Prenatal exposure to methylmercury and PCBs affects distinct stages of information processing: An event-related potential study with Inuit children

Abstract

Methylmercury (MeHg) and polychlorinated biphenyls (PCBs) are seafood contaminants known for their adverse effects on neurodevelopment. This study examines the relation of developmental exposure to these contaminants to information processing assessed with event-related potentials (ERPs) in school-aged Inuit children from Nunavik (Arctic Québec). In a prospective longitudinal study on child development, exposure to contaminants was measured at birth and 11 years of age. An auditory oddball protocol was administered at 11 years to measure ERP components N1 and P3b. Multiple regression analyses were performed to examine the associations of levels of the contaminants to auditory oddball performance (mean reaction time, omission errors and false alarms) and ERP parameters (latency and amplitude) after control for potential confounding variables. A total of 118 children provided useable ERP data. Prenatal MeHg exposure was associated with slower reaction times and fewer false alarms during the oddball task. Analyses of the ERP parameters revealed that prenatal MeHg exposure was related to greater amplitude and delayed latency of the N1 wave in the target condition but not to the P3b component. MeHg effects on the N1 were stronger after control for seafood nutrients. Prenatal PCB exposure was not related to any endpoint for sample as a whole but was associated with a decrease in P3b amplitude in the subgroup of children who had been breast-fed for less than 3 months. Body burdens of MeHg and PCBs at 11 years were not related to any of the behavioural or ERP measures. These data suggest that prenatal MeHg exposure alters attentional mechanisms modulating early processing of sensory information. By contrast, prenatal PCB exposure appears to affect information processing at later stages, when the information is being consciously evaluated. These effects seem to be mitigated in children who are breast-fed for a more extended period.

Introduction

Methylmercury (MeHg) and polychlorinated biphenyls (PCBs) are widespread environmental pollutants contaminating the marine food web. Both contaminants are known to be neurotoxic to humans. Vulnerability of the central nervous system to these substances is increased during early development, especially during the prenatal period (Grandjean and Landrigan, 2006). MeHg derives from methylation of inorganic mercury (Hg), a toxic metal that is ubiquitous in the environment, by aquatic micro-organisms. The effects of acute MeHg intoxication have been documented following large-scale poisoning episodes that occurred in Japan (1953 and 1964–1965) and Iraq (1971–1972). The Japanese episodes resulted from industrial Hg releases in waters supplying the population with fish and shellfish (Tsubaki and Irukayama, 1977). Consumers of MeHg-contaminated seafood displayed symptoms, such as ataxia, constriction of the visual fields and hearing impairments (Eto, 2000). The Iraqi contamination was caused by the intake of bread made from wheat treated with a MeHg-contaminated fungicide (Bakir et al., 1973). In all cases, the most disastrous effects—mental retardation, seizures, cerebral palsy, blindness and death—were found in children exposed prenatally (Choi, 1989). Several epidemiological studies have been conducted within fish-eating populations to examine the consequences of chronic exposure to lower doses of MeHg on cognitive development using behavioural assessments. The most consistent findings include impairment in visuomotor function (Chevrier et al., 2009, Grandjean et al., 1997; cf. Davidson et al., 2008a) and alterations in early auditory processing (Murata et al., 2007) in relation to prenatal exposure. Verbal, attention and learning deficits have also been reported but somewhat less consistently (Grandjean et al., 1997, Grandjean et al., 1999a, Debes et al., 2006, Kjellstrom et al., 1989; cf. Davidson et al., 1998, Myers et al., 2003).

PCBs are synthetic organochlorine compounds widely used in industry during the mid-20th century, notably as lubricating oils and hydraulic fluids (Brinkman and De Kok, 1980). Developmental neurotoxicity of PCBs was documented following large-scale Japanese and Taiwanese poisoning episodes in 1968 and 1979, respectively, due to the intake of rice oil accidentally contaminated with PCBs and dioxins during production processes. Many children born to women exposed prior to or during pregnancy displayed symptoms, such as growth retardation, nail malformation, delays in cognitive development and behavioural problems (Guo et al., 2004, Hsu et al., 1985). Subsequent birth-cohort studies have reported detrimental PCB effects on neuropsychological functioning apparent in infancy (Jacobson et al., 1985, Darvill et al., 2000, Ko et al., 1994) and continuing through school age (e.g., Jacobson and Jacobson, 1996, Stewart et al., 2008), notably on IQ and executive and attentional function (reviewed in Boucher et al., 2009a). Some of these effects, however, were only present in children who had not been breast-fed (Jacobson and Jacobson, 2003, Patandin et al., 1999).

Despite the existence of a few large, well designed cohort studies documenting neurobehavioural outcomes following prenatal exposure to MeHg and PCBs, the nature of the effects of these contaminants on brain function remains unclear. The neurobehavioural tasks typically used in epidemiological studies depend on a broad range of cognitive processes making difficult the identification of specific aspect(s) of brain function impaired by a given contaminant. Sensory electrophysiological assessment, such as brainstem-auditory evoked potentials (BAEPs) and visual evoked potentials (VEPs), has successfully identified sub-clinical alterations associated with exposure to seafood contaminants (Murata et al., 2007, Saint-Amour et al., 2006). Further insights into brain processing can be obtained with cognitive electrophysiological assessment using event-related potentials (ERPs), which can reveal subtle and specific effects of these neurotoxicants on cognitive and attention processing (Otto, 1987).

One of the most frequently used ERP protocols is the oddball detection task, in which the participant is asked to respond to targets randomly distributed among a series of standard stimuli. The average EEG waveforms obtained from oddball protocols show several ERP components including the N1, a wave of negative voltage peaking around 100 ms at the vertex after stimulus onset (Näätänen and Picton, 1987), and the P3b, a positive wave peaking around 300 ms at centro-parietal electrodes, which is seen predominant in the target condition (Hansenne, 2000). The N1 wave is composed of several overlapping subcomponents (Näätänen and Picton, 1987, Woods, 1995). Some are automatically elicited by the occurrence of any detectable stimulus and are modality-specific. However, the vertex-recorded N1 obtained during an active task (e.g., oddball detection) appears to reflect a non-modality-specific subcomponent, which is significantly affected by the vigilance state of the participant, as its amplitude increases with the level of attention to task (García-Larrea et al., 1992, Näätänen, 1992, Herrmann and Knight, 2001, Campbell and Colrain, 2002). In this context, the vertex-recorded N1 has been proposed to reflect cerebral excitability during attention, or coarse mechanisms of selective attention to the attended input (Näätänen, 1992, Hillyard et al., 1973, Woldorff et al., 1993, Muller-Gass and Campbell, 2002). The P3b wave is elicited by the active detection of an anticipated and unpredictable stimulus, and has been attributed to working memory processing (Donchin, 1981, Donchin and Coles, 1988, Polich, 2007) or post-decision closure mechanisms (Desmedt, 1980, Verleger, 1988, Halgren et al., 1988). P3b latency is thought to reflect information categorization speed (Kutas et al., 1977, McCarthy and Donchin, 1981) and is inversely associated with behavioural performance in speeded attention tasks and on digit span tasks (Polich et al., 1983, Walhovd and Fjell, 2002). P3b amplitude is used as an index of allocation of attentional resources (Kok, 1997) and correlates with performance on tests of selective attention and verbal learning (Boucher et al., 2010, Gurrera et al., 2005, Karis et al., 1984).

Two epidemiological studies in children assessed the P3b component in an auditory oddball paradigm to study the impact of prenatal exposure to PCBs on brain processing. In Taiwan, 7–12-year-old children exposed to PCBs and polychlorinated dibenzofurans in utero (n = 27) due to maternal consumption of contaminated rice oil were found to have smaller P3b amplitudes and longer P3b latencies than matched controls (Chen and Hsu, 1994). In a birth-cohort study conducted in the Netherlands, 9-year-old children from a high PCB-exposed group (n = 32) were found to have longer P3b latencies than those from a low exposed group (n = 28) (Vreugdenhil et al., 2004). However, both studies were limited by small sample sizes, and neither assessed the N1 wave preceding the P3b component, which can provide information about the contaminant's effects on earlier stages of information processing. Furthermore, no study conducted to date has used ERPs to assess MeHg neurotoxicity in children. Findings from the behavioural assessments of attention and memory in the Faroe Islands study (Grandjean et al., 1997, Debes et al., 2006) suggest that ERPs associated with the domains of cognitive function assessed in the auditory oddball paradigm might also be affected by prenatal exposure to MeHg. We have previously reported an association between prenatal lead (Pb) exposure and increased P3b amplitude on a visual oddball task in Inuit children at 5 years, as well as an association of Pb exposure during the preschool period with delayed P3b latency (Boucher et al., 2009b). However, neither prenatal Pb nor 11-year Pb body burden was related to auditory oddball performance at 11 years.

The present study examined the association of prenatal and current exposures to MeHg and PCBs with ERP measures of information processing elicited during an auditory oddball task in a cohort of Inuit children in Arctic Québec, who were exposed to these contaminants through marine mammal and fish consumption. The Inuit are among the most highly exposed populations on earth due to long-range transport of these compounds via atmospheric and ocean currents and their bioaccumulation in fish and sea mammals that are staples of the Inuit diet (Muckle et al., 2001). It is hypothesized that higher prenatal exposure to PCBs and MeHg will be related to increased latencies and decreased amplitudes of N1 and P3b.