Monensin Improves the Effectiveness of meso-Dimercaptosuccinate when Used to Treat Lead Intoxication in Rats

Among divalent cations, the ionophore monensin shows high activity and selectivity for the transport of lead ions (Pb(2+)) across phospholipid membranes. When coadministered to rats that were receiving meso-dimercaptosuccinate for treatment of Pb intoxication, monensin significantly increased the amount of Pb removed from femur, brain, and heart. It showed a tendency to increase Pb removal from liver and kidney but had no effect of this type in skeletal muscle. Tissue levels of several physiologic (calcium, cobalt, copper, iron, magnesium, manganese, molybdenum, zinc) and nonphysiologic (arsenic, cadmium, chromium, nickel, strontium) elements were also determined after the application of these compounds. Among the physiologic elements, a number of significant changes were seen, including both rising and falling values. The size of these changes was typically around 20% compared with control values, with the largest examples seen in femur. These changes often tended to reverse those of similar size that had occurred during Pb administration. Among the nonphysiologic elements, which were present in trace amounts, the changes were smaller in number but larger in size. None of these changes appears likely to be significant in terms of toxicity, and there were no signs of overt toxicity under any of the conditions employed. Monensin may act by cotransporting Pb(2+) and OH(–) ions out of cells, in exchange for external sodium ions. The net effect would be to shuttle intracellular Pb(2+) to extracellular dimercaptosuccinic acid thereby enhancing its effectiveness. Thus, monensin may be useful for the treatment of Pb intoxication when applied in combination with hydrophilic Pb(2+) chelators

Lead Exposure Inhibits Fracture Healing and Is Associated with Increased Chondrogenesis, Delay in Cartilage Mineralization, and a Decrease in Osteoprogenitor Frequency

Lead exposure continues to be a significant public health problem. In addition to acute toxicity, Pb has an extremely long half-life in bone. Individuals with past exposure develop increased blood Pb levels during periods of high bone turnover or resorption. Pb is known to affect osteoblasts, osteoclasts, and chondrocytes and has been associated with osteoporosis. However, its effects on skeletal repair have not been studied. We exposed C57/B6 mice to various concentrations of Pb acetate in their drinking water to achieve environmentally relevant blood Pb levels, measured by atomic absorption. After exposure for 6 weeks, each mouse underwent closed tibia fracture. Radiographs were followed and histologic analysis was performed at 7, 14, and 21 days. In mice exposed to low Pb concentrations, fracture healing was characterized by a delay in bridging cartilage formation, decreased collagen type II and type X expression at 7 days, a 5-fold increase in cartilage formation at day 14 associated with delayed maturation and calcification, and a persistence of cartilage at day 21. Fibrous nonunions at 21 days were prevalent in mice receiving very high Pb exposures. Pb significantly inhibited ex vivo bone nodule formation but had no effect on osteoclasts isolated from Pb-exposed animals. No significant effects on osteoclast number or activity were observed. We conclude that Pb delays fracture healing at environmentally relevant doses and induces fibrous nonunions at higher doses by inhibiting the progression of endochondral ossification

Reduced Intellectual Development in Children with Prenatal Lead Exposure

OBJECTIVE: Low-level postnatal lead exposure is associated with poor intellectual development in children, although effects of prenatal exposure are less well studied. We hypothesized that prenatal lead exposure would have a more powerful and lasting impact on child development than postnatal exposure. DESIGN: We used generalized linear mixed models with random intercept and slope to analyze the pattern of lead effect of the cohort from pregnancy through 10 years of age on child IQ from 6 to 10 years. We statistically evaluated dose–response nonlinearity. PARTICIPANTS: A cohort of 175 children, 150 of whom had complete data for all included covariates, attended the National Institute of Perinatology in Mexico City from 1987 through 2002. EVALUATIONS/MEASUREMENTS: We used the Wechsler Intelligence Scale for Children–Revised, Spanish version, to measure IQ. Blood lead (BPb) was measured by a reference laboratory of the Centers for Disease Control and Prevention (CDC) quality assurance program for BPb. RESULTS: Geometric mean BPb during pregnancy was 8.0 μg/dL (range, 1–33 μg/dL), from 1 through 5 years was 9.8 μg/dL (2.8–36.4 μg/dL), and from 6 through 10 years was 6.2 μg/dL (2.2–18.6 μg/dL). IQ at 6–10 years decreased significantly only with increasing natural-log third-trimester BPb (β = −3.90; 95% confidence interval, −6.45 to −1.36), controlling for other BPb and covariates. The dose–response BPb–IQ function was log-linear, not linear–linear. CONCLUSIONS: Lead exposure around 28 weeks gestation is a critical period for later child intellectual development, with lasting and possibly permanent effects. There was no evidence of a threshold; the strongest lead effects on IQ occurred within the first few micrograms of BPb. RELEVANCE TO CLINICAL PRACTICE: Current CDC action limits for children applied to pregnant women permit most lead-associated child IQ decreases measured over the studied BPb range