Heavy on my Mind: Lead Poisoning (Part II)

Posted by Caroline Sferrazza on April 21, 2016 in Cognition, Environment, Memory | Leave a comment

When I first heard about the water crisis in Flint, Michigan, I didn’t have the slightest idea how serious the problem was. Sure, I’d heard that lead was no good for you. I thought back to the day I moved into my first apartment in New York City and the superintendent handed me a pamphlet about the dangers of lead and how to protect yourself from common sources of lead in the home. I read the section titles. I looked at the pictures. I remember thinking that shy of eating old peeling paint or taking a swim in the Gowanus Canal, I would be just fine. I put it in a drawer somewhere and didn’t see it again until the day I moved out.

Then Flint happened (or, more accurately, then we found out about what had been happening in Flint for years). It became alarmingly clear that lead was not the rare problem I thought it was. Near daily revelations about the very real, serious, and unacceptably common effects of lead exposure populated the headlines.

Part I of this series lays the foundation for understanding the gross effects of lead poisoning and our history with the pernicious heavy metal. Unfortunately, we’ve only scratched the surface of what lead is capable of doing to the body. Its capacity to have widespread, long-term effects on multiple systems renders the task of grasping the scope of this health hazard truly daunting.

Many of the most serious effects of lead exposure are related to our cognition and behavior. The brain and behavior share a close relationship, so to truly understand the effects of lead exposure, we must look inside the brain. So, who’s ready for a field trip?

 

“There is no threshold below which lead remains without effect on the central nervous system.” [4]

In Part I, we examined how much lead the CDC considers to be “too much lead” for the human body, and how that threshold has changed over the years. Given the seeming ubiquity of lead in the environment, it follows that we should expect some degree of lead exposure at some point in life. While lead is most dangerous in chronic or high dose exposures, the nervous system is particularly vulnerable to the effects of lead. In fact, any amount of lead whatsoever begins to do damage to our brains.[4]

Why is the brain so particularly susceptible to the effects of lead? It is partly due to the fact that lead causes significant disruption to a structure known as the blood-brain barrier (BBB). The BBB is sort of like the moat that surrounds a castle: it is supposed to keep stuff that’s bad for us out of our brains, but let down the drawbridge for things our brain does need, like nutrients from our blood. Even at low-level exposure, lead starts to drain this moat. It goes after the structural integrity of the BBB by damaging the endothelial and glial cells that comprise it. This is immediately a problem, as it is one of the earliest effects of lead exposure. At this point, one of the primary sources of defense in the nervous system has been compromised, increasing the likelihood of further insult not only by lead, but also by any other opportunistic intruders that the BBB could normally keep out.

Kinda like the BBB, just not to scale. (Flickr: Nick Rowland)

Once lead has infiltrated the brain it spreads out and harms various regions of the brain, just as lead is capable of damaging multiple systems throughout the body as a whole. The brain begins to swell. Blood vessels begin to leak.[7] Part of this damage is caused by lead’s ability to mimic calcium, as we discussed in Part I. This leaded imposter can cause neurons to do all kinds of weird things, like spontaneously sending messages by releasing neurotransmitters at inappropriate times. Lead achieves this by activating messengers within neurons like protein kinases and interfering with the normal function of the voltage-gated ion channels on the neuron’s membrane. The dynamics of this cellular machinery are very carefully regulated in a healthy nervous system to ensure that neurons function and communicate effectively.

Lead exposure produces myriad cognitive and behavioral problems in humans and other animals. Many of these symptoms can be traced back to a target brain region, like a signal flare rising over a sinking ship. If we keep following this metaphor, many of those flares would converge over two brain regions in particular: the cortex and the hippocampus.

The neurotoxic effects of lead on the cortex, and particularly the prefrontal cortex, are the most likely culprit for the behavioral abnormalities symptomatic of lead poisoning. The prefrontal cortex is considered to be the seat of executive function, inhibition, and decision-making in the brain. As a result, this region has a disproportionately large impact on a person’s overall personality. When the prefrontal cortex is injured, people tend to have trouble with attention, inhibition of inappropriate behaviors, and decision-making – all symptoms of lead poisoning. Studies in monkeys have shown that such effects can arise even after short periods of low-level exposure, on the order of only a few weeks.[6] (Just a reminder: the people of Flint have been drinking, showering, and washing with water that is substantially polluted with lead for years).

Lead exposure also produces deficits in memory, which is very likely due to its action within the hippocampus. It has long been known that damage to the hippocampus may result in a loss of memory, and in some cases a loss of the ability to form new memories. When lead is introduced, there is a significant decrease in the density of cholinergic inputs to the hippocampus.[1] Furthermore, other neurotransmitters crucial to the learning process, like dopamine and glutamate, are also aberrantly modulated.[2] All of these are important aspects of the machinery that enable us learn and remember, so messing with this carefully constructed landscape has serious cognitive impact, such as lowering your IQ as we discussed in Part I. Unfortunately, once these important neurotransmitter dynamics are lost, it does not appear to recover very well, just as memory does not tend to improve substantially once a problem has occurred. Lead can even accumulate within amyloid plaques, which may sound familiar, as they are enemy number one in the development of Alzheimer’s Disease. Alzheimer’s currently holds the title of most common neurodegenerative disease and does not seem poised to lose that title any time soon, even without interacting with lead.[5]

Li et al. demonstrate that lead may contribute to elevated Aβ levels in cultured cells.[5]

The fact that learning and memory problems produced by lead are persistent provides some insight into perhaps the most depressing aspect of lead poisoning. By far the population that is most vulnerable to the toxic effects of lead is children. In addition to the fact that lead produces irreversible symptoms that often persist into adulthood (effectively altering the trajectory of a child’s entire life), the developing nervous system is especially sensitive to the effects of lead. When we are born, the brain is very plastic, meaning that it can physically change in response to environmental stimuli particularly well early in life. (Conveniently, a fellow NeuWriter posted about the brain’s remarkable capacity for plasticity recently). This is why toddlers can learn multiple languages simply by listening, but we struggle to acquire another language as adults even with hours and hours of study.

The super-plastic developing brain, however, is made vulnerable by the very quality that gives it so much potential. The net effect of lead disrupting the normal development of a child’s brain is long-term cognitive deficit. The specific effects can vary, generally based upon the timing and duration of the lead exposure, and can range from difficulties with attention to poor memory. Studies in rodents have found that low-level lead exposure shortly before birth and in the few weeks following (during which rodents are still very much developing and dependent on their mothers), can significantly alter the baseline activity of neurotransmitters including acetylcholine and norepinephrine.[4] This leads to an imbalance of these neurotransmitters that has been observed within the hippocampus. A disruption to an area of the brain so important for memory, and at a time when the foundation of our cognitive abilities is hardly set in stone, is particularly devastating.

Part I of this story detailed just how debilitating global cognitive deficits – like decreases in IQ – can be to a person’s livelihood once they reach adulthood.  You may not think about your IQ each day when you go to work, but it’s so much more than just how you would fare on some standardized test. It’s meant to assess your overall ability to learn, which naturally can influence things like job performance, income, and even social relationships. Couple this with the other broad physiological effects of lead exposure, like deficits in sensory processing, behavioral problems, difficulties with posture or balance, or even increased likelihood of cardiovascular complications later in life, and a little bit of lead can go a long way in changing the direction of a person’s life.[4]

Many of the effects of lead are considered irreversible, but this is not a reason to start raising a white flag just yet. Chelation therapy was shown some time ago to have promise in improving the behavior of children with elevated blood lead levels, but more research is still needed before anyone can adequately determine just how helpful such a treatment will be in the long-term.[3] Until then, it is important to remember that the timing and duration of lead exposure are incredibly important factors when assessing the damaging effects of lead on a person’s health. While the precise timing of the exposure may not be preventable, we can all help to end the excessively long duration that the people of Flint have been living with obscene lead levels in their water.

The sooner that we come together, the more we can help Flint.

Donate today. #JusticeForFlint

 

References

[1] Bourjeily, N., and Suszkiw, J.B. (1997). Developmental cholinotoxicity of lead: loss of septal cholinergic neurons and long-term changes in cholinergic innervation of the hippocampus in perinatally lead-exposed rats. Brain Res, 771: 319-328.

[2] Cory-Slechta, D.A. (1997). Relationships between Pb-induced changes in neurotransmitter system function and behavioral toxicity. Neurotoxicology, 18: 673-688.

[3] David, O.J., Hoffman ST, P., Sverd, J,. Clark, J., and Voeller, K. (1976). Behavioral response to chelation: a pilot study. Am J Psychiatry, 133: 1155-1158.

[4] Finkelstein, Y., Markowitz, M.E., and Rosen, J.F. (1998). Low-level lead-induced neurotoxicity in children: an update on central nervous system effects. Brain Res Rev, 27: 168-176.

[5] Li, Y.Y., Chen, T., Wan, Y., and Xu, S.Q. (2010). Lead exposure in pheochromocytoma cells induces persistent changes in amyloid precursor protein gene methylation patterns. Environ Toxicol, 27: 495-502.

[6] Rice, D.C. (1989). Effect of lead on schedule-controlled behavior in monkeys, in: Finkelstein, Y., Markowitz, M.E., and Rosen, J.F. (1998). Low-level lead-induced neurotoxicity in children: an update on central nervous system effects. Brain Res Rev, 27: 168-176.

[7] Struzynska, L., Walski, M., Gadamski, R., Dabrowska-Bouta, B., Rafalowska, U. (1997). Lead-induced abnormalities in blood-brain barrier permeability in experimental chronic toxicity. Mol Chem Neuropathol, 31: 207-224.