Development of a Semiautomated Search Tool to Identify Grading From Pathology Reports for Tumors of the CNS and Prostate Cancers.

PURPOSE: This study demonstrates the functionality of semiautomated algorithms to classify cancer-specific grading from electronic pathology reports generated from military treatment facilities. Two Perl-based algorithms are validated to classify WHO grade for tumors of the CNS and Gleason grades for prostate cancer. METHODS: Case-finding cohorts were developed using diagnostic codes and matched by unique identifiers to obtain pathology records generated in the Military Health System for active duty service members from 2013 to 2018. Perl-based algorithms were applied to classify document-based pathology reports to identify malignant CNS tumors and prostate cancer, followed by a hand-review process to determine accuracy of the algorithm classifications. Inter-rater reliability, sensitivity, specificity, positive predictive values (PPVs), and negative predictive values were computed following abstractor adjudication. RESULTS: The high PPV for the Perl-based algorithms to classify CNS tumors (PPV > 98%) and prostate cancer (PPV > 99%) supports this approach to classify malignancies for cancer surveillance operations, mediated by a hand-reviewed semiautomated process to increase sensitivity by capturing ungraded cancers. Early detection was pronounced where 33.6% and 50.7% of malignant records retained a CNS WHO grade of II or a Gleason score of 6, respectively. Sensitivity metrics met criteria (> 75%) for brain (79.9%, 95% CI, 73.0 to 85.7) and prostate (96.7%, 95% CI, 94.9 to 98.0) cancers. CONCLUSION: Semiautomated, document-based text classification using Perl coding successfully leveraged identification of WHO and Gleason grades to classify pathology records for CNS tumors and prostate cancer. The process is recommended for data quality initiatives to support cancer reporting functions, epidemiology, and research.

Perfluoroalkyl substances exposure and immunity, allergic response, infection, and asthma in children: review of epidemiologic studies.

BACKGROUND: Increased exposure to perfluoroalkyl substances (PFAS) potentially affects infant and childhood health through immunosuppression. Given rapidly evolving research on PFAS, it is important to comprehensively examine the impact of PFAS exposure among the pediatric population as new research becomes available due to potential fragility of the developing immune system. OBJECTIVES: This review assessed the effects of PFAS fetal, infant and childhood exposures upon the development of immune function during early life stages. METHODS: Researchers completed a literature review, searching PubMed for human studies published since 2010 for PFAS and health outcomes among infants and children. Included articles incorporated key search terms in the title or abstract; non-research reports and non-English papers were excluded. The search identified 518 studies for possible inclusion. Following hands-on review, 34 were determined relevant. Subsequent analyses found 8 additional relevant articles, totaling 42 studies. RESULTS: Major immune-related sequelae from PFAS exposures on infant and child health outcomes documented in recent literature include:• Strong indication of immunosuppression, with diminished childhood antibody response to vaccination, particularly with PFOA, PFOS and PFHxS exposures.• Some indication of increased risks of childhood infectious diseases/infections, particularly from PFOS exposures.• Limited indication of an effect of PFAS exposure on allergic reactions/allergen specific IgE antibodies.• Limited indication of an effect of PFAS exposure on atopic dermatitis (AD).• Limited indication of an effect of PFAS exposure on asthma and lung function. CONCLUSION: This review summarizes recent findings of PFAS effects on infant and childhood immune health. Evidence of immunosuppression, diminished vaccine efficacy, and increased risk of infections, allergies, asthma and AD were described following in utero, infant, and early childhood PFAS exposures. Further investigation is warranted to characterize PFAS exposure pathways and potential modes of action in relation to PFAS effects on the developing immune system. Incontrovertible proof of PFAS immunotoxic effects could optimally be obtained by a large prospective study cohort of mothers and children from infancy through school-age. Regular assessments of circulating antibodies and response to infant and childhood vaccines during growth years could prove invaluable.

Development and Evaluation of Perl-Based Algorithms to Classify Neoplasms From Pathology Records in Synoptic Report Format.

PURPOSE: Synoptic reporting provides a mechanism for uniform and structured pathology diagnostics. This paper demonstrates the functionality of Perl alternation and grouping expressions to classify electronic pathology reports generated from military treatment facilities. Eight Perl-based algorithms are validated to classify malignant melanoma, Hodgkin lymphoma, non-Hodgkin lymphoma, leukemia, and malignant neoplasms of the breast, ovary, testis, and thyroid. METHODS: Case finding cohorts were developed using diagnostic codes for neoplasm groups and matched by unique identifiers to obtain pathology records. Preprocessing techniques and Perl-based algorithms were applied to classify records as malignant, in situ, suspect, or nonapplicable, followed by a hand-review process to determine the accuracy of the algorithm classifications. Interrater reliability, sensitivity, specificity, positive predictive values, and negative predictive values were computed following abstractor adjudication. RESULTS: The specificity of the Perl-based algorithms was consistently high, over 98%. Very few benign results were classified as malignant or in situ by the Perl-based algorithms; the leukemia algorithm classification was the only group to demonstrate a positive predictive value below 95%, at 91.9%. Three algorithm classification groups demonstrated a sensitivity of < 80%, including malignant neoplasm of the ovary (33.3%), leukemia (52.8%), and non-Hodgkin lymphoma (62.9%). The pathology records for these results included substantial linguistic variation. CONCLUSION: This paper contextualizes the utility and value of an algorithm logic built around synoptic reporting to identify neoplasms from electronic pathology results. The major strength includes the application of Perl-based coding in SAS, an accessible software application, to develop highly specific algorithms across institutional variation in diagnostic documentation.

Correction: Rates and risk factors for human cutaneous anthrax in the country of Georgia: National surveillance data, 2008-2015.

[This corrects the article DOI: 10.1371/journal.pone.0192031.].

Rates and risk factors for human cutaneous anthrax in the country of Georgia: National surveillance data, 2008-2015.

INTRODUCTION: Anthrax is endemic in the country of Georgia. The most common cutaneous anthrax form accounts for 95% of anthrax cases and often is self-resolving. Humans are infected from processing contaminated animal products, contacting sick animals, or by insect bites. OBJECTIVE: We aimed to describe the burden of human cutaneous anthrax and associated risk factors using the national surveillance data. METHODS: We extracted all human cutaneous anthrax cases from Electronic Integrated Disease Surveillance System (EIDSS) from 1 January 2008 to 31 December 2015. We conducted descriptive analyses to characterize the number of confirmed, probable and suspected cases by age groups, gender, ethnicity, year and geographic area. RESULTS: Out of 911 reported cutaneous anthrax cases, 299 (33%) were rejected. Out of remaining 612 cases, 437 (71%), 172 (28%), and 3 (<0.004%) were classified as confirmed, probable and suspected cases of cutaneous Anthrax, respectively; 467 (76.3%) were male. Georgians accounted for 56% (343/612) of cutaneous anthrax cases. Handling animal products (aOR 4.36, 95% CI 2.61-7.26) and living near pastoralist routes (aOR 2.74, 95%CI 1.57-4.76) were associated with cutaneous anthrax. CONCLUSIONS: This study provides eight-year trends for cutaneous anthrax in humans in the country of Georgia. A comprehensive explanation for the observed rise and fall of the incidence rates of human cutaneous anthrax in 2008-2015 remains to be clarified but is likely associated with discontinuation of mandatory national livestock vaccination in 2008 coupled with weakened human and animal national health systems which were disrupted after the Soviet Union collapsed. Our analysis identifies living near pastoralist routes, handling animal products and travel to endemic areas within two weeks before the disease onset as risk factors for cutaneous anthrax. The evidence underscores the importance of One Health recommendations to activate anthrax awareness campaigns, supervise the destruction of known anthrax carcasses, record global position system coordinates of sites and disinfect infected soils and introduce a participatory health education tool on anthrax.

Solvent neurotoxicity in vehicle collision repair workers in New Zealand.

OBJECTIVES: To assess whether solvent use and workplace practices in the vehicle collision repair industry are associated with symptoms of neurotoxicity in spray painters and panel beaters (auto body repair workers). METHODS: Neurobehavioural symptoms were assessed using a cross-sectional study design in 370 vehicle collision repair and 211 reference workers using the EUROQUEST questionnaire. Full-shift airborne solvent levels were measured in a subset (n=92) of collision repair workers. RESULTS: Solvent exposures were higher in spray painters than in panel beaters, but levels were below current international exposure standards. Collision repair workers were more likely to report symptoms of neurotoxicity than reference workers with ORs of 2.0, 2.4 and 6.4 (all p<0.05) for reporting ≥5, ≥10 and ≥15 symptoms respectively. This trend was generally strongest for panel beaters (ORs of 2.1, 3.3 and 8.2 for ≥5, ≥10 and ≥15 symptoms respectively). Associations with specific symptom domains showed increased risks for neurological (OR 4.2), psychosomatic (OR 3.2), mood (OR 2.1), memory (OR 2.9) and memory and concentration symptoms combined (OR 2.4; all p<0.05). Workers who had worked for 10-19 years or 20+ years in the collision repair industry reported consistently more symptoms than those who had only worked less than 10 years even after adjusting for age. However, those who worked more than 20 years generally reported fewer symptoms than those who worked 10-19 years, suggesting a possible healthy worker survivor bias. CONCLUSIONS: Despite low airborne solvent exposures, vehicle collision repair spray painters and panel beaters continue to be at risk of symptoms of neurotoxicity.

Modification of neurobehavioral effects of mercury by a genetic polymorphism of coproporphyrinogen oxidase 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 CPOX4, a genetic variant of the heme pathway enzyme coproporphyrinogen oxidase (CPOX) that affects susceptibility to mercury toxicity in adults, also modifies 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 in children. Subjects were evaluated at baseline and at 7 subsequent annual intervals for neurobehavioral performance and urinary mercury levels. Following the completion of the clinical trial, genotyping assays for CPOX4 allelic status were performed on biological samples provided by 330 of the trial participants. Regression modeling strategies were employed to evaluate associations between CPOX4 status, Hg exposure, and neurobehavioral test outcomes. Among girls, few significant CPOX4-Hg interactions or independent main effects for Hg or CPOX4 were observed. In contrast, among boys, numerous significant interaction effects between CPOX4 and Hg were observed spanning all 5 domains of neurobehavioral performance. All underlying dose-response associations between Hg exposure and test performance were restricted to boys with the CPOX4 variant, and all of these associations were in the expected direction where increased exposure to Hg decreased performance. These findings are the first to demonstrate genetic susceptibility to the adverse neurobehavioral effects of Hg exposure in children. The paucity of responses among same-age girls with comparable Hg exposure provides evidence of sexual dimorphism in genetic susceptibility to the adverse neurobehavioral effects of Hg in children and adolescents.

Disordered porphyrin metabolism: a potential biological marker for autism risk assessment.

Autism (AUT) is a complex neurodevelopmental disorder that, together with Asperger's syndrome and Pervasive Developmental Disorder-Not Otherwise Specified (PDD-NOS), comprises the expanded classification of autistic spectrum disorder (ASD). The heterogeneity of ASD underlies the need to identify biomarkers or clinical features that can be employed to identify meaningful subtypes of ASD, define specific etiologies, and inform intervention and treatment options. Previous studies have shown that disordered porphyrin metabolism, manifested principally as significantly elevated urinary concentrations of pentacarboxyl (penta) and coproporphyrins, is commonly observed among some children with ASD. Here, we extend these observations by specifically evaluating penta and coproporphyrins as biological indicators of ASD among 76 male children comprising 30 with validated AUT, 14 with PDD-NOS, and 32 neurotypical (NT) controls. ASD children (AUT and PDD-NOS) had higher mean urinary penta (P < 0.006) and copro (P < 0.006) concentrations compared with same-aged NT children, each characterized by a number of extreme values. Using Receiver Operating Characteristic curve analysis, we evaluated the sensitivity and specificity of penta, copro, and their combined Z-scores in ASD detection. The penta sensitivity was 30% for AUT and 36% for PDD-NOS, with 94% specificity. The copro sensitivity was 33% and 14%, respectively, with 94% specificity. The combined Z-score measure had 33% and 21% sensitivity for AUT and PDD-NOS, respectively, with 100% specificity. These findings demonstrate that porphyrin measures are strong predictors of both AUT and PDD-NOS, and support the potential clinical utility of urinary porphyrin measures for identifying a subgroup of ASD subjects in whom disordered porphyrin metabolism may be a salient characteristic.

Inter-rater reliability of assessed prenatal maternal occupational exposures to solvents, polycyclic aromatic hydrocarbons, and heavy metals.

Because direct measurements of past occupational exposures are rarely available in population-based case-control studies, exposure assessment of job histories by multiple expert raters is frequently used; however, the subjective nature of this method makes measuring reliability an important quality control step. We evaluated inter-rater reliability of 7729 retrospective jobs reported in the National Birth Defects Prevention Study. Jobs were classified as exposed, unexposed, or exposure unknown by two independent industrial hygienists; exposed jobs were further evaluated for intensity, frequency, and routes. Exposure prevalence ranged from 0.1-9.8%. Inter-rater reliability for exposure (yes/no), assessed by kappa coefficients, was fair to good for cadmium (κ = 0.46), chlorinated solvents (κ = 0.59), cobalt (κ = 0.54), glycol ethers (κ = 0.50), nickel compounds (κ = 0.65), oil mists (κ = 0.63), and Stoddard Solvent (κ = 0.55); PAHs (κ = 0.24) and elemental nickel (κ = 0.37) had poor agreement. After a consensus conference resolved disagreements, an additional 4962 jobs were evaluated. Inter-rater reliability improved or stayed the same for cadmium (κ = 0.51), chlorinated solvents (κ = 0.81), oil mists (κ = 0.63), PAHs (κ = 0.52), and Stoddard solvent (κ = 0.92) in the second job set. Inter-rater reliability varied by exposure agent and prevalence, demonstrating the importance of measuring reliability in studies using a multiple expert rater method of exposure assessment.

Does caring for a spouse with dementia promote cognitive decline? A hypothesis and proposed mechanisms.

OBJECTIVE: To discuss why spouse caregivers (CGs) of people with dementia may be at higher risk for cognitive problems and decline than demographically similar people not caring for a spouse with dementia (noncaregivers; NCGs). DESIGN: Literature review. SETTING: Community. PARTICIPANTS: Older adults caring for a family member (primarily spouses) with dementia. MEASUREMENTS: Cognitive, psychosocial, physiological, and behavioral. RESULTS: This article reports a review of the literature examining relationships between CG status and cognitive problems in the context of a theoretical model of chronic stress. The model suggests that spouse CGs may be at higher risk of cognitive impairment or dementia than NCG spouses in response to several mediators, including psychosocial (e.g., depression, loneliness, social isolation, sleep problems), behavioral (e.g., exercise, diet), and physiological (e.g., metabolic syndrome and inflammation) variables. CONCLUSION: This research has important implications because it considers modifiable risk factors for dementia that, if unchecked, may compromise the lives of CGs and their ability to function. It is hoped that an understanding of such stress-mediator-cognitive processes will help clinicians, researchers, policy-makers, and stakeholders mitigate what may be characterized as an "ironic tragedy"-dementia in both members of the caregiving dyad-if left unchecked.

Urinary porphyrin excretion in neurotypical and autistic children.

BACKGROUND: Increased urinary concentrations of pentacarboxyl-, precopro- and copro-porphyrins have been associated with prolonged mercury (Hg) exposure in adults, and comparable increases have been attributed to Hg exposure in children with autism (AU). OBJECTIVES: This study was designed to measure and compare urinary porphyrin concentrations in neurotypical (NT) children and same-age children with autism, and to examine the association between porphyrin levels and past or current Hg exposure in children with autism. METHODS: This exploratory study enrolled 278 children 2-12 years of age. We evaluated three groups: AU, pervasive developmental disorder-not otherwise specified (PDD-NOS), and NT. Mothers/caregivers provided information at enrollment regarding medical, dental, and dietary exposures. Urine samples from all children were acquired for analyses of porphyrin, creatinine, and Hg. Differences between groups for mean porphyrin and Hg levels were evaluated. Logistic regression analysis was conducted to determine whether porphyrin levels were associated with increased risk of autism. RESULTS: Mean urinary porphyrin concentrations are naturally high in young children and decline by as much as 2.5-fold between 2 and 12 years of age. Elevated copro- (p < 0.009), hexacarboxyl- (p < 0.01) and pentacarboxyl- (p < 0.001) porphyrin concentrations were significantly associated with AU but not with PDD-NOS. No differences were found between NT and AU in urinary Hg levels or in past Hg exposure as determined by fish consumption, number of dental amalgam fillings, or vaccines received. CONCLUSIONS: These findings identify disordered porphyrin metabolism as a salient characteristic of autism. Hg exposures were comparable between diagnostic groups, and a porphyrin pattern consistent with that seen in Hg-exposed adults was not apparent.

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.

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.

Depressed mood mediates decline in cognitive processing speed in caregivers.

PURPOSE: Very few studies have examined cognitive decline in caregivers versus noncaregivers, and only 1 study has examined mediators of such decline. We evaluated the relationship between caregiver status and decline on the digit symbol test (DST; a measure of processing speed, attention, cognitive-motor translation, and visual scanning) and whether this relationship was mediated by depressed mood. DESIGN AND METHODS: Caregivers for spouses with Alzheimer's disease (n = 122) were compared with demographically similar noncaregiver spouses (n = 117) at study entry (Time 1 = T1), T2 (1 year later), and T3 (2 years after T1). RESULTS: Caregivers had lower DST scores and higher Hamilton depression scores at T1, T2, and T3 than noncaregivers (all p < .05). Hierarchical linear modeling revealed that although caregivers started well below noncaregivers, they experienced a more rapid rate of decline than noncaregivers (p = .047). Caregivers declined 4.5 times faster than noncaregivers. Greater depressed mood at T1 (p < .01) and T2 (p < .01) predicted DST decline and mediated DST decline in caregivers vs. noncaregivers. IMPLICATIONS: Depressed mood in caregivers relative to noncaregivers may influence their greater risk for DST decline. This is important because the DST predicts problem solving and everyday functions necessary for independent living and the potential well-being of their care recipients.

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.

The association between serotonin transporter gene promoter polymorphism (5-HTTLPR), self-reported symptoms, and dental mercury exposure.

The associations between a polymorphism of the serotonin transporter gene (5-HTTLPR), dental mercury exposure, and self-reported symptoms were evaluated among 157 male dentists and 84 female dental assistants. Self-reported symptoms 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 was created from the work histories. 5-HTTLPR polymorphism status was determined using a polymerase chain reaction (PCR)-based assay. Scores for current, recent, and chronic self-reported symptom groups were evaluated with respect to recent and chronic mercury exposure and 5-HTTLPR polymorphism status. Multiple regression analysis controlled for age, socioeconomic status, tobacco and alcohol use, self-reported health problems, and medications. Analyses were restricted to Caucasian subjects due to the highly skewed distribution of the 5-HTTLPR polymorphism. Separate evaluations were conducted for dentists and dental assistants. In contrast to previous reports, no consistent associations were found between either urinary mercury concentration or the chronic index of mercury exposure and any category of symptoms. However, both significant and consistent associations were observed between increased symptoms and the 5-HTTLPR polymorphism involving two copies of the short or "s" allele (full mutation), but not with the polymorphism involving only one copy (heterozygous), demonstrating a gene-dose relationship for symptom reporting. These findings suggest that within this restricted population increased symptoms of depression, anxiety, and memory are associated with the 5-HTTLPR polymorphism among both males and females.

A cascade analysis of the interaction of mercury and coproporphyrinogen oxidase (CPOX) polymorphism on the heme biosynthetic pathway and porphyrin production.

Mercury (Hg) exposure in various forms remains a persistent public health concern in many parts of the world. In previous studies, we have described a biomarker of mercury exposure characterized by increased urinary concentrations of specific porphyrins, pentacarboxyporphyrin (5-CP) and coproporphyrin (4-CP), and the atypical keto-isocoproporphyrin (KICP), based on selective interference with the fifth (uroporphyrinogen decarboxylase, UROD) and sixth (coproporphyrinogen oxidase, CPOX) enzymes of the heme biosynthetic pathway. Whereas this response occurs in a predictable manner among approximately 85% of subjects with Hg exposure, an atypical porphyrinogenic response (APR) has been observed in approximately 15% of Hg-exposed persons, in which the three porphyrins that are affected by Hg, i.e., 5-CP, 4-CP and, KICP, are excreted in substantial excess of that predicted on the basis of Hg exposure alone. This APR has been attributed to a specific polymorphism in exon 4 of the CPOX gene (CPOX4). In the present study, we sought to further confirm the hypothesis that the observed changes in porphyrin excretion patterns might serve as a biomarker of Hg exposure and potential toxicity by statistically modeling the cascading effects on porphyrin concentrations within the heme biosynthetic pathway of Hg exposure and CPOX4 polymorphism in a human population with long-term occupational exposure to elemental mercury. Our results are highly consistent with this hypothesis. After controlling for precursor porphyrin concentrations, we demonstrated that 5-CP and 4-CP are independently associated with Hg concentration, while KICP is associated only with the CPOX4. An unpredicted association of Hg with heptacarboxyporphyrin (7-CP) may indicate a previously unidentified point of mercury inhibition of UROD. These findings lend further support to the proposed utility of urinary porphyrin changes as a biomarker of exposure and potential toxicity in subjects with mercury exposure. Additionally, these findings demonstrate the successful application of a computational model for characterizing complex metabolic responses and interactions associated with both toxicant exposure and genetic variation in human subjects.

The association between a genetic polymorphism of coproporphyrinogen oxidase, dental mercury exposure and neurobehavioral response in humans.

We previously described a polymorphism in exon 4 of the gene encoding the heme biosynthetic pathway enzyme, coproporphyrinogen oxidase (CPOX4), which significantly modifies the effect of mercury exposure on urinary porphyrin excretion in humans. Here, we examined potential consequences of this polymorphism ("CPOX4") on performance within neurobehavioral domains, symptoms, and mood that are known to be affected by elemental mercury (Hg degrees ) exposure in human subjects. A behavioral test battery was administered on the day of urine and buccal cell collections for 194 male dentists (DDs) and 233 female dental assistants (DAs) occupationally exposed to Hg degrees for an average of 19 and 10 years, respectively. Subjects had no history of health disorders and were employed for a minimum of 5 years in the dental profession. Respective mean urinary mercury (HgU) levels in DDs and DAs were 3.32 (4.87) microg/l and 1.98 (2.29) microg/l. Corresponding indices of chronic occupational Hg degrees exposure, weighted for historical exposure, were 27.1 (20.6) and 15.2 (12.3). The frequencies of the homogygous common (A/A), heterozygous (A/C), and homozygous polymorphic (C/C) genotypes were 75%, 23% and 2% for DDs and 73%, 25%, and 2% for DAs, respectively. DDs and DAs were evaluated separately. Regression analyses controlled for age, premorbid intelligence, alcohol consumption, and education. Statistically significant associations with HgU (p<0.05) were found for nine measures among DDs (BEES Digit SpanForward and Backward, WMS-R Visual ReproductionN Correct, BEES Symbol DigitRate, BEES Finger TappingDom/Non-dom, and Alternate Partialed, Hand SteadinessFactor1, and BEES Tracking), and eight measures among DAs (BEES Digit SpanForward, BEES Symbol DigitRate, BEES Pattern Discrimination Rate, BEES Trailmaking B, BEES Finger TappingDom/Non-dom, and Alternate Partialed, Hand SteadinessFactor1, and Vibration SensitivityHits). CPOX4 status was associated with four measures in DDs (BEES Spatial SpanForward, BEES Pattern MemoryN Correct, BEES Symbol DigitRate, and BEES VigilanceHit) and five measures in DAs (BEES Digit SpanForward, WMS-R Visual ReproductionsN Correct, BEES Symbol DigitRate, BEES Simple and Choice Reaction TimeMove. Both groups experienced an additive effect (no interaction term) for HgU and the CPOX4 polymorphisms on the DigitRate whereas DAs also had additive effects for BEES Digit SpanForward and for Beck's Depression factor 'Worthlessness'. These exploratory findings suggest that the CPOX4 polymorphism may affect susceptibility for specific neurobehavioral functions associated with mercury exposure in human subjects.

Chronic low-level mercury exposure, BDNF polymorphism, and associations with cognitive and motor function.

Potential cognitive and motor effects from exposure to elemental mercury (Hg(0)) were examined in the presence and absence of a polymorphism (Val66Met) in brain-derived neurotrophic factor (BDNF). A group of 194 male dentists (DDs) and 233 female dental assistants (DAs) were occupationally exposed to mercury and had no history of kidney or nervous system disorders. Acute exposure was measured using spot urinary Hg (HgU) concentrations (average 3.32 and 1.98 microg/l, respectively) and indices of chronic occupational exposure (26.3 and 14.9 years, respectively, weighted for historical exposures). The BDNF status was 68% and 66% wild type, 26% and 30% single substitution, and 5% and 4% full mutation for DDs and DAs, respectively. DDs and DAs were evaluated separately. Regression analyses controlled for age, premorbid intelligence, alcohol consumption, and education. Statistically significant adverse associations with HgU (p<.05) were found for nine measures among DDs (Digit Span (Forward), Digit and Spatial Span(Backward), Visual Reproduction, Finger Tapping(Dominant, Alternate, and Alternate Partialed), Hand Steadiness, and Tracking), and eight measures among DAs (Digit Span(Forward), Visual Reproduction, Pattern Discrimination(Rate), Symbol Digit(Rate), Trailmaking B, Finger Tapping(Dominant and Alternate Partialed), and Hand Steadiness). The BDNF status was associated with four measures in DDs and three measures in DAs. Joint effects were found for Finger Tapping(Alternate and Alternate Partialed) in DDs and Hand Steadiness and Trailmaking B in DAs. Joint effects were additive in all cases. Performance on verbal intelligence and reaction time were not associated with either HgU or BDNF status. A test of threshold effect for the association of Hand Steadiness with HgU demonstrated no lower boundary in both DDs and DAs. No associations were observed with estimates of chronic mercury exposure. Our findings are applicable to exposure levels of the general population and identify a potentially vulnerable group with a BDNF polymorphism.