Baby teeth show when metal exposure may affect brain development

A child’s earliest exposures may leave lasting biological signatures. This study shows how tiny layers in baby teeth can pinpoint when metals may influence brain development and behavior years later. 

Study: Fetal and postnatal metal metabolism–related changes in brain function are associated with childhood behavioral deficits. Image credit: Onjira Leibe/Shutterstock.com

A novel study using baby tooth biomarkers to trace metal exposure throughout the fetal and early infancy periods identified critical windows of early neurodevelopment in which such exposures are associated with long-term differences in behaviour and brain measures observed later in childhood and adolescence. The study was published in the journal Science Advances.

Baby teeth unlock hidden timeline of prenatal exposures

Environmental factors, including metal exposure, interact with genetic factors to contribute to the risk of mental health disorders, which currently affects about one in seven children and adolescents worldwide. However, accurately tracking factors acting in early pregnancy is difficult.

To retrospectively and accurately quantify fetal exposure, the authors of this study previously developed the use of deciduous or milk teeth as a validated novel biomarker. These teeth begin to develop in the second trimester of pregnancy, providing an extraordinary level of detail about exposure to time-varying metals week by week.

This has been confirmed by previous studies that demonstrate strong agreement between metal levels in tooth dentine and maternal, cord, and infant biomarkers.

The researchers examined baby teeth from a cohort of 489 children ages 8 to 14 years, enrolled in the ongoing Programming Research in Obesity, Growth, Environment, and Social Stressors (PROGRESS) study. Baby teeth were first sampled at points corresponding to metal deposition from four months of pregnancy to 10 postnatal months, with one sampling point every 7-10 days.

This allowed them to reconstruct the weekly concentrations of nine metals beginning from around 20 weeks before birth to about 40–44 weeks after birth. These included manganese (Mn), zinc (Zn), lead (Pb), magnesium (Mg), lithium (Li), copper (Cu), strontium (Sr), barium (Ba), and tin (Sn).

In addition, they assessed the children’s behavior using questionnaires (in a subset of participants) and magnetic resonance imaging (MRI) of brain structure and function (in a smaller subset). They used three MRI outcomes: total brain volume, global network efficiency (a measure of functional connectivity), and white matter integrity. These develop in early life, with the highest growth velocity occurring in the perinatal period (surrounding childbirth).

Differences in these phenotypes have been reported to correlate with poor developmental outcomes in adolescence. For instance, adolescents with reduced brain volume are more likely to show cognitive deficits and psychiatric illness.

Poor white matter integrity is linked to slower brain processing, with limited attention span and learning capabilities. Reduced global functional connectivity is associated with impaired executive function and emotional regulation, and with neuropsychiatric disease.

They found that dentine manganese levels peaked in the second trimester and decreased sharply before birth, with a shallower decrease after birth. Other metals, except for Ba and Sr, remained stable, increasing slightly after birth.

Association with behavioral changes

They identified a postnatal window at 4-8 weeks postnatally, and another from 32-42 weeks postnatally, when higher exposure to metal mixtures was associated with a risk of behavioral alterations in later life.

At 5 versus 38 postnatal weeks, the behavioral symptoms index (BSI) score increased by 0.1 standard deviation (SD) versus 0.13 SD per quartile increase in exposure, respectively. These were driven initially by Mn and in the later window by Mn, Mg, and Sn. However, these windows vanished when internalizing and externalizing factors were separated.

Association with MRI phenotypes

For all three MRI phenotypes, critical susceptibility windows were identified.

Total brain volume

Between postnatal weeks 15-43, total brain volume was lower with greater exposure to metal mixtures. Thus, at 32 weeks, during the eighth postnatal month, an increase in exposure by one quartile was associated with a 0.45 SD reduction in total brain volume, primarily due to changes in Zn, Sn, and Mn levels.

Global network function efficiency

Global network efficiency (which denotes efficiency of communication within the brain) decreased by 0.18 SD per quartile increase in exposure at 17 weeks of gestation, and by 0.21 SD at 33 postnatal weeks. These points fall within two critical windows: one prenatal (8-19 weeks prior to delivery) and one postnatal (weeks 17-43). These associations were mostly due to variations in prenatal Mn levels and postnatal Mg and Pb.

White matter integrity

The white matter comprises connecting nerve fiber pathways. The researchers identified two windows, one prenatal and one postnatal, when metal mixture exposure was correlated with reduced white matter integrity. At 15 prenatal weeks and 33 postnatal weeks, white matter integrity was decreased by 0.19 SD and 0.32 SD per quartile increase, respectively. These were linked to changes in Mn, Zn, Cu, and Mg, prenatally, and Mn, Ba, and Li postnatally.

Putative mechanisms of association

The authors point out that the sixth to ninth postnatal months are a critical window of development. During this period, infants begin to crawl and are weaned. This may coincide with increased opportunities for exposure and altered absorption and metabolism of nutrients and toxins, potentially influencing susceptibility to metals.

In addition, this is a period of greater neurodevelopmental plasticity, with ongoing but incomplete maturation of the blood-brain barrier, coupled with rapid brain growth and synaptic pruning.

The authors point out the prominent role of Mn, agreeing with earlier studies showing its ability to disrupt normal neurodevelopment at high levels during critical windows. They also highlight existing links between Zn and Mg, which influence nerve signaling, and neurodevelopmental disorders such as autism spectrum disorder, attention-deficit hyperactivity disorder, and behavioral issues in children.

The current study builds on these findings by aligning the effects of exposure to metals, especially Mn, Mg, and Zn, with the timing of exposure, and with coexposure to other metals that act on neuronal tissue.

Study limitations

Brain changes and behavioral alterations were not examined in the same individuals, and sex-specific effects were not tested for due to the inadequate sample size. Most participants were from poorer neighborhoods, limiting generalizability. Metal exposure prior to the second trimester could not be examined. Interactions between metals could also not be assessed. In addition, several metals studied, such as Zn, Mn, and Mg, are essential nutrients, and both deficiency and excess may be harmful.

Exposures in critical windows may shape the risk of adverse neurological outcome

The developing brain is especially vulnerable to metals in early life, with lasting effects into adolescence.

Different periods of vulnerability were identified for different metal mixtures, associated with specific outcomes. Behavioral problems and reduced brain volume were linked to postnatal windows. Conversely, the other MRI phenotypes were associated with exposure during prenatal and postnatal windows.

Future research is required to validate these findings and address the limitations of this study. It should also identify sensitive periods when environmental factors disrupt development, thus shaping preventive public health strategies.

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