An “Amazing” Reversal of Lead's Effects

Scientists rarely admit to being amazed.

But that’s the very first thing Tomás Guilarte, professor of Environmental Health Sciences, says about his recent lead study. Guilarte and colleagues wanted to see if keeping rats in a cage enriched with opportunities for exploration and learning could reverse cognitive deficits caused by lead poisoning during development. The answer was a resounding, unequivocal yes.

“On a physical basis, the animals had no differences—they weighed the same and looked the same,” says Guilarte, PhD ’80. “But when we tested their learning and memory, we could easily recognize which animals had come from an enriched environment, and which came from an isolated environment.”

Guilarte’s results, published online in the Annals of Neurology in November, prompted a whirlwind of attention from the media and excited clinical and public health workers striving to prevent and treat lead poisoning.

Lead-based paints continue to be a problem in an estimated 39 million American homes. Experts from the Centers for Disease Control and Prevention estimate that about 300,000 American children still suffer from elevated blood-lead levels that can lead to learning deficits, behavioral problems, and other impairments. Making the picture more grim: A recent report shows that chelation therapy, used to reduce lead levels in children, doesn’t reverse lead’s effects on cognition.

Guilarte, who for more than a decade has studied lead’s effects at the molecular level on rat brain development, had heard of research suggesting that environmental enrichment—giving a test animal or a child many opportunities to explore, interact, and play—could promote many of the brain development processes disrupted by lead. He decided to see if this effect could help after lead had already impaired brain development.

 “We know that there are things that you can do prophylactically prior to lead exposure or during the lead exposure, and that’s fine; but we said, ‘If this is going to be helpful, we want to have something that is going to be helpful after the kids have been exposed to lead and they have learning deficits,’” Guilarte explains.

For the experiment, Guilarte, graduate student Christopher Toscano, senior research technician Jennifer McGlothan, and research associate Shelley Weaver established four groups of rats. Two control groups had no lead exposure, and two experimental groups were exposed to high levels of lead from gestation until weaning. In each pair of groups, one group was kept in an “isolated” environment, a standard-issue lab animal cage; the other group was kept in the enriched cage, which included multiple levels, exercise wheels, tunnels, hammocks, and a variety of toys.

“From the moment you put them in the enriched cage, the difference is amazing,” Guilarte says. “Not only in how they interact with the environment, which is in terms of greater exploration, but also in terms of how they interact with the other animals.”

To test the rats’ learning and memory, Guilarte used a water maze, a large pool of opaque water with a submerged platform. Rats are taught to find the platform, then randomly placed back in the maze and timed for their ability to find their way back to the platform.

Significant differences between the groups emerged in the water maze. Nearly half the animals in the lead-exposed/isolated group hadn’t learned to find the platform in time by day four. “It’s not that [they] can’t learn,” he notes. “They eventually do. But I roughly equate it to a normal child learning a math problem in one day versus a month for a child harmed by lead exposure.” 

In contrast, most of the lead-exposed/enriched group found the platform by day three or four, on a par with the time it took non-lead-exposed groups to find it.

Changes in cognitive function were also observable at a molecular level. Guilarte's group had previously shown that lead exposure greatly reduces the expression of the gene for a subunit of a protein critical to brain development. When they examined the brains of lead-exposed/enriched rats, the group found the protein subunit levels had returned to normal. They also found increased levels of a nerve growth factor compared to lead-exposed/isolated rats.

“So we’re now making associations between a change in behavior and changes in the expression of genes that are important for learning and memory,” says Guilarte, who has several follow-up studies under way. “It all goes along with what we have been characterizing in these animals... it’s just absolutely amazing.”