In Harm’s Way: New Research Elucidates the Never-Ending Impacts of Endocrine-Disrupting Chemicals

Science has shown that virtually all of us are exposed to endocrine-disrupting chemicals (EDCs) essentially as soon as we’re born … and even before! The ENDO 2024 symposium “Endocrine-Disrupting Chemicals in Reproductive Endocrinology” looks at these impacts in three different sessions that look at EDCs prenatally, postnatally, and environmentally.

When you head to Boston, Mass., this June to attend the Endocrine Society’s signature annual meeting, be sure to put “Endocrine-Disrupting Chemicals in Reproductive Endocrinology,” happening June 3, 2024, from 4:30 PM to 6:00 PM on your itinerary.

Three presenters will offer their distinctive perspectives on the far-reaching impairments imposed by endocrine-disrupting chemicals (EDCs) in 30-minute presentations. Two focus on EDCs’ effects on the female reproductive system, one from a biological/toxicological point of view and the other specifically on the epidemiological maternal-child aspect. A third zooms out to look at community-wide health effects. From rodent models to individual humans to populations and their environments, these presentations will offer a 360º view of how EDCs affect our micro and macro ecologies.

The session will be chaired by Shuo Xiao, PhD, from the School of Pharmacy and Environmental and Occupational Health Science Institute (EOHSI) at Rutgers University, in Piscataway, N.J. Xiao told Endocrine News he feels “privileged and enthusiastic” about chairing this session, which aligns with his own work on female reproductive biology, disease, and toxicology. “Our laboratory research leverages multiple classic and cutting-edge models such as rodents, organoids, and organ-on-a-chip,” he explains. “Using these models, we aim to understand how reproductive toxicants, including EDCs, adversely affect female ovarian functions and early pregnancy events.”

“This session will include three distinguished speakers with diverse experience and expertise, including EDC mixtures, forever chemical PFAS, maternal and fetal health, community engagement, and analytical chemistry. The research updates from their presentations will shed light to a more comprehensive understanding of the reproductive and endocrine impacts of EDCs.”

Shuo Xiao, PhD, School of Pharmacy and Environmental and Occupational Health Science Institute, Rutgers University, Piscataway, N.J.

The crux of the matter is that multiple health issues can occur prior to conception and during pregnancy, from infertility to birth defects to other reproductive diseases and cancers, yet our understanding of the underlying mechanisms is woefully insufficient. “However, increasing experimental and epidemiological research evidence reveals exposure to environmental EDCs as a key factor,” Xiao says. “So, this session will include three distinguished speakers with diverse experience and expertise, including EDC mixtures, forever chemical PFAS, maternal and fetal health, community engagement, and analytical chemistry. The research updates from their presentations will shed light to a more comprehensive understanding of the reproductive and endocrine impacts of EDCs.”

Prenatal Exposure to EDC Mixtures: Effects on Maternal and Fetal Health

Speaking first will be Marissa Sobolewski Terry, PhD, of the University of Rochester Medical Center in New York, about her team’s work at the Sobolewski lab. Sobolewski says they “put together a curated cocktail of four EDCs that have been well studied and shown in single-chemical models to influence the endocrine system as well as the metabolic health of the pregnant [mouse] dam and the developing fetus.”

Terry explains that since the discovery and definition of EDCs — one definition being any chemical that can interfere with any aspect of endogenous hormone activity — more than 1,000 different chemicals or xenobiotics have been shown to have some endocrine activity and therefore fall into the EDC category. “This creates a quandary for toxicological research that typically focuses on single chemicals at a time,” she says, “when the reality of human exposure, particularly during pregnancy, is that humans are not exposed to one EDC but to low doses of dozens of EDCs.”

The team combines low doses of well-known chemicals from four broad classes that align with real-life exposures: atrazine, a pesticide; perfluorooctanoic acid (PFOA), a perfluorinated alkylated substance (PFAS) and therefore a “forever” chemical; bisphenol A (BPA), a plasticizer once used in infant bottles; and 2,3,7,8 -tetrachlorodibenzo-p-dioxin (TCDD), an industrial byproduct. The cocktail was then given to pregnant dams to study its effects on the mouse fetuses. Sobolewski says this in itself represents scientific advancement — toxicological research has historically been done on males — but it also dawned on the team that they should additionally look at pregnancy itself as a “sensitive window” for these kinds of exposures, to answer, in other words, how is the pregnant mouse different than a female mouse when it comes to exposure to EDCs? “Those targets may be particularly sensitive to endocrine disruption since there’s so much fluctuation going on, and the modulation of these different hormonal and metabolic pathways are so critical to a healthy pregnancy,” Sobolewski says.

“There’s a lot to discuss: When do we worry about concentrations? What kind of research do we need to expand beyond four compounds? How do we make sure we’re building the best models we can to appropriately translate the work that we’re doing to human populations?”

Marissa Sobolewski Terry, PhD, University of Rochester, Rochester, N.Y.

After studying dam pregnancies to confirm similarities in the hormonal and physiological shifts seen in human pregnancy, the team (led by graduate student Alyssa Merrill for this arm) compared a broad battery of phenotypes of pregnant and non-pregnant dams after exposure to the four-chemical cocktail. The results were both not all that surprising and surprising, and we won’t give away too much here. Suffice to say, the not-so-surprising outcome is that EDC exposure significantly impacted endocrine physiology across pregnancy. Also expected was that pregnant and non-pregnant dams reacted differently to exposures, highlighting the sensitivity of pregnancy. However, this is not to say that non-pregnant dams were spared all effects.

The more surprising findings include that not just the endocrine axis was disrupted, but multiple metabolic ramifications also occurred. Sobolewski’s presentation will deliver more than one revelation here. Another potential surprise are the behavioral changes the team noted. Unlike several of the irreversible effects already hinted at, these behavioral manifestations appeared temporary.

Sobolewski hopes to leave time for discussion about future research avenues. “There’s a lot to discuss: When do we worry about concentrations? What kind of research do we need to expand beyond four compounds? How do we make sure we’re building the best models we can to appropriately translate the work that we’re doing to human populations?” Another question implicit in all of this work is, for otherwise transient blips in the homeostasis of a particular system, does EDC exposure exacerbate, lengthen, or make those interruptions permanent?

Sobolewski says she is looking forward to how her presentation dovetails with the others and to a really exciting discussion.

Effects of Per- and Polyfluoroalkyl Substances on Lactation and Human Milk

The presentation by Megan E. Romano, PhD, MPH, of the Department of Epidemiology at the Dartmouth Geisel School of Medicine, in Lebanon, N.H., synergizes well with Sobolewski’s, answering the next logical questions. If human pregnancy is potentially negatively affected by EDCs, are endocrine-driven process like lactation likewise impacted?

Romano has been interested in the effects of PFAS on mammary health since her postdoc years. This presentation will focus on breastfeeding duration and human milk composition and is the culmination of three studies she has been involved in, including findings from the New Hampshire Birth Cohort Study (NHBCS). That study was originally undertaken by Margaret R. Karagas, PhD, also at the Dartmouth Geisel School of Medicine, who was investigating the effects of arsenic contamination in drinking water, as inhabitants of rural New Hampshire largely get their water supply from private, unregulated wells.

Tapping into this existing population and dataset to examine several PFAS commonly used commercially was important to Romano. “10 years ago, the idea that EDCs might influence lactation was a very controversial idea, but we’re increasingly realizing that lactation is a vulnerable function, especially because mammary glands don’t actually reach full development until lactation begins,” she says. “So, it makes sense that this extremely hormonally mediated process would be very sensitive to exogenous chemicals and EDCs.”

The issue now at hand, explains Romano, is not if EDCs are potentially harmful, but which EDCs influence lactation and how. “[Sobolewski’s] work in rodent models parallels the work that we do in human populations and helps us to really unpack the biological mechanisms,” she adds.

From their work with the NHBCS, Romano and team have identified some unfortunate trends. “We observed that participants with greater overall plasma PFAS concentrations had greater risk of stopping exclusive breastfeeding before six months, and associations were driven largely by PFOA,” she says. Importantly, these findings are not restricted to that cohort, but fall in line with other reports encompassing socioeconomically diverse and geographically distinct populations. Although PFOA is apparently somehow causing the shorter breastfeeding duration, questions remain, says Romano — is there something about PFAS that makes initiating and sustaining lactation more difficult for either the infant or the lactating parent? Is insufficient milk produced? Is the quality of the milk less nutritious or otherwise less satisfying and less desirable? For a bit of a teaser, Romano reports that the team saw “potentially important differences in the metabolomic profiles of the milk with PFAS exposure,” but more follow-up is needed before definitive conclusions can be drawn about milk composition and quality.

“10 years ago, the idea that EDCs might influence lactation was a very controversial idea, but we’re increasingly realizing that lactation is a vulnerable function, especially because mammary glands don’t actually reach full development until lactation begins. So, it makes sense that this extremely hormonally mediated process would be very sensitive to exogenous chemicals and EDCs.”

Megan E. Romano, PhD, MPH, Department of Epidemiology, Dartmouth Geisel School of Medicine, Lebanon, N.H.

Ultimately, however, shorter lactation has clear health implications. “Lactation was, in many ways, overlooked for many years as an important endocrine endpoint. We’re now learning more about the health protective effects of longer durations of breastfeeding for the lactating person, in terms of reduced risk for adverse cardiovascular outcomes; metabolic benefits; and, possibly, reduced risk of breast cancer. It’s part of the story that we haven’t really understood in the past that is a real linchpin for long-term health well after pregnancy,” Romano says.

Even so, she says, “I try hard not to give any prescriptive advice because breastfeeding is an incredibly personal decision. It’s a ‘team sport’ — everything has to fall into place. But the reason why I do this work is because I don’t think the things in our environment should get in the way of people’s decision making. That should not be a barrier.”

Integrating Communities and Environments to Address PFAS Toxicity

Speaking of the environment, in the second presentation of the day, Scott M. Belcher, PhD, of the Center for Environmental and Health Effects of PFAS at North Carolina State University in Raleigh takes a more population-health bent. Even though the problems EDCs present to human health have been accepted science for decades, Belcher says that EDCs do not currently have a specified niche in chemical regulatory policy. “That’s where there are still challenges in creating a framework that protects public health. Getting that balance between corporations’ abilities to maintain a robust economy versus public human and environmental health is truly where the challenge is.”

Belcher and team take this challenge head on with the “One Health” initiative, “a collaborative, multisectoral, and transdisciplinary approach” originally established in recognition that animals and humans share disease processes — the idea behind sending canaries into coal mines to ascertain the presence of toxic gases. The recent COVID-19 pandemic, Belcher explains, showed us another example of the way all elements in environments are linked; we more intimately understand the interaction between the animal world and human disease. “We’re trying to integrate human biology, plus the environment and even communities. Bringing more social science into the work is really the foundation of that societal balance between what we believe in for economies’ well-being, plus the impacts of chemicals on health,” he says. “That requires transdisciplinary science, where people doing environmental sciences are talking to biologists, and health scientists are talking to people in the geological and hydrological engineering world. It brings all of these things together.”

Belcher and his team look for biomarkers of disease by studying both household pets and livestock as well as wildlife in a community to home in on what the holistic impacts of chemical pollutants and environmental factors are in disease processes in the health and well-being of both the environment and the people living within them. This is where PFAS come in. “I’ll be talking about all the PFAS that are associated with both background contamination, which is global, as well as elevated from sources that are known within our study area. I’ll be linking studies that we’ve done over the last six years as a kind of holistic grouping and an example of how the One Health approach in working very closely with impacted communities can be very powerful,” Belcher says.

“We tend to bias the importance of human health effects, but we can also use the impacts on humans to make some predictions about what’s going on, for example, with certain endangered species.”

Scott M. Belcher, PhD, Center for Environmental and Health Effects of PFAS, North Carolina State University, Raleigh, N.C.

The “canaries” — the “sentinel species — for Belcher and team are the alligators native to North Carolina. Alligators and humans not only have similar immune and endocrine systems; thus alligators provide a reasonable basis for comparison, but also, explains Belcher, alligators do not move around much so additionally provide a clear snapshot over time of the health of a specific environment. In one study, they compared a population of alligators with known exposure to high PFAS levels to a reference population and found that the PFAS-exposed animals had disrupted immune activity, with clear implications for human health — the water these alligators inhabit is the water going into the community drinking water stores. In another, they looked at the bioaccumulation of PFAS in fish, which the alligators eat. Again, we can extrapolate the effects this has on humans, but, says Belcher, One Health is bidirectional. “We tend to bias the importance of human health effects, but we can also use the impacts on humans to make some predictions about what’s going on, for example, with certain endangered species.” Back to the alligators, in fact, this is the first known occurrence of autoimmune-like effects in reptiles.

As mentioned, Belcher and team also look at pets (dogs) and livestock (horses) to compare effects of what’s being consumed within and immediately outside households in known contaminated areas (due to local fluorochemical production). More on that to come in Belcher’s presentation. One essential takeaway, however, will be that One Health is not just about communicating effects (and potential dangers) to a community, it’s equally about listening. “For the last six or seven years, we’ve been working with community partners such as law enforcement to learn what’s most important to the communities they work in, so they’re developing the scientific question alongside us,” he says. “That naturally creates a dialogue that translates into information they can use to improve the health of the community.”

Horvath is a Baltimore, Md.-based freelance writer. In the March issue she wrote about the conundrum of pediatric dyslipidemia in childhood obesity.