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°) 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° 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) μg/l and 1.98 (2.29) μg/l. Corresponding indices of chronic occupational Hg° 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 Span Forward and Backward, WMS-R Visual Reproduction N Correct, BEES Symbol Digit Rate, BEES Finger Tapping Dom/Non-dom, and Alternate Partialed, Hand Steadiness Factor1, and BEES Tracking), and eight measures among DAs (BEES Digit Span Forward, BEES Symbol Digit Rate, BEES Pattern Discrimination Rate, BEES Trailmaking B, BEES Finger Tapping Dom/Non-dom, and Alternate Partialed, Hand Steadiness Factor1, and Vibration Sensitivity Hits). CPOX4 status was associated with four measures in DDs (BEES Spatial Span Forward, BEES Pattern Memory N Correct, BEES Symbol Digit Rate, and BEES Vigilance Hit) and five measures in DAs (BEES Digit Span Forward, WMS-R Visual Reproductions N Correct, BEES Symbol Digit Rate, BEES Simple and Choice Reaction Time Move. Both groups experienced an additive effect (no interaction term) for HgU and the CPOX4 polymorphisms on the Digit Rate whereas DAs also had additive effects for BEES Digit Span Forward 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.