Metallomics analysis for early assessment and individualized intervention of neurodevelopmental disorders.

The children today are in the midst of the epidemic of neurodevelopmental disorders. In this metallomics study for the scalp hair samples of total 2550 children with autistic disorders (2108 males and 442 females aged 0-15 years), it was demonstrated that near one-half of the infantile individuals aged 0-3 years are suffering from zinc deficiency and toxic metal burdens. Zinc level correlated closely to the index of zinc/iron ratio more than zinc/copper ratio. Furthermore, there were significant relationships between zinc deficiency and toxic metal burdens such as lead and aluminum, which were inversely associated with not only zinc level but also zinc/iron ratio with higher regression coefficients of r = -0.486 and -0.551 (P < 0.00001), respectively. High-significant inverse association was detected between zinc and molybdenum concentration (r = -0.509) and also between zinc/iron ratio and molybdenum (r = -0.548). These findings suggest that infantile zinc deficiency relates to the high burdens of not only toxic but also some essential metals such as molybdenum, iron, and manganese and that these various mineral imbalances play principal roles in the etiology of neurodevelopmental disorders. We expect that the early assessment and intervention of the mineral imbalances (or dis-homeostasis) in individual child open an avenue for evidence-based individualized treatment of neurodevelopmental disorders and also of the comorbid immune disorders, in near future.

Metallomics Analysis for Assessment of Toxic Metal Burdens in Infants/Children and Their Mothers: Early Assessment and Intervention Are Essential.

Accumulation of toxic metals in infants/children is of serious concern worldwide, from the viewpoint of their harmful effects on the normal growth and development. This metallomics study investigates the extent of toxic metal burdens in infants/children and the relationship to those in their mothers for 77 child/mother pair subjects. For mercury, its geometric mean concentration in infants/children was of similar level to that in their mothers, and a high-significant close correlation was observed between infants/children and their mothers (ß = 0.758, r = 0.539, p < 0.0001). A significant but less intimate mother/child relationship was observed for arsenic (ß = 0.301, r = 0.433), lead (ß = 0.444, r = 0.471) and aluminum (ß = 0.379, r = 0.451). Remarkably, the burden levels of lead, cadmium and aluminum in infants/children were approximately three times higher than those in their mothers (p < 0.0001), and the burden levels in some individuals were several tens of times higher than in the mothers. In contrast, some essential metal levels such as zinc, magnesium and calcium in infants/children were significantly lower than those in their mothers, and 29 individuals (37.7%) in the child subjects were estimated to be zinc-deficient. In addition, significant inverse correlations were observed between zinc and lead (r = -0.267, p = 0.019), and magnesium and arsenic (r = -0.514, p < 0.0001). These findings suggest that these toxic metal burdens and essential metal deficiencies in infants/children are of serious concern for their neurodevelopment, indicating that the early assessment and intervention are crucial. It is expected that larger epidemiological and intervention studies will provide a reasonable and essential pathway for intervention of neurodevelopment disorders.

Infants and elderlies are susceptible to zinc deficiency.

The importance of zinc for human health has been recognized since the early 1960s, but today there is little concern about zinc deficiency in developed countries. In this study, we measured the zinc concentration in hair from 28,424 Japanese subjects (18,812 females and 9,612 males) and found that 1,754 subjects (6.17%) had zinc concentrations lower than 2 standard deviations (86.3 ppm) below the control reference range, which qualifies as zinc deficiency. In particular, a considerable proportion of elderlies and children (20% or more) were found to have marginal to severe zinc deficiency. A zinc concentration of 9.7 ppm was the lowest observed in a 51-year-old woman; this concentration was approximately 1/13 of the mean reference level. The prevalence of zinc deficiency in adults increased with aging to a maximum of 19.7% by the 8(th) decade of life, and decreased to 3.4% above 90-year-old. The proportion of zinc deficiency in infants 0-4 years was 36.5% in males and 47.3% in females; these percentages were higher than the maximum prevalence in elderly subjects. These findings suggest that infants and elderlies are prone to zinc deficiency and that intervention of zinc deficiency is necessary for normal human development, health and longevity.

Assessment of infantile mineral imbalances in autism spectrum disorders (ASDs).

The interactions between genes and the environment are now regarded as the most probable explanation for autism. In this review, we summarize the results of a metallomics study in which scalp hair concentrations of 26 trace elements were examined for 1,967 autistic children (1,553 males and 414 females aged 0-15 years-old), and discuss recent advances in our understanding of epigenetic roles of infantile mineral imbalances in the pathogenesis of autism. In the 1,967 subjects, 584 (29.7%) and 347 (17.6%) were found deficient in zinc and magnesium, respectively, and the incidence rate of zinc deficiency was estimated at 43.5% in male and 52.5% in female infantile subjects aged 0-3 years-old. In contrast, 339 (17.2%), 168 (8.5%) and 94 (4.8%) individuals were found to suffer from high burdens of aluminum, cadmium and lead, respectively, and 2.8% or less from mercury and arsenic. High toxic metal burdens were more frequently observed in the infants aged 0-3 years-old, whose incidence rates were 20.6%, 12.1%, 7.5%, 3.2% and 2.3% for aluminum, cadmium, lead, arsenic and mercury, respectively. These findings suggest that infantile zinc- and magnesium-deficiency and/or toxic metal burdens may be critical and induce epigenetic alterations in the genes and genetic regulation mechanisms of neurodevelopment in the autistic children, and demonstrate that a time factor "infantile window" is also critical for neurodevelopment and probably for therapy. Thus, early metallomics analysis may lead to early screening/estimation and treatment/prevention for the autistic neurodevelopment disorders.

Estimation of autistic children by metallomics analysis.

Clarification of the pathogenesis and treatment of autism spectrum disorders is one of the challenges today. In this study, we examine scalp hair concentrations of 26 trace elements for 1,967 children with autistic disorders (1,553 males and 414 females). Five-hundred and eighty-four (29.7%), 347 (17.6%) and 114 (5.8%) subjects was found deficient in zinc, magnesium and calcium, respectively, and 2.0% or less in the other essential metals. The incidence rate of mineral deficiency was highly observed in infants aged 0-3 year-old. In contrast, 339 (17.2%), 168 (8.5%) and 94 (4.8%) individuals was found suffering from high burden of aluminium, cadmium and lead, and 2.8% or less from mercury and arsenic burden. These findings suggest that infantile zinc- and magnesium-deficiency and/or toxic metal burdens may epigenetically play principal roles as environmental factors in autistic disorders and that metallomics approach may lead to early screening and prevention of the neurodevelopment disorders.

Two age-related accumulation profiles of toxic metals.

In order to investigate the body burden levels of toxic metals in Japanese, five toxic metal concentrations in scalp hair samples from 28,424 subjects from infant to elderly were determined with inductively coupled plasma mass spectrometry (ICP-MS). The geometric mean of hair mercury concentrations showed a high-significant age-correlated increase (r = 0.341, p < 0.0001) with a peak at the 6th decade of life and then decreased with further aging in both sexes. The mean mercury concentrations in male adults were significantly higher than those in female (p < 0.001), indicating the gender difference (male > female) in mercury accumulation. Arsenic also showed a similar accumulation profile with age dependency and gender difference in adult subjects. In contrast, cadmium, lead and aluminium exhibited another type of accumulation profile: the highest burden level was observed in infants aged 0-3 years old for every element in both sexes. In addition, cadmium was found to have a character accumulating in aged females, with significant age-dependency (r = 0.134, p < 0.0001) and gender difference (female > male). These findings suggest that toxic metals are classified into two families on the basis of their accumulation profiles, and that the three elements of mercury, arsenic and cadmium which accumulate age-dependently in adults, may play a role in aging process and higher burden with them may lead to acceleration of aging.

Infantile zinc deficiency: association with autism spectrum disorders.

Elucidation of the pathogenesis and effective treatment of autism spectrum disorders is one of the challenges today. In this study, we examine hair zinc concentrations for 1,967 children with autistic disorders (1,553 males and 414 females), and show considerable association with zinc deficiency. Histogram of hair zinc concentration was non-symmetric with tailing in lower range, and 584 subjects were found to have lower zinc concentrations than -2 standard deviation level of its reference range (86.3-193 ppm). The incidence rate of zinc deficiency in infant group aged 0-3 year-old was estimated 43.5 % in male and 52.5 % in female. The lowest zinc concentration of 10.7 ppm was detected in a 2-year-old boy, corresponding to about 1/12 of the control mean level. These findings suggest that infantile zinc deficiency may epigenetically contribute to the pathogenesis of autism and nutritional approach may yield a novel hope for its treatment and prevention.

Metallomics study using hair mineral analysis and multiple logistic regression analysis: relationship between cancer and minerals.

OBJECTIVES: The objective of this metallomics study is to investigate comprehensively some relationships between cancer risk and minerals, including essential and toxic metals. METHODS: Twenty-four minerals including essential and toxic metals in scalp hair samples from 124 solid-cancer patients and 86 control subjects were measured with inductively coupled plasma mass spectrometry (ICP-MS), and the association of cancer with minerals was statistically analyzed with multiple logistic regression analysis. RESULTS: Multiple logistic regression analysis demonstrated that several minerals are significantly correlated to cancer, positively or inversely. The most cancer-correlated mineral was iodine (I) with the highest correlation coefficient of r = 0.301, followed by arsenic (As; r = 0.267), zinc (Zn; r = 0.261), and sodium (Na; r = 0.190), with p < 0.01 for each case. In contrast, selenium (Se) was inversely correlated to cancer (r = -0.161, p < 0.05), followed by vanadium (V) (r = -0.128). Multiple linear regression value was highly significantly correlated with probability of cancer (R (2) = 0.437, p < 0.0001), and the area under the receiver-operating characteristic (ROC) curve was calculated to be 0.918. In addition, using contingency table analysis and the chi-square test, the precision of discrimination for cancer was estimated to be 0.871 (chi-square = 99.1, p < 0.0001). CONCLUSIONS: These findings suggest that some minerals such as arsenic, selenium, and probably iodine, zinc, sodium, and vanadium contribute to regulation of cancer and also that metallomics study using multiple logistic regression analysis is a useful tool for estimating cancer risk.

Reduced exposure to mercury in patients receiving enteral nutrition.

The exposure to mercury (Hg) of various groups of people with different dietary backgrounds has been assessed because of its hazardous effects, but little is known about that in patients receiving enteral nutrition. Therefore, we studied the Hg exposure in 25 patients with severe motor disabilities, who received liquid enteral feedings for more than one year, by determining total mercury (T-Hg) in their hair samples with inductively coupled plasma-mass spectrometry. The geometric mean of the T-Hg level in hair from the patients was 88 ng/g hair (+/- 1 geometric standard deviation [GSD], 34 - 228 ng/g), whereas that for the control group on a normal diet was 1,900 ng/g (+/- 1 GSD, 1,022 - 3,531 ng/g). The T-Hg levels in the patients' hair were far lower than those in the controls (p < 0.001). The T-Hg levels in the enteral feedings used were below the detection limit of cold-vapor atomic absorption spectrophotometry (< 10 ng/g). The present study has shown that Hg exposure is low in patients receiving enteral nutrition, indicating that food is a primary source of Hg exposure.

A preliminary analysis of trace elements in the scalp hair of patients with severe motor disabilities receiving enteral nutrition.

The concentrations of essential trace elements (copper, zinc, selenium, manganese, chromium, molybdenum, cobalt, and iodine) in the scalp hair of 21 patients with severe motor disabilities receiving enteral nutrition were measured using inductively coupled plasma-mass spectrometry. Preliminary results show that copper, selenium, and molybdenum concentrations in the patients' hair were significantly lower than those in an age-matched control group (p<0.01). This suggests that intake of these elements may be reduced in patients receiving restricted enteral nutrition, although the clinical significance of these results should be discussed.