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?
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| Mark Nowlin / The Seattle Times |
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.
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| Disrupting and remaking disulfide bridges between proteins is the basis of chemicals used by hairdressers to straighten and curl up hair. |
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
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