Hormone Disruptors
Hidden foes
On a biting cold January day, the water lapping the high-tide mark on the James River is crusting into ice. A piping call makes me look up just as a pair of Bald Eagles fly overhead. They ride the breeze on broad wings, spiraling in courtship toward the nest they are repairing on Jamestown Island. Soon there will be two warm eggs nestled in their twiggy cradle.
Fifty years ago—indeed, not all that long ago—you could spend a whole season on the James between here and Richmond without seeing a single eagle. America’s national bird was sliding toward extinction.
The chief villain was DDT. Its wanton dispersal in the post-war decades to control insect pests hit raptors especially hard. The breakdown product, DDE, inhibits prostaglandin synthesis required for calcium uptake in the shell gland. The result was fragile, thin-shelled eggs that broke under the weight of their parents. Organochlorine pesticides are concentrated at higher levels of the food chain—from freshwater plants to invertebrates to fish to eagles (and ospreys). Rachel Carson’s warning still rings:
“Over increasingly large areas of the United States, spring now comes unheralded by the return of the birds… early mornings are strangely silent where once they were filled with the beauty of bird song.”
The James endured a second catastrophe when an industrial plant upstream at Hopewell discharged another pesticide, Kepone, as casually as emptying a lavatory bowl. Out of sight is out of mind! The plant was finally shuttered in 1975 after lawsuits for violating environmental law and chronic exposure left workers with tremors and sterile.
In time, the poison sank under layers of sediment, and eagle numbers rebounded. Advisories against eating sport fish were lifted. Today, the eagle population is nearing its regional carrying capacity, a density thought to be close to when English colonists built their first fort at Jamestown. The mighty river, two miles wide at this point, once supported an astonishing wealth of wildlife. That pristine state won’t return in our time, even if industry stopped producing pesticides and herbicides because they persist in the environment for decades—sometimes centuries.
A biological reckoning
We now live in what might rightly be called “the chemical century.” Chemists have generated an astonishing array of synthetic compounds—more than 100,000 listed across national and international databases, and far more if one includes mixtures, derivatives, and intermediates. Only a fraction has been rigorously evaluated. No agency, even with statutory authority, can keep pace with the number of compounds added each year. Too often, as with the eagles, a crisis must unfold before action follows.
Wildlife continues to provide early warnings of threats to human health that start even in the womb. Pollutants in some Virginia rivers and the Chesapeake Bay have produced high rates of intersex bass. The herbicide atrazine is implicated in demasculinizing frogs and toads in American and German ponds—likely elsewhere, too, if we looked. An accidental DDT spill in 1980 caused a distorted sex ratio, abnormalities, and high juvenile mortality in alligators in Florida’s Lake Apopka.
Reproduction and endocrinology
Growth, development, and hormonal regulation make the reproductive system of both sexes, and especially pregnant women, vulnerable to pollution from endocrine-disrupting chemicals (EDCs), although many other hormone-regulated systems are also affected —notably the thyroid gland. Molecular impostors of hormones are ubiquitous, coming in many guises.
Public awareness of endocrine disruption arguably began with diethylstilbestrol (DES), a synthetic estrogen widely prescribed to pregnant women in the mid-20th century. It caused rare gynecological cancers and reproductive abnormalities in their daughters (and, later recognized, in sons) exposed in utero. It is now clear that fetuses and infants are more vulnerable to EDCs than adults.
My own awareness, first sparked by the plight of eagles, deepened when I followed the research of Patricia Hunt’s team at Washington State University. By coincidence, a DES daughter herself, Hunt stumbled upon a discovery that helped shift the paradigm of EDCs in human health. Her laboratory mice developed an excess of chromosomally abnormal eggs. The culprit was traced to bisphenol-A (BPA) leaching from worn polycarbonate cages. BPA is weakly estrogenic and widely used in plastics—including baby bottles at the time. Manufacturers rushed to replace it, but many substitutes have a similar molecular architecture and so prove to be just as biologically active.
Research broadened to scrutinize phthalates. This is a large group of plasticizers found in personal care products, medical tubing, vinyl flooring, food packaging, etc. Some are estrogenic, some anti-estrogenic, or mimic other hormones. Plastics have become so central to modern life that looking back to when paper, glass, and stainless steel were forerunners seems almost quaint.
Many of these compounds are environmentally persistent, with biological effects extending across generations. The old assumption that epigenetic marks are fully erased between generations is no longer tenable; deep epigenetic reprogramming occurs during gametogenesis, but exceptions abound. General evidence comes not only from animal studies but from human society and medicine, such as the 1944–45 Dutch famine and from DES-exposed families whose grandchildren and even their children still bear measurable effects. Safety tests are complicated if EDCs have non-monotonic dose-response curves (i.e., not linear or exponential), meaning that extremely low doses that might go untested still have effects.
EDCs affect every level of gonadal physiology—ovarian follicles and corpora lutea, Leydig cells and seminiferous tubules, and the hypothalamic–pituitary axis in both sexes. Comparable vulnerabilities apply to the thyroid, where disruption of the sodium-iodide symporter, thyroid peroxidase, and thyroglobulin can impair the fetal and postnatal brain. EDCs may be contributing factors to the prevalence of autoimmune thyroid disorders, especially in women.
Ways and means
Many endocrine disruptors act via the estrogen signaling pathway. This is partly because the estrogen receptor is structurally “promiscuous,” accommodating other molecules with structurally modified benzene rings. Although many EDCs bind weakly, their environmental abundance compensates for low affinity.
Other mechanisms are equally important:
• interference with aromatase, altering androgen–estrogen balance
• disruption of hypothalamic nerve signaling
• immune modulation, including B- and T-cell activation
• inflammatory signaling that indirectly affects endocrine tissues
EDCs that mimic androgens are also multifactorial, targeting Sertoli cells or directly impairing spermatogenesis. Environmental exposures are frequently implicated in the global decline in human sperm counts. Men with low counts often have higher urinary phthalates and lower testosterone (though still in the normal range). Correlated data are not proof, yet the clinical findings align with animal and cell-based evidence. DES showed unequivocally that endocrine disruptors can cause reproductive cancers.
The ring structures of BPA and many phthalates explain their estrogenicity. A similar logic applies to some organochlorine pesticides, but other disruptors have unrelated structures. The chemistry–biology relationship is not always obvious.
Per- and polyfluoroalkyl substances (PFAS) command intense attention today. These “forever chemicals” comprise thousands of variants and are found everywhere—in homes, workplaces, groundwater, and elsewhere in the environment. Their carbon–fluorine bonds are exceptionally stable, making them remarkably persistent.
And we are nowhere near the end of the list. Smoke from wildfire, phytoestrogens in food, perchlorate in groundwater, dioxins from pulp mills, oral contraceptive residues in drinking water, lead and mercury used in artisanal gold mining—they all contribute to a complex, cumulative, and hidden burden.
How to stay safe?
The reflex response is to call for regulation and hope the same scientific ingenuity that created the problem will solve it. And indeed, there is progress. High-throughput multiplex assays, coupled with AI-assisted modeling, promise to accelerate testing. Enzyme engineering has shown that PFAS can be degraded, and a Rice University team recently developed a method to remove them faster from water. Still, scaling these innovations to the real world will be difficult. The genie is out of the bottle, and we will continue to live with the legacy of the chemical century.
Consumers take action through product choices. Hospitals and laboratories increasingly seek safer materials. Yet, the most insidious source of pollution in our neighborhood might be public water supplies from reservoirs and fossil water near one of the world’s largest concentrations of military bases, a major source of PFAS (not only flame-retardant foams). The county water utility is required to test about ninety contaminants, just a drop in the bucket. I installed a filtration system reputed to reduce PFAS and other pollutants, but I have no idea what or by how much, although it tastes better.
Calls for stronger regulation and investment in reproductive toxicology are well-placed. Regulatory action and oversight by the Environmental Protection Agency (EPA) helped to restore the Bald Eagle. The EPA’s first administrator, William Ruckelshaus, famously defined its mission in 1970 as having “no obligation to promote agriculture or commerce; only the critical obligation to protect and enhance the environment”. The agency has changed—now less a guardian of public interest in the environment and health, more in line with corporate interest in profit.
I will confess my personal interest. Isocycloseram is a new insecticide/acaricide approved last month by the EPA. The European Union banned it from farms and imported crops based on animal studies and its PFAS structure (which the EPA fudged). What caught my attention as a backyard beekeeper was its extreme toxicity to honeybees—similar to neonicotinoids widely used here and many of them banned in the E.U. Spraying flowering vegetables and turf in daytime puts all pollinating insects at risk at a time when Virginia farmers lament crop losses, and we lose 40 percent of hives annually from colony collapse disorder. When my bees come home with a full stomach, I wonder if the goodness in their honey is spiked with a menace.
Image credits: Dall-E (heading), Bald Eagles (the late Inge Curtis), beehive (the author)