Genetic polymorphisms of GRIN2A and GRIN2B modify the neurobehavioral effects of low-level lead exposure in children.

Lead (Pb) is neurotoxic and children are highly susceptible to this effect, particularly within the context of continuous low-level Pb exposure. A current major challenge is identification of children who may be uniquely susceptible to Pb toxicity because of genetic predisposition. Learning and memory are among the neurobehavioral processes that are most notably affected by Pb exposure, and modification of N-methyl-D-aspartate receptors (NMDAR) that regulate these processes during development are postulated to underlie these adverse effects of Pb. We examined the hypothesis that polymorphic variants of genes encoding glutamate receptor, ionotropic, NMDAR subunits 2A and 2B, GRIN2A and GRIN2B, exacerbate the adverse effects of Pb exposure on these processes in children. Participants were subjects who participated as children in the Casa Pia Dental Amalgam Clinical Trial and for whom baseline blood Pb concentrations and annual neurobehavioral test results over the 7 year course of the clinical trial were available. Genotyping assays were performed for variants of GRIN2A (rs727605 and rs1070503) and GRIN2B (rs7301328 and rs1806201) on biological samples acquired from 330 of the original 507 trial participants. Regression modeling strategies were employed to evaluate the association between genotype status, Pb exposure, and neurobehavioral test outcomes. Numerous significant adverse interaction effects between variants of both GRIN2A and GRIN2B, individually and in combination, and Pb exposure were observed particularly among boys, preferentially within the domains of Learning & Memory and Executive Function. In contrast, very few interaction effects were observed among similarly genotyped girls with comparable Pb exposure. These findings support observations of an essential role of GRIN2A and GRIN2B on developmental processes underlying learning and memory as well as other neurological functions in children and demonstrate, further, modification of Pb effects on these processes by specific variants of both GRIN2A and GRIN2B genes. These observations highlight the importance of genetic factors in defining susceptibility to Pb neurotoxicity and may have important public health implications for future strategies aimed at protecting children and adolescents from potential health risks associated with low-level Pb exposure.

Genetic polymorphisms of catechol-O-methyltransferase modify the neurobehavioral effects of mercury in children.

Mercury (Hg) is neurotoxic and children may be particularly susceptible to this effect. A current major challenge is identification of children who may be uniquely susceptible to Hg toxicity because of genetic disposition. This study examined the hypothesis that genetic variants of catechol-O-methyltransferase (COMT) that are reported to alter neurobehavioral functions that are also affected by Hg in adults might modify the adverse neurobehavioral effects of Hg exposure in children. Five hundred and seven children, 8-12 yr of age at baseline, participated in a clinical trial to evaluate the neurobehavioral effects of Hg from dental amalgam tooth fillings. Subjects were evaluated at baseline and at seven subsequent annual intervals for neurobehavioral performance and urinary Hg levels. Following the clinical trial, genotyping assays were performed for single-nucleotide polymorphisms (SNPs) of COMT rs4680, rs4633, rs4818, and rs6269 on biological samples provided by 330 of the trial participants. Regression-modeling strategies were employed to evaluate associations between allelic status, Hg exposure, and neurobehavioral test outcomes. Similar analysis was performed using haplotypes of COMT SNPs. Among girls, few interactions for Hg exposure and COMT variants were found. In contrast, among boys, numerous gene-Hg interactions were observed between individual COMT SNPs, as well as with a common COMT haplotype affecting multiple domains of neurobehavioral function. These findings suggest increased susceptibility to the adverse neurobehavioral effects of Hg among children with common genetic variants of COMT, and may have important implications for strategies aimed at protecting children from the potential health risks associated with Hg exposure.

Regenerative rehabilitation with conductive biomaterials for spinal cord injury.

The individual approaches of regenerative medicine efforts alone and rehabilitation efforts alone have not yet fully restored function after severe spinal cord injury (SCI). Regenerative rehabilitation may be leveraged to promote regeneration of the spinal cord tissue, and promote reorganization of the regenerated neural pathways and intact spinal circuits for better functional recovery for SCI. Conductive biomaterials may be a linchpin that empowers the synergy between regenerative medicine and rehabilitation approaches, as electrical stimulation applied to the spinal cord could facilitate neural reorganization. In this review, we discuss current regenerative medicine approaches in clinical trials and the rehabilitation, or neuromodulation, approaches for SCI, along with their respective translational limitations. Furthermore, we review the translational potential, in a surgical context, of conductive biomaterials (e.g., conductive polymers, carbon-based materials, metallic nanoparticle-based materials) as they pertain to SCI. While pre-formed scaffolds may be difficult to translate to human contusion SCIs, injectable composites that contain blended conductive components and can form within the injury may be more translational. However, given that there are currently no in vivo SCI studies that evaluated conductive materials combined with rehabilitation approaches, we discuss several limitations of conductive biomaterials, including demonstrating safety and efficacy, that will need to be addressed in the future for conductive biomaterials to become SCI therapeutics. Even so, the use of conductive biomaterials creates a synergistic opportunity to merge the fields of regenerative medicine and rehabilitation and redefine what regenerative rehabilitation means for the spinal cord. STATEMENT OF SIGNIFICANCE: For spinal cord injury (SCI), the individual approaches of regenerative medicine and rehabilitation are insufficient to fully restore functional recovery; however, the goal of regenerative rehabilitation is to combine these two disparate fields to maximize the functional outcomes. Concepts similar to regenerative rehabilitation for SCI have been discussed in several reviews, but for the first time, this review considers how conductive biomaterials may synergize the two approaches. We cover current regenerative medicine and rehabilitation approaches for SCI, and the translational advantages and disadvantages, in a surgical context, of conductive biomaterials used in biomedical applications that may be additionally applied to SCI. Furthermore, we identify the current limitations and translational challenges for conductive biomaterials before they may become therapeutics for SCI.

The association between serotonin transporter gene promotor polymorphism (5-HTTLPR) and elemental mercury exposure on mood and behavior in humans.

A functional polymorphism in the serotonin transporter (5-HTT) gene-linked polymorphic region (5-HTTLPR) is reported to affect mood and behavior in humans. In this study, the effects of 5-HTTLPR polymorphism on neurobehavioral and mood domains that are known to be affected by elemental mercury (Hg degrees ) exposure in human subjects were examined. The Behavioral Evaluation for Epidemiologic Studies (BEES) test battery was administered concurrently with urine and buccal-cell collections for 164 male dentists (DD) and 101 female dental assistants (DA) with occupational exposure to Hg degrees for an average of 19 and 10 yr, respectively. Geometric mean urinary mercury (Hg) levels in DD and DA were 2.52 (2.22) microg/L and 1.98 (1.98) microg/L, respectively. Corresponding indices of chronic occupational Hg degrees exposure, weighted for historical exposure, were 1212 (1877) and 316 (429). 5-HTTLPR status was 40% and 20% wild type, 40% and 56% single allelic substitution, and 20% and 24% double allelic substitution for the two genders. DD and DA were evaluated separately. Regression analyses controlled for age, premorbid intelligence, frequency of alcohol per week, and education. 5-HTTLPR polymorphism was associated with 5 behavioral measures in DD and with 12 behavioral measures in DA. Mood scores were more consistently associated with the variant in both groups. The strongest evidence for an additive effect for urinary Hg and 5-HTTLPR polymorphism in both groups was for tests of Finger Tap(Alternate) and Hand Steadiness(Factor1). Other significant additive effects that were less consistent across groups were also observed. These results add to the growing evidence of genetic determinants of mood and behavior that potentially increase susceptibility to Hg toxicity in humans.

Tooth agenesis patterns in bilateral cleft lip/palate (BCLP) indicate possible common genetic pathways.

ARTICLE TITLE AND BIBLIOGRAPHIC INFORMATION: Tooth agenesis patterns in bilateral cleft lip and palate. Bartzela TN, Carels CEL, Bronkhorst EM, Ronning E, Rizell S, Kuijpers-Jagtman AM. Eur J Oral Sci 2010;118:47-52. REVIEWER: Michael D. Martin, DMD, MSD, MPH, MA, PhD. PURPOSE/QUESTION: Are there patterns of tooth agenesis in BCLP that may indicate genetic contributions common to tooth developmental anomalies and cleft lip/palate? SOURCE OF FUNDING: Supported by the Department of Dentistry, Radboud University Nijmegen Medical Center, the Netherlands. TYPE OF STUDY/DESIGN: Retrospective cohort. LEVEL OF EVIDENCE: Level 2: Limited-quality, patient-oriented evidence. STRENGTH OF RECOMMENDATION GRADE: Not applicable.

Genomic Adaptations and Evolutionary History of the Extinct Scimitar-Toothed Cat, Homotherium latidens.

Homotherium was a genus of large-bodied scimitar-toothed cats, morphologically distinct from any extant felid species, that went extinct at the end of the Pleistocene [1-4]. They possessed large, saber-form serrated canine teeth, powerful forelimbs, a sloping back, and an enlarged optic bulb, all of which were key characteristics for predation on Pleistocene megafauna [5]. Previous mitochondrial DNA phylogenies suggested that it was a highly divergent sister lineage to all extant cat species [6-8]. However, mitochondrial phylogenies can be misled by hybridization [9], incomplete lineage sorting (ILS), or sex-biased dispersal patterns [10], which might be especially relevant for Homotherium since widespread mito-nuclear discrepancies have been uncovered in modern cats [10]. To examine the evolutionary history of Homotherium, we generated a ∼7x nuclear genome and a ∼38x exome from H. latidens using shotgun and target-capture sequencing approaches. Phylogenetic analyses reveal Homotherium as highly divergent (∼22.5 Ma) from living cat species, with no detectable signs of gene flow. Comparative genomic analyses found signatures of positive selection in several genes, including those involved in vision, cognitive function, and energy consumption, putatively consistent with diurnal activity, well-developed social behavior, and cursorial hunting [5]. Finally, we uncover relatively high levels of genetic diversity, suggesting that Homotherium may have been more abundant than the limited fossil record suggests [3, 4, 11-14]. Our findings complement and extend previous inferences from both the fossil record and initial molecular studies, enhancing our understanding of the evolution and ecology of this remarkable lineage.

Catechol O-methyltransferase (COMT) VAL158MET functional polymorphism, dental mercury exposure, and self-reported symptoms and mood.

Associations were evaluated between a functional single nucleotide polymorphism (Val158Met) in the gene encoding the catecholamine catabolic enzyme catechol O-methyltransferase (COMT), dental mercury exposure, and self-reported symptoms and mood among 183 male dentists and 213 female dental assistants. Self-reported symptoms, mood, and detailed work histories were obtained by computerized questionnaire. Spot urine samples were collected and analyzed for mercury concentrations to evaluate recent exposures, whereas a chronic mercury exposure index for all subjects was created from the work histories. COMT polymorphism status was determined using a polymerase chain reaction (PCR)-based assay. Scores for current, recent, and chronic self-reported symptom groups and six self-reported mood factors were evaluated with respect to recent and chronic mercury exposure and COMT polymorphism status. Multiple regression analysis controlled for age, socioeconomic status, tobacco and alcohol use, self-reported health problems, and medications. Separate evaluations were conducted for dentists and dental assistants. No consistent patterns of association between either urinary mercury concentration or the chronic index of mercury exposure and any category of symptoms were observed. However, consistent and significant associations were found between increased symptoms and the COMT polymorphism involving the double allelic substitution (full mutation) compared to subjects with no substitutions. Associations with mood were limited to polymorphism status among female dental assistants, and were observed for four of six mood factors and overall mood score. These findings extend evidence of genetic factors potentially affecting human susceptibility to the toxic effects of mercury and other environmental chemicals.

Urinary porphyrin excretion in children with mercury amalgam treatment: findings from the Casa Pia Children's Dental Amalgam Trial.

Increases in the urinary concentrations of pentacarboxyl- and coproporphyrins and the appearance of the atypical precoproporphyrin have been defined in relation to mercury (Hg) body burden in animal studies, and this change in the porphyrin excretion pattern has been described as a biomarker of occupational Hg exposure and toxicity in adult human subjects. In the present studies, urinary porphyrins were determined in relation to Hg exposure in children and adolescents, 8-18 yr of age, over the 7-yr course of a clinical trial designed to evaluate the neurobehavioral and renal effects of dental amalgam in children. Subjects were randomized to either dental amalgam or composite resin treatments. Urinary porphyrins and creatinine concentrations were measured at baseline and annually in all subjects. Results were evaluated using linear regression analysis. No significant differences between treatment groups (amalgam versus composite) were found when comparing all subjects for any of the porphyrins of interest. However, incipent amalgam treatment-specific increases were observed in the mean concentrations of penta-, precopro- and coproporphyrins especially when the analyses were restricted to younger subjects (8 to 9 yr old at baseline), and these increases were most apparent during yr 2 through 3 of follow-up, the period of highest mercury exposure from amalgam treatment. Based on the mean number of amalgam fillings received by children in this group (17.8), the renal Hg concentration associated with incipient increases in urinary porphyrins was estimated to be approximately 2.7 microg/g renal cortex. This value corresponds to an observed mean urinary Hg concentration of 3.2 microg/g creatinine, which is approximately fivefold less than that at which renal damage from Hg exposure is estimated to occur in children. These findings are consistent with growing evidence supporting the sensitivity of urinary porphyrins as a biological indicator of subclinical Hg exposure in children.

Biomarkers of kidney integrity in children and adolescents with dental amalgam mercury exposure: findings from the Casa Pia children's amalgam trial.

Mercury is toxic to the kidney, and dental amalgam is a source of mercury exposure. Few studies have evaluated the effects of dental amalgam on kidney function in a longitudinal context in children. Here, we evaluated urinary concentrations of glutathione S-transferases (GSTs) alpha and pi as biomarkers of renal proximal and distal tubular integrity, respectively, and albumin as a biomarker of glomerular integrity in children and adolescents 8-18 years of age over a 7-year course of dental amalgam treatment. Five hundred seven children, 8-12 years of age at baseline, participated in a clinical trial to evaluate the neurobehavioral and renal effects of dental amalgam in children. Subjects were randomized to either dental amalgam or resin composite treatments. Urinary GSTs alpha and pi, albumin, and creatinine concentrations were measured at baseline and annually in all subjects. Results were evaluated using linear regression analysis. GST-alpha concentrations were similar between treatment groups and in each sex and race (white vs. non-white) group in each follow-up year. GST-pi levels tended upward over the course of follow-up by four- to six-fold. This increase was seen in all groups irrespective of the treatment, race, or gender. Females had GST-pi levels approximately twice those of males at all ages. Albumin concentrations were constant throughout the follow-up period and did not differ by treatment, although females had 39% higher albumin levels than males. Additionally, we found no significant effects of amalgam treatment on the proportion of children with microalbuminuria (>30 mg/g creatinine). These findings are relevant within the context of children's health risk assessment as relates to the safety of mercury exposure from dental amalgam on kidney function. These data also provide normative values for sensitive indices of renal functional integrity that may serve in the evaluation of children and adolescents with renal disorders.

The serial use of child neurocognitive tests: development versus practice effects.

When serial neurocognitive assessments are performed, 2 main factors are of importance: test-retest reliability and practice effects. With children, however, there is a third, developmental factor, which occurs as a result of maturation. Child tests recognize this factor through the provision of age-corrected scaled scores. Thus, a ready-made method for estimating the relative contribution of developmental versus practice effects is the comparison of raw (developmental and practice) and scaled (practice only) scores. Data from a pool of 507 Portuguese children enrolled in a study of dental amalgams (T. A. DeRouen, B. G. Leroux, et al., 2002; T. A. DeRouen, M. D. Martin, et al., 2006) showed that practice effects over a 5-year period varied on 8 neurocognitive tests. Simple regression equations are provided for calculating individual retest scores from initial test scores.

Neurological outcomes in children with and without amalgam-related mercury exposure: seven years of longitudinal observations in a randomized trial.

BACKGROUND: Although large-scale, randomized trials involving children have been completed and their results demonstrate an absence of neurobehavioral effects from clinical exposure to mercury amalgam, neurological findings from such studies have not been reported. METHODS: The authors conducted a randomized, prospective trial examining the safety of dental amalgam in which 507 children aged 8 through 12 years were assigned to treatment with either amalgam or resin-based composite. During seven years of follow-up, the authors performed annual clinical neurological examinations, including an evaluation of neurological hard signs (NHSs), presence of tremor and neurological soft signs (NSSs). RESULTS: The authors found no significant differences between treatment groups in any of the neurological measures. Groups did not differ with respect to the presence or absence of NHSs or tremor, nor the presence or absence or severity of NSSs at any point. As expected, NSS severity scores diminished with increasing age. CONCLUSIONS: Even at the levels of amalgam exposure in this study (a mean of 7.7-10.7 amalgam surfaces per subject across the seven years of follow-up), the authors conclude that exposure to mercury from dental amalgam does not adversely affect neurological status. CLINICAL IMPLICATIONS: The current evidence is that potential neurobehavioral or neurological effects from dental amalgam mercury exposure in children are inconsequential.

The contribution of dental amalgam to urinary mercury excretion in children.

BACKGROUND: Urinary mercury concentrations are widely used as a measure of mercury exposure from dental amalgam fillings. No studies have evaluated the relationship of these measures in a longitudinal context in children. OBJECTIVE: We evaluated urinary mercury in children 8-18 years of age in relation to number of amalgam surfaces and time since placement over a 7-year course of amalgam treatment. METHODS: Five hundred seven children, 8-10 years of age at baseline, participated in a clinical trial to evaluate the neurobehavioral effects of dental amalgam in children. Subjects were randomized to either dental amalgam or resin composite treatments. Urinary mercury and creatinine concentrations were measured at baseline and annually on all participants. RESULTS: Treatment groups were comparable in baseline urinary mercury concentration (approximately 1.5 microg/L). Mean urinary mercury concentrations in the amalgam group increased to a peak of approximately 3.2 microg/L at year 2 and then declined to baseline levels by year 7 of follow-up. There was a strong, positive association between urinary mercury and both number of amalgam surfaces and time since placement. Girls had significantly higher mean urinary mercury concentrations than boys throughout the course of amalgam treatment. There were no differences by race in urinary mercury concentration associated with amalgam exposure. CONCLUSIONS: Urinary mercury concentrations are highly correlated with both number of amalgam fillings and time since placement in children. Girls excrete significantly higher concentrations of mercury in the urine than boys with comparable treatment, suggesting possible sex-related differences in mercury handling and susceptibility to mercury toxicity.

The association of dental caries with blood lead in children when adjusted for IQ and neurobehavioral performance.

UNLABELLED: Associations between childhood lead exposures and dental caries in children have been reported for over 30 years, with widely varying findings and conclusions, and using measures of lead exposure which ranged from food sources and water to tooth, hair or blood lead concentrations. OBJECTIVES: This study examined the relationship of lead exposure and dental caries in a population of normatively healthy children. METHODS: This cross-sectional study used a population of 507 children aged 8-12 who were participating in a clinical trial of dental materials to examine the relationship between lead and caries. Blood lead concentrations and dental caries were examined for association in both primary and permanent teeth. Because it is possible that neurobehavioral status could be associated with both lead exposure and dental caries prevalence, we also examined neurobehavioral status of the subjects. RESULTS: A gender-specific association (males only) between lead exposure and dental caries was found in primary teeth only. Neurobehavioral measures and IQ were not associated with caries status in this population. CONCLUSIONS: This study did not support neurobehavioral status as mediating any association between lead exposure and caries in a normatively healthy population. A gender-specific association between lead and caries not previously reported was found in primary teeth, and no biological explanation for this has been suggested. We conclude that this study provides only weak evidence, if any, for an association of low-level lead exposure with dental caries.

Survival and reasons for failure of amalgam versus composite posterior restorations placed in a randomized clinical trial.

BACKGROUND: Failure of dental restorations is a major concern in dental practice. Replacement of failed restorations constitutes the majority of operative work. Clinicians should be aware of the longevity of, and likely reasons for the failure of, direct posterior restorations. In a long-term, randomized clinical trial, the authors compared the longevity of amalgam and composite. SUBJECTS, METHODS AND MATERIALS: The authors randomly assigned one-half of the 472 subjects, whose age ranged from 8 through 12 years, to receive amalgam restorations in posterior teeth and the other one-half to receive resin-based composite restorations. Study dentists saw subjects annually to conduct follow-up oral examinations and take bitewing radiographs. Restorations needing replacement were failures. The dentists recorded differential reasons for restoration failure. RESULTS: Subjects received a total of 1,748 restorations at baseline, which the authors followed for up to seven years. Overall, 10.1 percent of the baseline restorations failed. The survival rate of the amalgam restorations was 94.4 percent; that of composite restorations was 85.5 percent. Annual failure rates ranged from 0.16 to 2.83 percent for amalgam restorations and from 0.94 to 9.43 percent for composite restorations. Secondary caries was the main reason for failure in both materials. Risk of secondary caries was 3.5 times greater in the composite group. CONCLUSION: Amalgam restorations performed better than did composite restorations. The difference in performance was accentuated in large restorations and in those with more than three surfaces involved. CLINICAL IMPLICATIONS: Use of amalgam appears to be preferable to use of composites in multisurface restorations of large posterior teeth if longevity is the primary criterion in material selection.

Neurobehavioral effects of dental amalgam in children: a randomized clinical trial.

CONTEXT: Dental (silver) amalgam is a widely used restorative material containing 50% elemental mercury that emits small amounts of mercury vapor. No randomized clinical trials have determined whether there are significant health risks associated with this low-level mercury exposure. OBJECTIVE: To assess the safety of dental amalgam restorations in children. DESIGN: A randomized clinical trial in which children requiring dental restorative treatment were randomized to either amalgam for posterior restorations or resin composite instead of amalgam. Enrollment commenced February 1997, with annual follow-up for 7 years concluding in July 2005. SETTING AND PARTICIPANTS: A total of 507 children in Lisbon, Portugal, aged 8 to 10 years with at least 1 carious lesion on a permanent tooth, no previous exposure to amalgam, urinary mercury level <10 microg/L, blood lead level <15 microg/dL, Comprehensive Test of Nonverbal Intelligence IQ > or =67, and with no interfering health conditions. INTERVENTION: Routine, standard-of-care dental treatment, with one group receiving amalgam restorations for posterior lesions (n = 253) and the other group receiving resin composite restorations instead of amalgam (n = 254). MAIN OUTCOME MEASURES: Neurobehavioral assessments of memory, attention/concentration, and motor/visuomotor domains, as well as nerve conduction velocities. RESULTS: During the 7-year trial period, children had a mean of 18.7 tooth surfaces (median, 16) restored in the amalgam group and 21.3 (median, 18) restored in the composite group. Baseline mean creatinine-adjusted urinary mercury levels were 1.8 microg/g in the amalgam group and 1.9 microg/g in the composite group, but during follow-up were 1.0 to 1.5 microg/g higher in the amalgam group than in the composite group (P<.001). There were no statistically significant differences in measures of memory, attention, visuomotor function, or nerve conduction velocities (average z scores were very similar, near zero) for the amalgam and composite groups over all 7 years of follow-up, with no statistically significant differences observed at any time point (P values from .29 to .91). Starting at 5 years after initial treatment, the need for additional restorative treatment was approximately 50% higher in the composite group. CONCLUSIONS: In this study, children who received dental restorative treatment with amalgam did not, on average, have statistically significant differences in neurobehavioral assessments or in nerve conduction velocity when compared with children who received resin composite materials without amalgam. These findings, combined with the trend of higher treatment need later among those receiving composite, suggest that amalgam should remain a viable dental restorative option for children. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00066118.

Dental fear in a special needs clinic population of persons with disabilities.

This study reports findings from a survey of dental fear in a special needs dental clinic population. Subjects were recruited from the University of Washington's Dental Education in Care of Persons With Disabilities (DECOD) clinical program (n = 132). Dental fears were assessed using the Kleinknecht Dental Report. Fear levels were examined among patients with differing categories of primary disabilities and between genders, races and educational levels. Some level of dental fear was reported by 43.2% of the respondents, indicating that dental fear may be an important factor in dental care for this population. Gender and educational level were significantly associated with fear levels (both p < 0.05). Significant differences in fear levels were found between individuals with differing classes of disability. Accompanying caregivers also were interviewed (n = 72) to allow for a comparison of patient and caregiver perceptions. Both patient and caregiver were interviewed whenever possible to create paired reports. Generally, caregivers significantly overestimated fear levels compared with patients (p < 0.01). However, when scores were compared in matched caregiver-patient analyses, the fear scores were not significantly different, indicating that caregivers accurately estimated their client's level of dental fear. A regression model including disability group, gender, and years of education was significant for predicting fear level as measured by the Kleinknecht survey (p = 0.02). We conclude that dental fear may be a significant, though little understood problem for a population of persons with disabilities as well as for their oral care providers, and that further investigation is needed.

Genetic polymorphisms affecting susceptibility to mercury neurotoxicity in children: summary findings from the Casa Pia Children's Amalgam clinical trial.

Mercury (Hg) is neurotoxic, and children may be particularly susceptible to this effect. A current major challenge is identification of children who may be uniquely susceptible to Hg toxicity because of genetic predisposition. We examined the possibility that common genetic variants that are known to affect neurologic functions or Hg handling in adults would modify the adverse neurobehavioral effects of Hg exposure in children. Three hundred thirty subjects who participated as children in the recently completed Casa Pia Clinical Trial of Dental Amalgams in Children were genotyped for 27 variants of 13 genes that are reported to affect neurologic functions and/or Hg disposition in adults. Urinary Hg concentrations, reflecting Hg exposure from any source, served as the Hg exposure index. Regression modeling strategies were employed to evaluate potential associations between allelic status for individual genes or combinations of genes, Hg exposure, and neurobehavioral test outcomes assessed at baseline and for 7 subsequent years during the clinical trial. Among boys, significant modification of Hg effects on neurobehavioral outcomes over a broad range of neurologic domains was observed with variant genotypes for 4 of 13 genes evaluated. Modification of Hg effects on a more limited number of neurobehavioral outcomes was also observed for variants of another 8 genes. Cluster analyses suggested some genes interacting in common processes to affect Hg neurotoxicity. In contrast, significant modification of Hg effects on neurobehavioral functions among girls with the same genotypes was substantially more limited. These observations suggest increased susceptibility to the adverse neurobehavioral effects of Hg among children, particularly boys, with genetic variants that are relatively common to the general human population. These findings advance public health goals to identify factors underlying susceptibility to Hg toxicity and may contribute to strategies for preventing adverse health risks associated with Hg exposure.

Modification of neurobehavioral effects of mercury by genetic polymorphisms of metallothionein in children.

Mercury (Hg) is neurotoxic, and children may be particularly susceptible to this effect. A current major challenge is the identification of children who may be uniquely susceptible to Hg toxicity because of genetic disposition. We examined the hypothesis that genetic variants of metallothionein (MT) that are reported to affect Hg toxicokinetics in adults would modify the neurotoxic effects of Hg in children. Five hundred seven children, 8-12 years of age at baseline, participated in a clinical trial to evaluate the neurobehavioral effects of Hg from dental amalgam tooth fillings. Subjects were evaluated at baseline and at 7 subsequent annual intervals for neurobehavioral performance and urinary Hg levels. Following the completion of the clinical trial, we performed genotyping assays for variants of MT isoforms MT1M (rs2270837) and MT2A (rs10636) on biological samples provided by 330 of the trial participants. Regression modeling strategies were employed to evaluate associations between allelic status, Hg exposure, and neurobehavioral test outcomes. Among girls, few significant interactions or independent main effects for Hg exposure and either of the MT gene variants were observed. In contrast, among boys, numerous significant interaction effects between variants of MT1M and MT2A, alone and combined, with Hg exposure were observed spanning multiple domains of neurobehavioral function. All dose-response associations between Hg exposure and test performance were restricted to boys and were in the direction of impaired performance. These findings suggest increased susceptibility to the adverse neurobehavioral effects of Hg among children with relatively common genetic variants of MT, and may have important public health implications for future strategies aimed at protecting children and adolescents from the potential health risks associated with Hg exposure. We note that because urinary Hg reflects a composite exposure index that cannot be attributed to a specific source, these findings do not support an association between Hg in dental amalgams specifically and the adverse neurobehavioral outcomes observed.