Impact of prenatal methylmercury exposure on neurobehavioral function at age 14 years
Introduction
Methylmercury (MeHg) is a widespread contaminant of seafood and freshwater fish. The developing brain is considered the main target for MeHg toxicity, and the risk to consumers from MeHg exposure has been assessed by national and international agencies [11], [23], [28], [34]. Results from prospective epidemiological studies of birth cohorts from the Faroe Islands [18], [29] have contributed significantly to the data used for derivation of recommendations concerning human exposure limits, especially for pregnant women.
For the purposes of risk assessment, valid dose–effect relationships are essential, and the research in the Faroes has endeavored to represent both ends of the exposure–outcome relationship with the highest possible precision and sensitivity. Because of the need to obtain precise measures of the causative exposure [7], [14], the mercury concentration has been measured in cord blood and other biological samples from exposed participants. Detailed comparison of various prenatal exposure indices within the cohort has shown that the cord-blood concentration is consistently the most precise predictor of nervous system deficits determined during postnatal follow-up [7], [14].
At the same time, valid outcome variables must be sensitive to MeHg neurotoxicity and relatively robust to impacts of confounders. In choosing feasible effect parameters, an important consideration includes suitability for the age group and culture. As confounder-independent outcomes, neurophysiological measurements have provided evidence that developmental MeHg neurotoxicity is detectable through age 14 years [26]. Clinical neurological tests have shown mercury-related adverse effects neonatally [29], but such tests may not be sensitive enough at school age [18]. Standardized neuropsychological tests are useful to gain insight into functional domains and overall cognitive functioning and have been widely applied as sensitive indicators of central nervous system (CNS) dysfunction associated with exposure to neurotoxicants in both environmental and occupational exposure settings [9], [39]. In choosing such measures for the study of children, it is important to consider the developmental stage of the child at both exposure and at the time of testing as well as cultural and psychometric parameters of the tests being administered [2], [39].
Risk assessments have so far been based on functional outcomes up to early school age obtained in three prospective epidemiological studies [11], [23], [28], [34]. Data from older children and adolescents have been available only from less informative cross-sectional studies. Developmental exposure to inorganic lead is known to cause permanent CNS damage, thus suggesting that deficits attributable to early developmental neurotoxicant exposure may be irreversible [2], [40]. However, long-term effects of prenatal and early childhood exposures to neurotoxicants may become more difficult to demonstrate with time, because an increasing number of other factors play a role in test performance and it may be difficult, if not impossible, to define and measure these covariates. Thus, the increasing complexity of confounder adjustment may cause problems in the statistical analysis of cognitive test data. Despite these potential problems, prospective assessment of cohorts with well defined exposures occurring early in development is essential to understanding how neuropsychological outcome measures can be utilized as long-term indicators of early neurotoxicant insults.
We have prospectively followed a birth cohort from the Faroe Islands for 14 years. The Faroes are located in the North Atlantic between Norway, Shetland, and Iceland. In this Nordic fishing community, excess exposure to MeHg is mainly due to the traditional habit of eating meat from the pilot whale, while baseline exposures are due to frequent intake of other types of seafood that contains lower MeHg concentrations [38]. In a study conducted when the cohort children were 7 years of age, the main finding was that decrements in specific functional domains were associated with prenatal MeHg exposure [18]. Tests assessing the domains of attention, language, and verbal memory showed the most robust effects, while measures of motor speed and visuospatial function showed less consistent effects. Among several measures of prenatal and post-natal exposure, the strongest associations were obtained with the cord-blood mercury concentration as the exposure indicator [17], [18], [19]. These findings were robust in analyses controlled for age, sex and confounders, and they persisted after exclusion of high-exposure participants (i.e., maternal hair-mercury concentrations above 10 μg/g) [18]. Ingestion of whale blubber causes exposure to lipophilic contaminants, notably polychlorinated biphenyls (PCBs), but the possible neurotoxic influence of this exposure did not explain the MeHg-associated neurobehavioral deficits [6], [16], [29]. The examination at age 14 years that is described in this paper included a clinical test battery similar to the one applied at age 7 years.
Section snippets
Materials and methods
The cohort was assembled in the Faroe Islands during a 21-month period in 1986–1987 [13]. The primary indicator of intrauterine exposure to MeHg was the mercury concentration in cord blood, and concentrations in maternal hair at parturition were also determined. Subsequently, mercury concentrations were measured in stored cord tissue (dry weight) from about half of the cohort members examined [16]. MeHg exposure was found to vary considerably: 15% of the mothers had hair-mercury concentrations
Results
The prenatal MeHg exposures of the participants of the 14-year examinations (Table 2) were similar to those of the cohort as a whole [13]. Exposure levels at age 14 years averaged about one-fifth of those experienced prenatally, although exposures at age 7 years were slightly higher [26].
Table 3 shows associations with potential confounders. Continuous variables were trichotomized for the purpose of this table only. The expected pattern of associations reflects dietary habits and local
Discussion
This study presents results on neuropsychological performance of adolescents with widely differing degrees of prenatal exposure to MeHg from maternal seafood diets during pregnancy and lower postnatal exposures to this neurotoxicant. Adverse effects were identified in regard to motor speed, attention, and language. These effects were apparent both in multiple regression analyses and in structural equation models that take into account multiple testing, exposure imprecision, and incomplete data.
Acknowledgments
This study was supported by grants from the US National Institute of Environmental Health Sciences (ES09797) and the Danish Medical Research Council. The contents of this paper are solely the responsibility of the authors and do not represent the official views of the NIEHS, NIH or any other funding agency. Advice on neurobehavioral test selection was contributed by the following members of the steering committee convened by NIEHS: David Bellinger, Kim Dietrich, Annette Kirshner, and David
References (41)
- et al.
Neurobehavioral deficits associated with PCB in 7-year-old children prenatally exposed to seafood neurotoxicants
Neurotoxicol. Teratol.
(2001) - et al.
Cognitive deficit in 7-year-old children with prenatal exposure to methylmercury
Neurotoxicol. Teratol.
(1997) - et al.
Prenatal methylmercury exposure in the Seychelles (letter)
Lancet
(2003) - et al.
Delayed brainstem auditory evoked potential latencies in 14-year-old children exposed to methylmercury
J. Pediatr.
(2004) - et al.
Prenatal methylmercury exposure from ocean fish consumption in the Seychelles child development study
Lancet
(2003) - et al.
Maternal seafood diet, methylmercury exposure, and neonatal neurological function
J. Pediatr.
(2000) - et al.
Long-chain polyunsaturated fatty acids at birth and cognitive function at 7 y of age
Eur. J. Clin. Nutr.
(2003) Lead
Pediatrics
(2004)Children's Category Test (Manual)
(1993)Structural Equations with Latent Variables
(1989)