Ag and Ti were reported in the limited studies on non-occupationally exposed adults in the US and Poland [12], [39]. Specific populations are of greater concern including children potentially exposed to environmental contamination of Ti and patients undergoing surgical implantation of a Ti alloy [16], [17], [40], [41]. Specific sections of hair reflect exposure of the corresponding time window by assuming a constant growth rate, which can overcome the recall bias of self-report exposure information in retrospective studies [42]. Hence, we hypothesized that maternal exposure to Ti or Ag during the periconception period is associated with an elevated risk for NTDs in offspring. The main objective of the present study was to investigate the association between NTD risk and levels of Ti and Ag in maternal hair growing from 1 month before conception to 2 months after conception.
Section snippets
Study population
The present study was conducted in four counties (Taigu, Pingding, Xiyang, and Zezhou) and in the city of Taiyuan, Shanxi Province, as well as in six counties (Mancheng, Yuanshi, Shijiazhuang, Laoting, Fengrun, and Xianghe) in Hebei Province from January 2003 to December 2007 in North China. These two provinces have the highest prevalence of NTDs, and both are located in northern China [43]. Our study included the three NTD subtypes of anencephaly, spina bifida, and encephalocele. When a woman
Population characteristics
We examined maternal hair samples from 191 NTD cases and 261 controls. Response rate for questionnaire was more than 80% for questionnaire investigation, and about 69% for hair sample collection. The characteristics of the cases and controls are shown in Table 1. All the subjects were from the largest ethnic group in China, i.e. Han ethnicity. Case mothers were more likely than controls to have received a primary education or lower, to have a history of pregnancy affected by a NTD, to contract
Discussion
In our study, we analyzed associations between maternal hair concentrations of Ti and Ag during the periconception period and the risk for NTDs in offspring. We found that the risk for all NTDs and anencephaly were significantly higher in women with higher hair Ti concentrations. Such an effect may be ascribed partly to maternal dietary habits. No difference in maternal hair Ag concentrations was observed between the case and control groups.
Metal concentrations in human hair are widely used as
Conclusions
We concluded that maternal exposure to Ti may play an important role in the formation of NTDs in offspring. No association was found between maternal exposure to Ag and risk of NTDs. Further investigations are needed to clarify the exact exposure level of the general population to further evaluate the adverse health effects of Ti.
Conflict of interest
The authors declare they have no actual or potential competing financial interests.
Role of the funding sources
The funding agencies have no role in study design, implementation, data analysis, and interpretation.
Acknowledgements
This research was supported by the National Natural Science Foundation of China (Grant No.41401583, No. 81373014, and No. 81511130088) and the National Key Research and Development Program, Ministry of Science and Technology, P.R. China (Grant No. 2016YFC1000501). The authors thank Dr. Nicholas D. E. Greene from the UCL Institute of Child Health, University College London, United Kingdom for his helpful comments on the manuscript.
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