Metabolic and Genetic Effects
Lead impairs multiple biochemical processes that leads to its toxic effects, including its ability to inhibit calcium and react with proteins. On entering the body, Pb takes the place of calcium and then interacts with biological molecules, interfering with their normal function. Lead reduces the activity of various enzymes, causing changes in their structure, and inhibits their activity by competing with the necessary cations for binding sites. Oxidative stress caused by lead is the main mechanism responsible for its toxicity, causing changes in the composition of fatty acids in membranes (affects processes such as exocytosis and endocytosis and signal transduction processes). Pb can also cause gene expression alterations. Protein protamines are involved in Pb toxicity because of gene expression alterations and then lead interact with zinc binding sites on protamines. Some research has investigated the effect of Pb on the activity of glucose-6-phosphate dehydrogenase (G6PD), by causing anemia, it may interfere with the integrity of the RBC membrane, making it more fragile. Pb can also inhibit the enzyme ferrochelatase, reducing iron (Fe) incorporation into heme. The heavy metal inhibits δ-aminolevulinic acid dehydratase (δ-ALAD) enzymethusle adding to increased blood levels of δ-aminolevulinic acid (δ-ALA). Pb induced oxidative damage is the result of disturbance in the balance of glutathione (GSH) to glutathione disulfide (GSSG). The presence of lead in the body can cause rapid depletion of antioxidants in the body and can increase the production of reactive oxygen, as well as reactive forms of nitrogen. Thus, increased oxidative stress causes a reduction in the levels of glutathione reductase, leading to a reduction in the concentration of the antioxident glutathione [11,19].
Location of Lead in the Body
Most lead is stored in the bones [16,20]. Lead in bones is not uniformly distributed. It tends to accumulate in bone regions undergoing the most active calcification at the time of exposure. The rate of development and accumulation of lead in bone in childhood and adulthood suggests that its accumulation will occur mainly in the trabecular bone during childhood, and in in adulthood in the cortical bone. Bone-to-blood lead mobilization increases during advanced age, broken bones, chronic disease, hyperthyroidism, kidney disease, pregnancy and lactation, menopause, and physiologic stress. Calcium deficiency exacerbates, or worsens, bone-to-blood lead mobilization in all of the above instances [1,3].
WHO experts stress the importance of Pb control in this age group because research consistently shows lead adversely affects the central nervous system and development of children . Pb is especially harmful to children under the age of six, most likely because of rapid brain growth and development with associated periods of heightened vulnerability, and because of high demand for nutrients [2, 9, 21]. Children are particularly vulnerable to the effects of lead. The heavy metal can interfere with the ability to learn, impair memory, lower IQ, and interfere with growth and development. Pb has documented effects on speech, hearing, hyperactivity, nerve conduction, intestinal discomfort, constipation, vomiting, weight loss, muscle aches. At high blood concentrations (Table 1), lead poisoning can lead to anemia, nephropathy, paralysis, convulsions or death [4,11].
Table 1. Symptoms of poisoning according to the degree of exposure in children and adults [English translated from original paper: 4].
Lead’s damage to the child can begin as early as pregnancy. Maternal lead can be passed through the placenta to the developing fetus [11,22]. The Pb content in the placenta is the result of many complex biochemical reactions and various factors related to the mother's body. The concentration of Pb in umbilical cord blood can be up to 85% of the Pb concentration in the mother's blood. When a woman becomes pregnant, the lead stored in her bones can be released and transferred through the blood to the fetus, especially if the mother’s calcium intake is low. Therefore, fetal development can be influenced by both current and past maternal exposure to Pb via the heavy metal’s storage in the mother’s bones [23,24].
Research has found that even slight Pb exposure is associated with increased the risk of miscarriage, stillbirth, low birth weight and underdeveloped children. It is still not known what Pb levels can cause mutations and congenital abnormalities in the fetus, as well as the exact mechanisms of these changes. Based on current evidence, the WHO has targeted a blood Pb concentration of 5 μg/dl or less for children. Damage from lead exposure can occur at levels below this value [2,9,21,23,24].
Severe lead poisoning in children can cause dementia, irritability, headaches, muscle twitches, hallucinations, memory disorders, learning or behavioral problems, concentration and attention issues, reductions in IQ, hearing loss, restlessness or hyperactivity. Acute poisoning can lead to convulsions, paralysis and coma. In fatal cases, brain damage can occur due to edema and changes in the blood vessels [4,8,11].
Children are exposed to environmental lead via inhalation and ingestion. Inhalation contributes to higher blood levels in children than in adults. Dirt, dust and food are the largest contributors of Pb in children, while ingestion from water is generally a less significant source (Figure 3). Young children’s exposure to lead is substantially enhanced by the common infant and toddler behaviors of tasting objects, putting hands into the mouth immediately after play, etc. [2,11]. When young children live in environments with Pb contamination, ingestion of the heavy metal is likely. Increased risk of lead poisoning occurs in families where one parent works in a high-level lead environment. Parents who are exposed to lead in workplaces too often bring leaded dust to the home with clothes or on the skin, thereby increasing the chances of their children being exposed to the heavy metal. Monitoring of Pb concentrations in children's blood is recommended (atsdr.cdc.gov) because of their vulnerability to the heavy metal [2,9].
Figure 3. Possible sources of lead poisoning among children in the environment home .
The effects of lead exposure in adults are underappreciated. High lead concentrations can result in serious morphological and functional changes in some organs [2,24]. Lead in adults can cause changes in the nervous system (affecting slow nerve conduction, fatigue, mood swings, drowsiness, concentration disorders, headaches, coma), the circulatory system (increase in blood pressure, in severe cases encephalopathy), the gastrointestinal effects (colic/pain, nausea, vomiting, diarrhea, and constipation), hormonal (fertility disorders, decreased libido), other symptoms include astringency of the mouth, metallic taste in the mouth, and thirst or death . In particular, Pb can seriously affect the cardiovascular system. People exposed to very high doses of Pb (blood lead concentrations between 500-870 μg/L blood) can experience sinus node dysfunction, atrioventricular conduction disturbances and atrioventricular block . Pb exposure can also lead to morphological changes in the heart, including the heart muscle. Visible changes in the electrocardiographic picture, impaired systolic and diastolic function of the heart and changes in repolarization dispersion, increases blood pressure [18,25].
The relationship between lead concentrations in blood and blood pressure has been widely studied. The effect of lead on blood pressure is dependent on the size of the exposure dose and the time of exposure . Even low lead exposure can adversely influence cardiovascular disease . Many researchers have observed a positive relationship between lead and blood pressure, while others have not. However, exposure to even low lead levels is associated with oxidative stress and deficiency of the enzyme catalase and may contribute to hypertension. Increasing the level of lead in the body causes greater cardiovascular responses to acute stressors. Thus, increased cardiovascular reactivity predicts higher baseline blood pressure, increased left ventricle mass and atherosclerosis in adults. Consequently, increased blood pressure reactions to acute stressors are one of the possible mechanisms by which lead can affect resting blood pressure. Also lead levels in the blood may affect cardiac output or total resistance of peripheral vessels, and thus increase the response to blood pressure to acute stressors [3,15,27]. The main problem of lead is the effect on myocytes of the muscular layer of blood vessels. Many researchers point to vasoconstrictor effects in chronic lead intoxication, but it is not this fact is sufficiently confirmed . Some experimental and epidemiological data suggest that prolonged exposure to lead may result in an increase in blood pressure. There is a need to confirm and further verify the above assumptions and to determine the place that lead occupies among other factors playing a role in the pathogenesis of hypertension .
Lead compounds can adversely affect blood and the metabolism of blood cells. This red blood cell effect is manifested by a disorder of cell metabolism of the red blood cell line in the bone marrow or mature erythrocytes. Pb impairs the integrity of the permeability of the membrane, to which RBC’s are more susceptible. Heme synthesis is disturbed by Pb exposure .
As in children, lead exposure can have adverse effects on the nervous system. The blood Pb concentration threshold for asymptomatic CNS function disturbances has been set at 400-600 μg/L (atsdr.cdc.gov) . Adverse effects include impaired visual intelligence and eye-hand coordination, decreased learning ability, impairment of the ability to praise, memory, potential visual and auditory disturbances.
In men who have been exposed to Pb, there can be reduction in sperm count, quality of semen, and their motility, morphological disorders, longer time to pregnancy in pairs, sterility / impotency and endocrine disorders. In men, the number of spermatozoa is reduced and sperm volume changes (> 40 μg/dl). And in women, toxic lead levels can lead to miscarriages, low birth weight, prematurity, or developmental problems in children. Lead present in the mother's blood passes to the fetus through the placenta and through breast milk . The symptoms of poisoning according to the degree of exposure in children and adults shows Table 1 .
Lead colic is a frequent result of short-term exposure to large doses. At the beginning, the person is hungry, and has indigestion and constipation. Following this is extensive paroxysmal abdominal pain, pale skin and bradycardia. Acute coronary encephalopathy is rare in adults. When this has occurred, the blood lead concentration in people with symptoms of enecephalopathy was 800-1000 to 3000 μg/L (atsdr.cdc.gov) .