Elsevier

Reproductive Toxicology

Volume 66, December 2016, Pages 115-121
Reproductive Toxicology

Association between titanium and silver concentrations in maternal hair and risk of neural tube defects in offspring: A case-control study in north China

https://doi.org/10.1016/j.reprotox.2016.10.006Get rights and content

Highlights

  • Products containing Ti or Ag had been widely released into the environment.

  • We investigated an association of Ti or Ag with risk of neural tube defects (NTDs).

  • The recruited pregnant women from north China had a higher exposure level of Ti.

  • Concentration of Ti in maternal hair was associated with an elevated risk of NTDs.

  • An association of Ag in maternal hair with risk of NTDs was not observed.

Abstract

Increasing uses of titanium and silver in various products raise concerns for their potential adverse effects on pregnancy outcomes. We aimed to examine the associations between titanium and silver concentrations in maternal hair growing during the periconception period and the risk of neural tube defects (NTDs) in offspring. Our case–control study recruited 191 women with NTD-affected pregnancies and 261 women delivering healthy infants. Metal concentrations in maternal hair were measured by inductively coupled plasma-mass spectrometry. The adjusted odds ratios (AOR) of titanium concentration above the median were 1.46 (95% confidence interval (CI), 0.99–2.13) for total NTDs and 2.10 (95% CI, 1.12–3.94) for anencephaly, while OR of silver wasn't statistically significant. Titanium concentration was positively correlated with consumptions of vegetables and fruits. Maternal exposure to titanium during the periconception period was associated with an increased NTD risk in offspring, which may be partly mediated through maternal dietary habits.

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.

References (55)

  • E. Hidalgo et al.

    Study of cytotoxicity mechanisms of silver nitrate in human dermal fibroblasts

    Toxicol. Lett.

    (1998)
  • I. Sondi et al.

    Silver nanoparticles as antimicrobial agent: a case study on E-coli as a model for gram-negative bacteria

    J. Colloid Interface Sci.

    (2004)
  • C.M. Powers et al.

    Silver nanoparticles alter zebrafish development and larval behavior: distinct roles for particle size, coating and composition

    Neurotoxicol. Teratol.

    (2011)
  • Y. Wu et al.

    Effects of silver nanoparticles on the development and histopathology biomarkers of Japanese medaka (Oryzias latipes) using the partial-life test

    Aquat. Toxicol.

    (2010)
  • R. Pereira et al.

    Scalp hair analysis as a tool in assessing human exposure to heavy metals (S. Domingos mine Portugal)

    Sci. Total Environ.

    (2004)
  • T. Wang et al.

    Use of scalp hair as indicator of human exposure to heavy metals in an electronic waste recycling area

    Environ. Pollut.

    (2009)
  • Z. Li et al.

    A simultaneous analysis method of polycyclic aromatic hydrocarbons, nicotine, cotinine and metals in human hair

    Environ. Pollut.

    (2016)
  • N. Miekeley et al.

    How reliable are human hair reference intervals for trace elements?

    Sci. Total Environ.

    (1998)
  • I. Rodushkin et al.

    Application of double focusing sector field ICP-MS for multielemental characterization of human hair and nails. Part I. Analytical methodology

    Sci. Total Environ.

    (2000)
  • K. Sera et al.

    Quantitative analysis of untreated hair samples for monitoring human exposure to heavy metals

    Nucl. Instrum. Methods Phys. Res. B

    (2002)
  • Y. Wu et al.

    Concentrations and health risk assessment of trace elements in animal-derived food in southern China

    Chemosphere

    (2016)
  • J. Hans et al.

    Neurulation and neural tube defects

    Clinical Neuroembryology

    (2014)
  • J.B. Wallingford et al.

    The continuing challenge of understanding, preventing, and treating neural tube defects

    Science

    (2013)
  • K.S. Au et al.

    Epidemiologic and genetic aspects of spina bifida and other neural tube defects

    Dev. Disabil. Res. Rev.

    (2010)
  • H. Blencowe et al.

    Folic acid to reduce neonatal mortality from neural tube disorders

    Int. J. Epidemiol.

    (2010)
  • A.E. Czeizel et al.

    Prevention of the first occurrence of neural-tube defects by periconceptional vitamin supplementation

    N. Engl. J. Med.

    (1992)
  • B. Wang et al.

    Levels of polycyclic aromatic hydrocarbons in maternal serum and risk of neural tube defects in offspring

    Environ. Sci. Technol.

    (2015)
  • Cited by (19)

    • Prenatal titanium exposure and child neurodevelopment at 1 year of age: A longitudinal prospective birth cohort study

      2023, Chemosphere
      Citation Excerpt :

      The fetal period is particularly sensitive to environmental threats due to the underdeveloped defense mechanisms (Barker, 2007). Recently, several epidemiological evidences have shown that higher titanium exposure was related to the increasing risk of adverse birth outcomes, including neural tube defects, preterm birth, fetal distress and low birth weight (Jin et al., 2021; Li et al., 2016; Zheng et al., 2014). Titanium can also cross the blood-brain barrier and may be harmful to the central nervous system of the developing fetus (Song et al., 2015).

    • Environmental titanium exposure and reproductive health: Risk of low birth weight associated with maternal titanium exposure from a nested case-control study in northern China

      2021, Ecotoxicology and Environmental Safety
      Citation Excerpt :

      Increasing numbers of epidemiological studies have shown evidence that Ti exposure may be associated with several adverse health effects including diabetes, colitis, and cardiopulmonary disorders (Ruiz et al., 2017; Yuan et al., 2018; Zhao et al., 2018). In pregnant women who were more vulnerable to environmental exposure than the general population (Silver et al., 2018; Freire et al., 2019), Ti exposure was found to be associated with adverse reproductive outcomes including fetal distress, preterm birth, and neural tube defects (Zheng et al., 2014; Li et al., 2016). However, the evidence of maternal exposure to Ti on low birth weight (LBW) —an adverse birth outcome affecting infants’ mortality, development, and disease risks throughout the life course with an incidence of 5–6% in China (McCormick, 1985; Gluckman et al., 2008; Tang et al., 2017)—was inconsistent and insufficient.

    • Non-cytotoxic silver nanoparticle levels perturb human embryonic stem cell-dependent specification of the cranial placode in part via FGF signaling

      2020, Journal of Hazardous Materials
      Citation Excerpt :

      Although AgNP neurotoxicity may suggest potential early effects on neural ectoderm specification, the impact of AgNPs on the development of all the major ectodermal lineages has been scarcely investigated. For instance, there is controversial evidence about the relationship between neural crest defects and Ag exposure (Ramirez-Altamirano Mde et al., 2012, Li et al., 2016). In addition, Zhang et al. found that AgNPs affected lens’ development in zebrafish embryos, implying defects in cranial placode (Zhang et al., 2018).

    View all citing articles on Scopus
    View full text