Nanoplastics and 'forever chemicals' disrupt molecular structures, functionality

Researchers at The University of Texas at El Paso have made significant inroads in understanding how nanoplastics and per- and polyfluoroalkyl substances (PFAS) -- commonly known as forever chemicals -- disrupt biomolecular structure and function. The work shows that the compounds can alter proteins found in human breast milk and infant formulas -- potentially causing developmental issues downstream.

Nanoplastics and forever chemicals are manmade compounds present throughout the environment; a series of recent studies have linked them to numerous negative health outcomes. While nanoplastics originate primarily as a result of the degradation of larger plastic materials, like water bottles and food packaging, forever chemicals are found in various products like cookware and clothing.

The UTEP research team focused on the compounds' impact on three proteins critical to human development and function: beta-lactoglobulin, alpha-lactalbumin and myoglobin. Their findings, which provide an atomic-level insight into the detrimental effects of nanoplastics and PFAS on human health, are described in two recent articles in the Journal of the American Chemical Society and ACS Applied Materials and Interfaces.

"By understanding the molecular mechanisms of how nanoplastics and forever chemicals disrupt cellular functions, scientists can develop safer alternatives to these materials," said Mahesh Narayan, Ph.D., a professor, fellow of the Royal Society of Chemistry and chief of the Division of Biochemistry in UTEP's Department of Chemistry and Biochemistry, who oversaw the two studies. "The insights gained from this research have far-reaching implications."

Narayan said that, most importantly, their research revealed that nanoplastics and PFAS completely "dissolved" a region of proteins known as the alpha helix, converting them into structures called beta sheets.

"We weren't expecting them all to have this similar impact on the alpha helix," Narayan said. "It was a complete coincidence." The team observed that this alteration also occurs in amyloid proteins, which can cause neurodegeneration and neurotoxic outcomes if the synthetic chemicals reach the brain.

Additional key findings of the studies are described below.

Milk Protein: Beta-Lactoglobulin (BLG)

BLG is a protein found in the milk of sheep and cows and is commonly used as an ingredient in infant formula. The protein binds to retinol (vitamin A) and fatty acids and is crucial for vision and brain development in infants.

The research team discovered that the binding efficiency of BLG to retinol and fatty acids decreases upon exposure to nanoplastics and PFAS. This decrease, modeled by Lela Vukovic, Ph.D., associate professor in the Department of Chemistry and Biochemistry, can lead to significant developmental issues in neonatal infants, the team said.

Additionally, for the first time ever, the team observed that PFAS binds to the milk protein, turning it into a carrier for these compounds.

Human Breast Milk: Alpha-Lactalbumin

Alpha-lactalbumin is found in human breast milk, participates in lactose synthesis and is ingested by infants to help meet nutritional needs. UTEP researchers found that nanoplastics and PFAS corrupt the structure of alpha-lactalbumin protein, thereby potentially compromising lactose formation. The team said the disruption can lead to downstream developmental defects in neonatal infants, such as compromised immunity and reduced mineral absorption.

Oxygen Storage: Myoglobin

Myoglobin, found in the blood and muscle tissue of most mammals, is crucial for storing oxygen. The UTEP research team found that nanoplastics and PFAS compromise the functionality of the myoglobin protein, disrupting its ability to store oxygen. This disruption could lead to health issues such as breathlessness and anemia.

Additional experiments by the team demonstrated that exposure to nanoplastics impairs locomotion in worms, with effects comparable to paraquat -- an herbicide that has been tied to causing Parkinson's disease.

"This work has the potential to significantly impact public health and environmental policies, highlighting the vital role of scientific research in addressing global challenges," said Robert Kirken, Ph.D., dean of the College of Science. "I am proud of the groundbreaking research conducted by Dr. Narayan, Dr. Vukovic and their teams. Their innovative approach to understanding how these manmade materials disrupt biomolecular functions is a prime example of the transformative work UTEP researchers do on a regular basis."

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Why breast-fed premature infants have a healthier gut than formula-fed ones

Human breastmilk has long been considered "liquid gold" among clinicians treating premature infants in a newborn intensive care unit (NICU). Breastmilk-fed "preemies" are healthier, on average, than those fed formula. Why is that true, however, has remained a mystery.

New research from the University of Maryland School of Medicine's (UMSOM) Institute for Genome Sciences (IGS), published online in the journal mBio in June found it is not just the content of breastmilk that makes the difference. It is also the way the babies digest it.

The research, led by Bing Ma, PhD, Assistant Professor of Microbiology and Immunology at UMSOM and a researcher at IGS, discovered a strain of the Bifidobacterium breve bacteria or B. breve in the gut of breastfed babies who received higher volumes of breastmilk than their counterparts. Those preemies had better nutrient absorption because they developed an intact intestinal wall, one week after birth. B. breve was much less prevalent in both formula-fed babies and breastfed babies with "leaky gut." Babies with leaky gut do not develop a barrier to protect against bacteria and digested food from getting into the bloodstream. For the first time, the team also found that the way B. breve metabolizes breastmilk keeps breastfed babies healthier and allows them to gain weight by strengthening their underdeveloped intestinal barrier.

An immature or "leaky" gut can lead to necrotizing enterocolitis (NEC), which is the third leading cause of newborn death in United States and worldwide. In fact, NEC impacts up to 10 percent of premature babies with a devasting mortality rate as high as 50 percent.

"Our discovery could lead to promising and practical clinical interventions to strengthen the babies' gut and, therefore, increase survival rates of the most vulnerable preemies," said Dr. Ma.

Bifidobacterium in the gut or microbiome has long been known to have health benefits. It includes a diverse set of strains that have very different properties. Some strains are only found in adults; some are mostly in adolescence. One strain, Bifidobacterium infantis, has been seen predominantly in full-term infants.

The researchers followed 113 premature babies who were born between 24 and 32 weeks' gestation. This study found Bifidobacterium breve (B. breve) only in preemies who had improved gut barrier function within one week after birth. Dr. Ma and her colleagues discovered that Bifidobacterium breve is genetically equipped to digest nutrients within the cell membrane rather than the more typical external digestion process in which bacteria secrete digestive enzymes onto nutrients to break them down.

At the most basic level, the gut microbiome in these breastfed preemies with more B. breve metabolizes carbohydrates differently than it does formula. The researchers say they hypothesize that this process of metabolism then strengthens and matures the intestinal barrier faster, protecting fragile newborns from disease.

"We now know that it is not the breastmilk alone that helps preemies develop their intestinal barrier faster," Dr. Ma said. "We will need to find the best way to prophylactically administer B. breve early in life, rather than rely on transmission from breastmilk or even the mother's gut or vaginal microbiota during the birthing process. This is especially critical in formula-fed preemies."

Dr. Ma said that more studies are needed to determine if the B. breve originated in the breastmilk, gut, mother's vagina, or even environment.

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How breastfeeding offers immune benefits

When infants breastfeed, they receive an immune boost that helps them fight off infectious diseases, according to recent research from Binghamton University Associate Professor of Anthropology Katherine Wander.

She is the lead author of "Tradeoffs in milk immunity affect infant infectious disease risk," published this June in Evolution, Medicine, and Public Health. Co-authors include Masako Fujita from Michigan State University's Anthropology Department, Siobhan Mattison from the University of New Mexico's Anthropology Department and the National Science Foundation; and Frida Mowo, Ireen Kiwelu and Blandina Mmbaga in Tanzania, whose associations include the Kilimanjaro Christian Medical Centre and the Kilimanjaro Clinical Research Institute. Binghamton University graduate students were also part of the research team, with tasks ranging from data collection in Tanzania to data-cleaning and analysis. They include Margaret Duris, Megan Gauck, Tessa Hopt, Katherine Lacy, Angela Foligno, Rebecca Ulloa and Connor Dodge.

For the project, the research team studied almost 100 mother and baby pairs in rural Kilimanjaro. Prolonged breastfeeding is the norm in this population and infectious diseases during infancy are very common, even compared to other areas of East Africa. This makes Kilimanjaro an ideal setting to begin to understand how immune protection from milk might affect infectious disease risk, Wander said.

"You most often hear about the immune system of milk in terms of transferring maternal antibodies to infants via milk -- which is probably very important -- but it seems there's much more going on as well. The immune system of milk is a whole system, capable of mounting immune responses," Wander said. "We're only beginning to understand the full extent and role of the immune system of milk."

Milk and immunity

Mother's milk contains everything needed to mount immune responses, from antibodies to multiple types of immune cells and more. While they originate from the mother's immune system, these components of milk appear to be curated rather than selected at random from the mother's blood, although that mechanism remains poorly understood, Wander explained.

To test the impact of milk's immune system on infant health, the researchers combined a few milliliters of milk with a small amount of bacteria, then placed the mixture in an incubator overnight. They then measured the increase of interleukin-6, an immune cell communication molecule that promotes inflammation. This in-vitro response gives an indication of how the milk's immune system is likely to respond to bacteria encountered in the infant's body -- the gut, for example.

The research team also followed the Tanzanian infants to assess whether those who received milk that mounted stronger immune responses during the in-vitro tests were at lower risk for infectious diseases. That appeared to be the case: infants whose mothers' milk mounted larger responses to Salmonella had fewer infectious diseases, particularly respiratory infections such as pneumonia.

But milk that mounted larger responses to Salmonella also tended to mount stronger responses to a benign strain of E. coli, which is common in the human intestinal tract, and these responses weren't beneficial to infants. Infants who received milk that mounted stronger responses to E. coli were at higher risk for gastrointestinal infections. This may indicate that inappropriate responses by milk's immune system -- for example, to bacteria normally present in the gut -- can be disruptive. Gut bacteria play an important role in preventing diarrhea and other infectious disease, the authors note.

While all immune responses have tradeoffs, the downside of milk -- both immediate and common -- was a surprising discovery.

"With so much at stake, we really expected the immune system of milk to be very finely tuned to protecting infants against infection," Wander said.

Researchers expected to see, at most, negative effects of inappropriate immune responses somewhere down the line, such as in slower growth or less than ideal microbial flora. But differentiating between microbial friend or foe is a tricky business even for adults' mature immune systems, as is eliminating an infection without damaging the person's own tissues. So, the authors say, maybe they shouldn't have been surprised to see these tradeoffs play out in infants, as well.

In addition to reducing risk for respiratory infectious, milk immune responses may help "train" the infant's developing immune system to respond to dangerous bacteria. More research is needed to determine how immune development calibrates to input, such as experience with infectious diseases, microbial flora and the immune system within milk.

"These findings are interesting, but the implications for public health and healthcare will only become clear with additional research," said co-author Mmbaga of the Kilimanjaro Clinical Research Institute. "We need to understand how milk immune responses are affected by things we can design public health programs around, like HIV infection or malnutrition."

This research may have applications that go beyond infancy and breastfeeding. Figuring out how the immune system has evolved to strike a balance between protection and harm could help shed light on health problems from infant diarrhea and pneumonia to autoimmune diseases.

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Study reveals the dynamics of human milk production

For the first time, MIT researchers have performed a large-scale, high-resolution study of the cells in breast milk, allowing them to track how these cells change over time in nursing mothers.

By analyzing human breast milk produced between three days and nearly two years after childbirth, the researchers were able to identify a variety of changes in gene expression in mammary gland cells. Some of these changes were linked to factors such as hormone levels, illness of the mother or baby, the mother starting birth control, and the baby starting daycare.

"We were able to take this really long view of lactation that other studies haven't really done, and we showed that milk does change over the entire course of lactation, even after years of milk production," says Brittany Goods, a former MIT postdoc who is now an assistant professor of engineering at Dartmouth College, and one of the senior authors of the study.

The researchers hope that their findings will lay the groundwork for more in-depth studies of how breast milk changes over time. Such studies could eventually yield new ways to boost mothers' milk production or to improve the composition of infant formula.

Bonnie Berger, the Simons Professor of Mathematics at MIT and head of the Computation and Biology group at the Computer Science and Artificial Intelligence Laboratory (CSAIL), is a senior author of the study, as is Alex Shalek, an associate professor of chemistry at MIT and a member of the Institute for Medical Engineering and Science (IMES); the Koch Institute for Integrative Cancer Research; the Ragon Institute of MGH, MIT and Harvard; and the Broad Institute of Harvard and MIT.

MIT graduate student Sarah Nyquist is the lead author of the paper, which appears this week in the Proceedings of the National Academy of Sciences.

Cellular changes

Human mammary glands can produce more than a liter of milk in a day, for months or years after childbirth. Studying how mammary gland cells accomplish this feat has been difficult in humans because the tissue itself can't be biopsied or otherwise accessed during lactation. However, recent studies have shown that breast milk contains many cells from the mammary gland, offering a noninvasive way to study these cells.

For this study, the MIT team collected breast milk samples from 15 nursing mothers. Each donor provided samples at multiple time points, ranging from three to 632 days after giving birth. The researchers also collected information about health and lifestyle changes that occurred throughout the lactation period.

The researchers isolated more than 48,000 cells from 50 samples and analyzed them using single-cell RNA-sequencing, a technology that can determine which genes are being expressed in a cell at a given moment in time. This analysis revealed 10 types of cells -- a population of fibroblast cells, two types of epithelial cells, and seven types of immune cells.

More than half of the immune cells that they found were macrophages. These cells appear to express genes that help make the mammary gland more tolerant of the milk proteins that they are producing, so they don't trigger an immune response. The researchers also found populations of B cells, T cells, and other immune cells, but their numbers were too small to do any in-depth studies of their functions.

By far the most abundant cells that they found were lactocytes, which are a type of epithelial cell. These cells expressed many genes for proteins that are found in breast milk, such as lactalbumin, as well as transporters needed to secrete milk proteins, micronutrients, fat, and other breast milk components.

Among the lactocytes, the researchers identified one cluster of cells that appears to be the primary producer of milk, and another that plays more of a structural role in the mammary gland. Each of these cell types could be divided into further subtypes, which the researchers hypothesize may be specialized for particular roles.

As time went on, the researchers found that the proportion of lactocytes involved in milk production went down, while the proportion involved in structural support went up. At the same time, genes involved in responding to the hormone prolactin became more active in the milk-producing lactocytes but dropped off in structural lactocytes. The researchers theorize that these changes may be related to the changing nutritional needs of infants as they grow.

"This study, along with some other studies that are out there, paves the way for mapping out and better understanding some of the pathways that these cells use to accomplish the tremendous amount of work that they do," Goods says.

Milk composition

The researchers also found links between the composition of cells in breast milk and events such as babies starting to go to daycare, starting formula, or the mother starting to use hormonal birth control.

"There are clearly changes in the composition of breast milk that are related to these lifestyle and health changes, such as infant illness or maternal hormonal birth control," Nyquist says. "These changes in lactation don't necessarily have a positive or negative impact on anyone's health, but they do occur and they may lead us to insights into how mammary epithelial cells are producing milk and the types of components that they may be producing."

The researchers now hope to do larger studies that could help them find stronger links between environmental factors and milk composition, and also discover more about how milk naturally changes over time. This could eventually help scientists devise better infant formulas or create formulas adapted to different stages of infancy. The researchers also hope to find ways to help nursing mothers boost their milk production or slow it down when babies are being weaned.

Other follow-up studies may explore how pumping affects milk composition and breast health, or how to prevent conditions such as mastitis.

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Genetic mutation may identify women with difficulty producing breast milk

Leading health care organizations recommend exclusive breastfeeding for six months after birth, yet some mothers report stopping due to a perceived lack of milk supply. Penn State College of Medicine researchers found in a recent study that women who stopped breastfeeding because they believed they had inadequate milk supply -- a condition called perceived inadequate milk supply (PIMS) -- are more likely to have a specific mutation in a gene found in mammary tissue. These women were also more likely to have babies who gained less weight. The researchers said that screening for this mutation, when combined with maternal characteristics like age and body mass index, could be useful in identifying mothers at risk for stopping breastfeeding prematurely due to a perceived lack of milk supply.

"The World Health Organization, the American Academy of Pediatrics and the American College of Obstetricians and Gynecologists recommend exclusive breastfeeding for at least six months because it provides developing infants with optimum nutrition and is associated with improved health outcomes," said Dr. Steven Hicks, lead researcher and pediatrician at Penn State Health Children's Hospital. "While 83% of women initiate breastfeeding, only a reported 57% continue to six months. Socioeconomic and environmental factors may contribute to early cessation, but milk supply is also an often-cited reason. Identifying women who are more likely to have low milk supply could help get them resources to continue breastfeeding such as lactation consultation services."

Previous research has linked maternal genetics with nutrients in breast milk, but few studies have explored how genetics may relate to supply. The researchers studied 18 genes highly expressed in mammary, or milk-producing, tissue in women. They looked for mutations in those genes to see whether mutations were associated with mothers' perceived milk supply.

The study team followed 88 women between 19 and 42 years old for the first year of their baby's life. The mothers completed surveys about their infant's feeding habits at one, four, six and twelve months of age that asked questions about perceived milk supply, whether women supplemented their child's diet with formula and reasons why they did so. Decreased or low milk production, signs of allergies from breastfeeding and other personal reasons such as work, day care or time constraints were included as possible reasons for why women began to supplement with formula. Mothers also provided a DNA sample by having saliva collected.

Using responses from the surveys, the researchers classified the mothers as having either PIMS or perceived adequate milk supply (PAMS). They found that the 45 mothers with PIMS were more likely to breastfeed for shorter periods, report lower milk supply and have infants who were not gaining adequate weight.

The researchers analyzed the mothers' DNA samples and looked for mutations among 18 genes that are involved in the secretion of breast milk. Although modifications in 10 of the genes studied were found among some women, the team found that only one, a variant in the milk fat globule EGF and factor V/VIII domain containing gene (MFGE8), occurred more frequently in women with PIMS. Those without the mutation were more likely to have adequate milk supply and report a longer duration of breastfeeding.

Using statistical modeling, the researchers found that maternal characteristics like age, previous breastfeeding duration and body mass index alone could not differentiate between mothers with PIMS and PAMS. However, when adding in MFGE8 mutation status into the model, it strongly predicted which women reported adequate or inadequate milk supplies. The researchers published their results in the journal Breastfeeding Medicine.

"Identifying risk of PIMS at the outset of breastfeeding could provide opportunities for early, targeted interventions such as guidance from a trained lactation support professional," Hicks said. He noted that current assessment of PIMS is guided by subjective reports and that counseling may help identify foods and medications that help or hinder milk production.

Hicks said that the study's findings will need to be validated in a larger study that includes more mothers. He also said that more research is needed to uncover the biological processes that determine how this particular gene affects milk supply in moms in order to better understand its association with PIMS status.

"Moms with this mutation still produce milk, even if it may be less than women without the mutation, but challenges like poor diet, hydration or sleep could be enough to hinder the supply that they do have," Hicks said. "Screening for this variant and combining that with maternal reports and characteristics could help identify moms and babies that may need additional support."

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Spicy breast milk?

Breast milk is the first food that babies consume. Various studies have suggested that the "taste experience" in early childhood influences eating behavior in adults. Unlike standardized infant formula, natural milk does not taste and smell the same every day. The differences are largely due to the maternal diet.

No one-to-one transfer

However, the taste and aroma of food consumed by the mother are not transferred one-to-one to her milk. Research has already shown that odor and taste active substances from garlic or coffee partly enter the mother's milk as an odor active metabolic product, while flavors from fish oil or nursing tea were of little to no significance in this respect.

The extent to which pungent substances from chili, ginger, or pepper are found in breast milk has been even less researched than aroma and taste substances. For this reason, a scientific team led by TUM has now investigated whether these substances are transferred from food to breast milk and if so, which ones.

Piperine detectable after just one hour

Through extensive mass spectrometric analyses, the team has shown that already one hour after consumption of a standardized curry dish, piperine is detectable in breast milk for several hours. "The observed maximum concentrations of 14 to 57 micrograms per liter were about 70- to 350-fold below the taste perception threshold of an adult," says Professor Corinna Dawid, who heads the Chair of Food Chemistry and Molecular Sensory Science at TUM commissarial for Professor Thomas Hofmann.

Roman Lang, who was initially involved in the study as a scientist at TUM and later at the Leibniz Institute for Food Systems Biology (LSB) adds, "It seems rather unlikely to us that the infants consciously perceive the sharpness. Nevertheless, it is conceivable that regular, low-threshold activation of the "pungent receptor" TRPV1 could help to increase tolerance for such substances later on."

Pungents from ginger or chili as well as the secondary plant compound curcumin, which is also abundant in curry, did not enter milk, according to the research. "We were particularly surprised by the latter, since piperine is supposed to significantly increase the bioavailability of curcumin according to the results of other studies," reports Roman Lang, who heads the Biosystems Chemistry & Human Metabolism research group at the LSB.

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