The effect of exposure to cadmium (Cd) and lead (Pb) on human health has been recognized for many years and recent information suggests that minimal exposure levels are themselves too high. Common scenarios for Pb exposure include occupational, residential, and/or behavioral (hand-to-mouth activity) settings. The main source of Cd exposure for nonsmokers is dietary, through plants or animals that accumulate the metal. Specific cellular importers for Pb and Cd are unlikely as these metals are nonessential and toxic. Accordingly, in the intestine, the operational mechanism is assumed to be inadvertent uptake through pathways intended for essential nutrients such as iron. Results from experimental and epidemiological studies indicated that diets low in iron (Fe) result in increased absorption of Pb and Cd, suggesting common molecular mechanisms of Cd and Pb transport. Indeed, recent mechanistic studies found that the intestinal transporter for nonheme iron, divalent metal transporter 1 (DMT1), mediates the transport of Pb and Cd. DMT1 is regulated, in part, by dietary iron, and chemical species of Cd and Pb that are transported by DMT1 would be made available through digestion and are also found in plasma. Accordingly, the involvement of DMT1 in metal uptake offers a mechanistic explanation for why an iron-deficient diet is a risk factor for Pb and Cd poisoning. It also suggests that diets rich in iron-containing food could be protective against heavy metal poisoning.

Divalent metal transporter 1 in lead and cadmium transport

Scope and perspectives of intravital microscopy - bridge over from in vitro to in vivo

Newborn rats that suckled mothers eating a diet containing 4 percent lead carbonate display hyperactivity, aggressiveness, and excessive stereotyped behavior starting at 4 weeks of age. There is an eightfold increase in the concentration of lead in brain, no change in norepinephrine, but a 20 percent decrease in dopamine relative to coetaneous controls. This suggests a relationship between central nervous system dysfunction due to lead and dopamine metabolism in brain.

https://science.sciencemag.org/content/sci/182/4116/1022.full.pdf

Hyperactivity and brain catecholamines in lead-exposed developing rats.

Hydronephrosis: a new method to visualize vas afferens, efferens, and glomerular network.

Lead entry Into the central nervous system and effects on brain metabolism were studied in immature rats. Lead 210 readily enters the brain after intravenous injection; uptake is proportional to dose. Although blood levels fall rapidly after injection, brain lead retention is prolonged and unaffected by edetic acid therapy. In individuals who ingest lead episodically, progressive accumulation in the brain can occur without detection of changes in blood. Excessive lead deposition in the brain of nursing rat pups provokes severe hemorrhagic reactions limited to the cerebellum although lead concentrations are the same as in other brain regions. A prehemorrhagic stage of lead encephalopathy could be identified in the cerebellum by monitoring brain edema. This appears to be due to capillary dysfunction and suggests that cerebellar capillaries are more vulnerable to lead than capillaries elsewhere in the brain.

Pathogenesis of Lead Encephalopathy: Uptake of Lead and Reaction of Brain Capillaries

The distribution of radioactive lead (210pb) in the cerebellum of developing rats

Experimental lead encephalopathy was produced in developing rats. The cerebellar changes that developed were studied by light and electron microscopy. Although edema was observed in all phases of the encephalopathy, changes in the blood vessels, formation of platelet thrombi, and alterations of the Purkinje cells and their dendrites warranted special attention. The lead and calcium content of the brain and of the blood in the lead poisoned and control groups were determined chemically. The results are discussed from a morphological point of view and a hypothesis of their pathogenesis is presented.

Considerations on the development of experimental lead encephalopathy.

Intraglomerular microcirculation: Measurements of single glomerular loop flow in rats

1.

Acute renal failure in man can best be simulated experimentally by using either temporary occlusion of the renal artery or perfusion of noradrenaline into the renal artery.




2.

The kidney of Tupaia belangeri, a primitive primate, which may allegedly die from psychogenically induced renal failure, is surprisingly more resistant to temporary occlusion of the renal artery than that of the rat.




3.

The results of physiological studies (measurements of intratubular pressures, proximal passage-times, inulin clearance) and the intravital microscopic appearances of the renal surface of the Tupaia kidney varied little from those of the rat. As intravital microscopic studies showed, however, only rarely are the distal tubuli visible on the surface of Tupaia kidneys, and stop-flow pressures measured in them proved remarkably high.




4.

In Tupaia as in rats, anuria developing 48 hours after temporary ischemia is brought about by intratubular proteinaceous casts blocking the flow of urinary filtrate, most likely at Henle's loop.

Both the diameter of the proximal tubular lumen and the intratubular pressures increase after temporary ischemia but the severity of the diuresis and inulin clearance decrease. To demonstrate that the proteinaceous casts block the tubular lumina, we have shown that when two micropipettes are inserted into the same nephron and that nephron is perfused, the intratubular pressure rises approaching systolic pressures. Renal failure becomes more severe the longer the duration of temporary ischemia (from 1 to 3 h). As renal damage progresses and intratubular pressures fail to rise, tubular permeability increases (leakage).




5.

As with occlusion of the renal artery, infusion of the artery with noradrenaline leads to massive blockage of the nephrons by proteinaceous material in 48 h in the rat. Renal function (clearance of inulin, tubular passage times etc.) decreases as the infusion is prolonged (from 45 to 120 min), whereas the diameter of the tubular lumen and intratubular pressures increase.

As studies with the double insertion of micropipettes and microperfusion have shown, tubular blockage by casts also occurs after perfusion of noradrenaline. Where the tubular damage is greatest, the tubules leak.




6.

Histologically, the proteinaceous material blocking the urinary flow is primarily found near the loops of Henle. Depending on the degree of damage, we often observe increasing necrosis of tubules; that represents the morphological equivalent of changes in tubular permeability (leakage).

Further evidence of tubular blockage after acute ischemic renal failure in Tupaia belangeri and rats.

Revadi and Thomas (1979) have established the existence of normal cyclic variations in the human uterine endocervical mucosa. Their further studies (1980) on endogenously-produced oestrogen states and the human uterine endocervix showed that oestrogen produces a progressive increase in endocervical mucosal cell heights which is unrivalled by the endocervix, even in the pregnant state. On the basis of these studies, they hypothesized, that though oestrogen, was probably responsible for the secretion of excessive quantities of endocervical mucus, the release of this mucus was probably mediated by progesterone. In their studies basal cell proliferation was never seen.

Frederick D. Dallenbach

Papers

The distribution of radioactive lead (210pb) in the cerebellum of developing rats

Considerations on the development of experimental lead encephalopathy.

Intraglomerular microcirculation: Measurements of single glomerular loop flow in rats

Further evidence of tubular blockage after acute ischemic renal failure in Tupaia belangeri and rats.

Endocervical changes in the guinea pig after treatment with 17-beta - oestradiol and 9,10 dimethylbenzanthracene.