Michael Meaney, a biologist at McGill University and a frequent collaborator with Szyf, has pursued an equally provocative notion: that some epigenetic changes can be induced after birth, through a mother's physical behavior toward her newborn. For years, Meaney sought to explain some curious results he had observed involving the nurturing behavior of rats. Working with graduate student Ian Weaver, Meaney compared two types of mother rats: those that patiently licked their offspring after birth and those that neglected their newborns. The licked newborns grew up to be relatively brave and calm (for rats). The neglected newborns grew into the sort of rodents that nervously skitter into the darkest corner when placed in a new environment.
Traditionally, researchers might have offered an explanation on one side or the other of the nature-versus-nurture divide. Either the newborns inherited a genetic propensity to be skittish or brave (nature), or they were learning the behavior from their mothers (nurture). Meaney and Weaver's results didn't fall neatly into either camp. After analyzing the brain tissue of both licked and nonlicked rats, the researchers found distinct differences in the DNA methylation patterns in the hippocampus cells of each group. Remarkably, the mother's licking activity had the effect of removing dimmer switches on a gene that shapes stress receptors in the pup's growing brain. The well-licked rats had better-developed hippocampi and released less of the stress hormone cortisol, making them calmer when startled. In contrast, the neglected pups released much more cortisol, had less-developed hippocampi, and reacted nervously when startled or in new surroundings. Through a simple maternal behavior, these mother rats were literally shaping the brains of their offspring.
How exactly does the mother's behavior cause the epigenetic change in her pup? Licking and grooming release serotonin in the pup's brain, which activates serotonin receptors in the hippocampus. These receptors send proteins called transcription factors to turn on the gene that inhibits stress responses. Meaney, Weaver, and Szyf think that the transcription factors, which normally regulate genes in passing, also carry methylation machinery that can alter gene expression permanently. In two subsequent studies, Meaney and his colleagues were even able to reverse the epigenetic signals by injecting the drug trichostatin A into the brains of adult rats. In effect, they were able to simulate the effect of good (and bad) parenting with a pharmaceutical intervention. Trichostatin, interestingly, is chemically similar to the drug valproate, which is used clinically in people as a mood stabilizer.
Meaney says the link between nurturing and brain development is more than just a curious cause and effect. He suggests that making postnatal changes to an offspring's epigenome offers an adaptive advantage. Through such tweaking, mother rats have a last chance to mold their progeny to suit the environment they were born into. "These experiments emphasize the importance of context on the development of a creature," Meaney says. "They challenge the overriding theories of both biology and psychology. Rudimentary adaptive responses are not innate or passively emerging from the genome but are molded by the environment."
 The hippocampus in a sheep's brain. Meany's research showed that, in rats, hippocampus size is influenced by maternal nurturing behavior such as licking after birth. Well-licked rats had more developed hippocampi and produced less of the stress hormone corstisol. (Courtesy of the University of Pennsylvania School of Veterinary Medicine) |
In an early study, which provided circumstantial evidence, Meaney examined magnetic resonance imaging brain scans of adults who began life as low-birth-weight babies. Those adults who reported in a questionnaire that they had a poor relationship with their mother were found to have hippocampi that were significantly smaller than average. Those adults who reported having had a close relationship with their mother, however, showed perfectly normal size hippocampi. Meaney acknowledges the unreliability of subjects reporting on their own parental relationships; nonetheless, he strongly suspects that the quality of parenting was responsible for the different shapes of the brains of these two groups.
In an effort to solidify the connection, he and other researchers have launched an ambitious five-year multimillion-dollar study to examine the effects of early nurturing on hundreds of human babies. As a test group, he's using severely depressed mothers who often have difficulty bonding and caring for their newborns and, as a result, tend to caress their babies less than mothers who don't experience depression or anxiety. The question is whether the babies of depressed mothers show the distinct brain shapes and patterns indicative of epigenetic differences.
The science of epigenetics opens a window onto the inner workings of many human diseases. It also raises some provocative new questions. Even as we consider manipulating the human epigenome to benefit our health, some researchers are concerned that we may already be altering our epigenomes unintentionally, and perhaps not for the better. Jirtle notes that the prenatal vitamins that physicians commonly encourage pregnant women to take to reduce the incidence of birth defects in their infants include some of the same chemicals that Jirtle fed to his agouti mice. In effect, Jirtle wonders whether his mouse experiment is being carried out wholesale on American women.
"On top of the prenatal vitamins, every bit of grain product that we eat in the country is now fortified with folic acid," Jirtle notes, and folic acid is a known methyl donor. "In addition, some women take multivitamins that also have these compounds. They're getting a triple hit."
While the prenatal supplements have an undisputed positive effect, Jirtle says, no one knows where else in the fetal genome those gene-silencing methyl donors might be landing. A methyl tag that has a positive effect on one gene might have a deleterious effect if it happens to fall somewhere else. "It's the American way to think, 'If a little is good, a lot is great.' But that is not necessarily the case here. You might be overmethylating certain genes, which could potentially cause other things like autism and other negative outcomes."
Szyf shares the concern. "Fueling the methylation machinery through dietary supplements is a dangerous experiment, because there is likely to be a plethora of effects throughout a lifetime." In the future, he believes, epidemiologists will have their hands full looking for possible epigenetic consequences of these public-health choices. "Did this change in diet increase cancer risk? Did it increase depression? Did it increase schizophrenia? Did it increase dementia or Alzheimer's? We don't know yet. And it will take some time to sort it out."
