title: The association between a genetic polymorphism of coproporphyrinogen oxidase, dental mercury exposure and neurobehavioral response in humans.
abstract: 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.
authors.affiliation: Battelle Centers for Public Health Research and Evaluation, 1100 Dexter Avenue North, Suite 400, Seattle, WA 98109, United States. echeverr@battelle.org
authors.forename: Diana
authors.initials: D
authors.lastname: Echeverria
authors.forename: James S
authors.initials: JS
authors.lastname: Woods
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Heyer
authors.forename: Dianne
authors.initials: D
authors.lastname: Rohlman
authors.forename: Federico M
authors.initials: FM
authors.lastname: Farin
authors.forename: Tingting
authors.initials: T
authors.lastname: Li
authors.forename: Claire E
authors.initials: CE
authors.lastname: Garabedian
mesh_terms: D000328:Adult; D001526:Behavioral Symptoms / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics; D003072:Cognition Disorders / Q000139:chemically induced* / Q000201:enzymology / Q000235:genetics; D003304:Coproporphyrinogen Oxidase / Q000235:genetics*; D004252:DNA Mutational Analysis; D003813:Dentistry / Q000706:statistics & numerical data*; D003866:Depressive Disorder / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D005838:Genotype; D006801:Humans; D008297:Male; D008628:Mercury / Q000009:adverse effects / Q000652:urine; D020262:Mercury Poisoning, Nervous System / Q000201:enzymology* / Q000235:genetics* / Q000503:physiopathology; D008875:Middle Aged; D009483:Neuropsychological Tests; D016273:Occupational Exposure / Q000009:adverse effects*; D011110:Polymorphism, Genetic / Q000235:genetics; D011597:Psychomotor Performance / Q000187:drug effects / Q000502:physiology
chemical_list: D003304:Coproporphyrinogen Oxidase; D008628:Mercury