PROVIDENCE – It is no secret that breastfeeding has many positive health benefits for both mothers and babies related to nutrition and nurturing.

But a new translational research study, led by Barry M. Lester, Ph.D., and published in the September 2018 edition of the journal, Pediatrics, suggests that breastfeeding may play an important role in neuronal development, helping to stimulate genetic changes that decrease cortisol stress reactivity in the brain of young infants.

Because disruption of what is known as HPA [hypothalamic-pituitary adrenal] stress reactivity is associated with a variety of complex diseases, such as obesity, heart disease and mental health disorders related to early life stress, Lester’s study points toward interventions focused on the importance of breastfeeding in creating a form of cellular memory in the brain, reducing stress response in infants.

A team of researchers, led by Lester, the director of Women & Infants Hospital’s Brown Center for the Study of Children at Risk, and a professor of Psychiatry and Pediatrics at the Warren Alpert Medical School, looked at 42, full-term healthy infants and their mothers, one half of whom breastfed for the first five months and one half of whom did not.

What Lester and his colleagues found, measuring cortisol stress activity in infant saliva and examining what is known as DNA methylation [changing the activity of a DNA segment without changing the sequence], breastfeeding positively impacts an important regulatory region of the glucocorticoid receptor gene, or GR gene, which regulates development, metabolism and immune response.

Translated, breastfeeding stimulates an infant’s physiological capacity to cope with stress.

Or, as Lester put it: “There was an epigenetic change in babies who were breastfed, resulting in reduced stress, [compared to] those were not breastfed.”

In the larger context, breastfeeding then becomes an important component of interventions to prevent what is known as toxic stress in infants.

[The research team also included: Linda LaGasse, Ph.D., and Dr. James F. Padbury, of Women & Infants Hospital/Warren Alpert Medical School; Elisabeth Condradt, Ph.D., of the University of Utah; Edward Tronick, Ph.D., of the University of Massachusetts Boston; and Carmen Marsit, Ph.D., of Emory University.]

The participants in the study were mothers and their infants who were born at the Women and Infants Hospital in Rhode Island that were enrolled as part of the larger Rhode Island Child Health Study and then recruited for this follow-up examination during the period of June 2013 through July 2014.

Larger context
The new study published in Pediatrics complements a larger federal national research effort known as ECHO, or Environmental influences on Child Health Outcomes, for which Lester and his research team were recently awarded approximately $20 million over five years for Phase Two research work, looking at a cohort of premature infants, focused in part on epigenetic changes and correlating their relationship to developmental issues.

Here is the ConvergenceRI interview with Dr. Barry Lester, the director of the Center for the Study of Children at Risk, talking about the new study published in Pediatrics.

ConvergenceRI: Having demonstrated the way that breastfeeding of infants can produce epigenetic changes to reduce stress response in infants, what are the next steps that your research indicates?
LESTER: There are two pieces to this; one has to do with the breastfeeding angle, the other has to do with epigenetic changes that are due to positive mothering, for lack of a better term.

[The impetus for this research] comes from the original animal research conducted by Michael Meaney [on the relationship between early maternal care and stress response in rat pups].

The original animal research work was absolutely groundbreaking and, in many ways, it was what got me into this field of research. Meaney was able to show in rodents, if you looked at good mothering in a rodent, in the first couple of days of life, it was defined by licking, grooming and feeding.

What Meaney’s research showed that if you divided rat mothers into those that do high amounts of licking and grooming, and those that do little licking and grooming, that behavior induces changes in the rat pups in the first six days of life – those changes being changes in the glucocorticoid receptor gene that, among other things, controls production of what in the human would be human cortisol.

As a result of licking and grooming, the rat pups showed fewer epigenetic markers in this particular gene, and that resulted in less production of coritsol, so that the rats are less reactive. These changes last through to adulthood and are passed through to the next generation.

That, to me, was just extraordinary, that mothering behavior can change gene activity so highly implicated in child and adult psychopathology and physical health, all the way up to obesity and metabolic disorders and mental disorders in kids.

[Lester’s study represents “the first translational study in which research recapitulate the effects of maternal care in rodents by demonstrating that in human infants, maternal breastfeeding impacts the infants’ epigenome and is associated with altered stress responsivity,” according to the article in Pediatrics.]

ConvergenceRI: What are the next steps in further research you would like to conduct?
LESTER: We took something documented in rodents and replicated it in humans. That is extraordinary, only because you can do things with animals that you can’t do with people.

We’ve shown that the same phenomenon that has been documented in rodents can now be documented in humans.

The next step will involve looking at epigenetic [changes] in people.

With epigenetics in other fields like cancer, there are FDA-approved pharmacological treatments for cancer, it has been going on now for 30-40 years.

When I first got interested in this research, the immediate implication is wow, if this stuff can be documented in humans, it opens the door for developing epigenetically-based treatments and interventions.

That is where I think this work should eventually go.

Meaning, if you know, for example, that you could do an assessment and determine what the cortisol levels of a baby are, and if they were too high, the implication would be that you could develop an intervention to improve mothering and care, which would presumably lower the baby’s circulating levels of cortisol, and make then less reactive and less prone to psychopathology and disease. That’s one way to think about it.

ConvergenceRI: Are there additional factors that need to be examined regarding the stress response in infants, such as what is the potential for lead and other toxins to interfere with the regulatory function of the glucocorticoid receptor gene?
LESTER: Absolutely. There is a lot of increasing literature on toxins and epigenetic changes, obviously lead being one of them.

The question becomes particularly relevant depending on the population you are looking at, because in the larger context of what people talk about as toxic stress, it would include things such as chemical insults, with lead being one of them.

But it also involves poverty and poor parenting, which is where you get into the mothering stuff, accumulating this toxic stress that depletes the ability to respond to what Bruce McEwen called “allostatic load/overload” [in his research on chronic stress].

Basically, what happens, over time, is that you are beating up on the HPA system, you wear it down, you wear it out, and it becomes inadequate in terms of responding to stress, which is where you get your psychopathology and medical disorders.

It all has to be looked at – the difficulties are all going to accumulate.

ConvergenceRI: How does your work correlate with the recent research of Audrey Tyrka, who has studied how early life stress and childhood adversity correlates with the shortening of telomeres in mitochondrial DNA?
LESTER: It is very similar. She is working on a different aspect of epigenetic phenomena. Telomeres are being looked as a way to think about epigenetic aging and epigenetic memory.

It is complementary. We are looking at a specific epigenetic mechanism called DNA methylation. She is looking at telomeres; there are many different ways to look at epigenetics. The research is related.

ConvergenceRI: How does this study fit into the work being done with the current ECHO research underway? Are they on parallel tracks, or are there points of intersection?
LESTER: It is absolutely related to ECHO. As you know, we’re part of the ECHO research program. ECHO is all about environmental exposures and the developmental origins of health and disease.

Epigenetics is part of ECHO, parenting is part of ECHO, lead exposure is part of ECHO; it is absolutely all in the same ballpark.

ConvergenceRI: Where do things currently stand in terms of your work as part of the ECHO study?
LESTER: The work for the first two years finished at the end of September, and we’re now moving into Phase Two. We just got refunded for another five years, for about $20 million.

Our particular cohort includes some 600 premature births; we will be examining them for the next five years, through age 7. In our study, we are looking at, and this is really cool, we’re measuring epigenetics once a year for all seven years. We will be able to look at the trajectory of epigenetic changes and see how those trajectories map onto the trajectories of development.

ConvergenceRI: What haven’t I asked about the study and its implications that you would like to talk about?
LESTER: The breastfeeding component. When you look at the rodent work studying this particular gene, it has 13 locations on the gene in the region where the animal work shows up, including one area that particularly has to do with nerve growth factors and neuronal development. That is why it is so important if you are increasing DNA methylation in this gene and increasing neuronal growth.

In our human study, what we found were effects in a different region of the gene, one that has connections to neuronal and nerve growth factors, but it was also related to immunological activity.

What our study is showing is that it’s not just about being a good mother; the nurturing we’re talking about in this particular finding is unique to breastfeeding. You are impacting immune response and potentially neuronal growth, and you’re impacting lowering the baby’s cortisol reactivity.

That is linked to breastfeeding.