Web edition: July 3, 2008
front, Holly Ingraham cautions that “I’m not an environmental scientist.” Say
what she wants, this molecular biologist really is. Even if her training and
the focus of her work is the machinery and genetic programming of cells —
especially cancer cells — her findings have application well beyond hospital
walls. They might just explain why certain agricultural chemicals are wreaking
havoc with the reproductive systems of wildlife. Like frogs.
At the suggestion of one of her colleagues, I called Ingraham at the University of California, San Francisco, to talk about amphibians. Ingraham told me she didn’t know much about these critters. So I asked about the hormonal impacts of agricultural chemicals and she told me she didn’t study those either, really.
After which she proceeded to explain how she had chronically administered atrazine — one of the weed killers most widely used by U.S. farmers — to zebrafish. These aquatic “lab rats” were quite young when exposures began, just 17 days post fertilization. Their exposures continued for the next six months. The herbicide exposures fostered a predominance of females to develop. How big a she-fish excess emerged depended on dose, but ranged from double to quadruple the ratio seen in unexposed zebrafish.
As with amphibians, the gender of these fish is not genetically determined. Whether males, females, or a particular ratio of them both eventually develops depends on the hormonal environment in the animals’ bodies.
To home in on the hormonal perturbations triggered by atrazine in these fish, her team screened the animal’s genes to identify which the weed killer might be turning on or off. One receptor in cells that responds to hormones that aren’t steroids (sex hormones) emerged as especially sensitive. Atrazine triggered a cascade of signals that eventually boosted the expression, or activity, of a particular gene in the nucleus of cells. Ingraham and colleague Miyuki Suzawa reported their new findings in the May 7 PLoS ONE.
Atrazine “regulates a whole bunch of programs and genes that either make hormones or are really important for the development of reproductive organs,” explains Ingraham. Doses needed to trigger these effects were in the range of 2 to 22 parts per billion in water. In the environment, especially near farms, Ingraham and Suzawa note, surface-water concentrations of this atrazine can approach nearly 500 ppb.
“Given the current pervasive use and persistence of atrazine in the environment,” the pair conclude in their paper, “our findings support environmental concerns that atrazine poses a potential risk to the reproductive health of young fish and other wild life.”
Like amphibians? Well, yes, the reluctant environmental scientist concedes. “Some of the same issues, in terms of their being especially sensitive to these endocrine disruptors [or hormone tinkerers], is true for them as it is for the fish,” Ingraham said.
What’s particularly interesting here is that she’s finding feminization of fish that’s roughly equivalent to giving them a gonzo dose of estrogen, the primarily female sex hormone. However, atrazine doesn’t bind to the estrogen receptor. So it’s not really masquerading as estrogen. In fact, atrazine’s action tinkers with genes — and hormones — upstream of estrogen’s production in the body.
So, while wildlife ecologists have long characterized feminizing agents in the environment as synthetic estrogens, Ingraham says her new data show that routes to “rewiring” gender and the development of reproductive organs can occur very early in an animal’s life and through mechanisms that are “far more complicated” than simply standing in for estrogens (female sex hormones) or blocking the body’s access to its androgens (male sex hormones).
Particularly troubling: Other vertebrates — including humans have the same receptor and gene that was perturbed by atrazine. Ingraham notes that her team’s data in fact show that atrazine “does essentially the same thing” to human cells growing in the test tube as it does to fish.
Ingraham “has done brilliant work,” says Tyrone Hayes of the University of California, Berkeley. “We had claimed we had pretty good evidence that atrazine binds to this [the receptor she studied] and acts like a hormone,” he says. “Her new paper says, no. It doesn’t bind to it.”
Right, Ingraham says. Atrazine “is is doing something inside the cell to alter a signaling cascade that causes an alteration [phosphorylation] of our receptor.” And when this change takes place, the altered receptor now boosts the expression of a certain gene in those cells.
The result, Hayes says, is that atrazine turns on aromatase. This enzyme converts androgens to estrogen — thereby pointing to at least one route by which atrazine might feminize frogs (as Hayes’ team has reported) — and perhaps triggers cancer or other health risks in people, he adds.
Whatever this and related chemicals might do, there’s a chance they’ll have a broad environmental impact in weeks to come owing to levee breaches along the Mississippi, Ingraham worries.
Indeed, as the first sentence in a Christian Science Monitor story succinctly noted yesterday: “The oil, gasoline, fertilizers, and herbicides swept away by floodwaters in June pose an environmental challenge to the rain-soaked Midwest.” That story focused on human impacts. But as Ingraham’s team and others have shown, there are a host of wildlife species that may experience lasting harm as well.
Suzawa, M. and H.A. Ingraham. 2008. The Herbicide Atrazine Activates Endocrine Gene Networks via Non-Steroidal NR5A Nuclear Receptors in Fish and Mammalian Cells. PLoS ONE 3(May 7):e2117. doi.10.1371/journal.pone.0002117. [Go to]