Wednesday, January 27, 2016

Lead: Breaking Down The Bridges Of Life For Centuries

In February of 2015, after months of seeing her children randomly lose hair and complain of stomachaches and other symptoms, LeeAnne Walters finally had the water in her house tested by city officials. As she feared, the results were not good. Lead levels showed a content of 104 parts per billion, nearly 7 times the EPA limit for lead in drinking water. In April she would go on to discover that all four of her children had lead in their blood, and that her son Gavin was actually poisoned by this heavy metal.

The Walters are one of the many families in Flint, Michigan suffering the consequences of the lead poisoning epidemic that resulted from city officials switching the source of city water from Lake Huron to the Flint River. We now know that the corrosive nature of Flint River water leached the lead from aging city pipes; what started as a cost saving measure resulted in nearly tripling the percentage of Flint children having elevated lead blood levels.

Repeated exposure to lead can cause diverse symptoms including abdominal pain, headaches, memory loss, weigh loss, and anemia. Children are particularly susceptible to the ill effects of lead toxicity, which can result in developmental delays and learning disabilities among other long-term, irreversible health issues. Thus, despite the change back to Lake Huron water in October, this man-made disaster will be affecting the residents of Flint for decades to come. Thanks to recent national press attention, the events that led to this water crisis as well as its health-related consequences are well known to most.

The weight equivalent of only ~1/16th teaspoon of salt in lead in the bloodstream of an adult sets off alarms of concern - but what is it about lead that makes it so toxic? What does lead do at the cellular and molecular level that contributes to such widespread and profound effects in the human body?

Mark Nowlin / The Seattle Times
Lead typically enters the body through either ingestion or inhalation of lead particles that contaminate water, food, or the environment. In the United States, up to 20% of the half a million children living with lead poisoning were exposed through the drinking of contaminated water. Once ingested, lead is absorbed through the gastro-intestinal (GI) system, a process that is greatly influenced by age:  while only 10% of lead ingested by adults is absorbed, up to half of that ingested by young children will be absorbed. In addition, diet and nutritional health play a role on absorption levels. Low calorie intake, vitamin, and iron deficiency, as well as a high-fat diet, have all been correlated with enhanced absorption of lead, which contributes to the higher prevalence of lead poisoning among children from economically depressed regions such as Flint, Michigan.

After absorption, lead enters the blood, where it is mostly associated with red blood cells (RBCs). One of the effects of lead is to weaken the membrane of cells leading to their rupture. In the context of RBCs, this results in a process known as hemolysis and contributes to the anemia often associated with lead poisoning. Another key effect of lead that contributes to anemia is the inhibition of enzymes responsible for making heme, a critical component of many proteins including hemoglobin. Unregulated inhibition of enzymes, like that caused by lead, generates an excess of reactive oxygen species (ROS), which in turn can disrupt nearly all components and functions of any cell. Unfortunately, not only does lead produce this so-called “oxidative stress”, but it also inhibits the antioxidant proteins and other molecules our cells would normally use to protect themselves. The net result is a perfect storm of damage and lack of protective mechanisms that spells the ultimate demise of the cell.

Interestingly, while the blood lead level is what health professionals use to monitor exposure, only a small fraction of the total lead burden in the body is found in the blood. A significant amount of lead accumulates in soft tissue organs such as liver, lungs, kidneys, and importantly the brain. Indeed, one of the primary targets of lead toxicity, especially in children, is the central nervous system. The adverse effect of lead in neurons is again a combination of ROS production and inhibition of antioxidants, plus the disruption of proteins responsible for neural functions such as the release of neurotransmitters. Nonetheless, nearly 90% of lead retained by adults and 75% of that retained by children ultimately ends up in the bones and teeth. It actually takes up to 30 years to eliminate half of the lead that enters the bone, and bone-to-blood transfer of lead, which increases during pregnancy, menopause, and aging, can serve as a source of lead toxicity long after initial exposure.

Lead’s uncanny ability to inhibit such a broad range of enzymes is due to its high affinity for sulfhydryl (sulfur and hydrogen) groups, including those attached to carbon, which are known as thiols. A biologically important thiol is the side chain of the amino acid cysteine, one of the 21 building blocks that make up proteins. Because two thiol groups can react with each other to form disulfide bonds, cysteines in different parts of a protein - or even in different proteins altogether - can bind to one another. The ability to form these disulfide bridges makes cysteine a very special amino acid that contributes to a protein’s structure, stability, function, and ability to interact with other proteins.

Disrupting and remaking disulfide bridges between proteins is the basis of chemicals used by hairdressers to straighten and curl up hair.
By strongly interacting with thiols, lead can break disulfide bridges and ruin the structure and function of enzymes, sometimes permanently. The ubiquitous presence of thiols in proteins and their importance to function is what allows lead to affect such a broad range of cells, organs, and processes. Another chemical property of lead that contributes to its toxicity is its divalency (ability to make two bonds). Once inside of cells, lead can take the place of biologically important divalent ions such as calcium and magnesium with dire consequences. Calcium, in particular, plays an important role as a signaling molecule and therefore its level inside of the cell is tightly regulated. When lead levels are high, it can activate proteins and processes, such as neurotransmitter and hormonal release, which are normally controlled by calcium fluxes.

Lead has been intrinsically interconnected with human history. Ancient civilizations considered it the father of metals and the Romans laced their wine and aqueducts with it. Soft, highly malleable, and with a low melting point, lead is in many ways an ideal material. But its more pernicious character as a poison has also been recognized for centuries. There is no known safe level of lead and its effects are widespread, long lasting, and unpredictable. While the pharmacokinetics, mechanism of toxicity, and chemical properties of lead are fascinating, they are insignificant and almost irrelevant in the context of the human cost lead poisoning has inflicted throughout history and continues to inflict. LeeAnne Walters’ son Gavin and the many other afflicted children from Flint, Michigan are unfortunately the latest to pay the price.

Contributed by:  Gustavo Arrizabalaga, Ph.D.

References and resources:

Flora G, Gupta D, & Tiwari A (2012). Toxicity of lead: A review with recent updates. Interdisciplinary toxicology, 5 (2), 47-58 PMID: 23118587

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