Prenatal Mercury at Real-World Levels Rewires Development Differently in Male and Female Rats

A single pollutant, swallowed by a pregnant mother in doses that would not raise eyebrows at a seafood counter, may be enough to bend the arc of her children’s development in profoundly different directions depending on their sex. That is the central message of a new rat study published in the journal Biology of Sex Differences, in which researchers at the University of North Texas Health Science Center and the University of North Texas tracked offspring from before birth all the way into puberty after exposing pregnant dams to methylmercury, the most toxic form of mercury and one that accumulates readily in the fish that humans eat. The findings, reported by Jessica L. Bradshaw, Rebecca L. Cunningham and colleagues, add to a growing body of evidence that environmentally relevant exposures during pregnancy can leave fingerprints that persist for months, and that those fingerprints look strikingly different in males and females.

Methylmercury is not an exotic industrial chemical but a routine contaminant of the aquatic food chain. Bacteria in sediments convert inorganic mercury, released by coal combustion and other human activities, into methylmercury, which then climbs the food web and concentrates in large predatory fish such as tuna, swordfish and shark. Because the compound crosses the placenta and the blood-brain barrier efficiently, a developing fetus can be exposed at levels higher than those measured in the mother’s blood. Regulatory agencies have long issued consumption advisories for pregnant people, but the doses used in laboratory toxicology have often been far higher than anything a person would encounter, making it difficult to translate animal findings into public health guidance. The new study was designed specifically to close that gap.

The researchers fed timed-pregnant Sprague-Dawley rats diets containing either a low dose of 400 parts per billion methylmercury or a high dose of 800 parts per billion, beginning on gestational day 8 and continuing through late gestation or parturition. These concentrations were chosen deliberately to mirror federal and state fish consumption advisory guidelines, meaning the animals were not receiving a toxicological hammer blow but something closer to what a person eating contaminated fish might experience. A control group received vehicle-treated diet. The team then measured mercury accumulation in maternal, placental, fetal and eventually pubertal tissues using direct thermal decomposition, gold amalgamation and atomic absorption spectrometry, a gold-standard analytical approach for total mercury quantification.

The first striking result concerns persistence. Mercury accumulated in a dose-dependent manner not only in the mothers and their placentas and fetuses, but also in the tissues of offspring examined at puberty, long after the exposure window had closed. This long-term retention demonstrates that even brief, environmentally realistic prenatal exposure leaves a measurable body burden that lingers through a substantial fraction of the animal’s life. Equally notable was the biodistribution: pubertal females carried more mercury in their brain, muscle and blood, whereas males accumulated more in the liver. Such sex-specific toxicokinetics had been underrecognized, and they suggest that the same exposure can seed different tissues with the toxicant depending on the sex of the offspring, potentially setting the stage for divergent downstream effects.

Developmental timing itself proved vulnerable. In the high-dose group, offspring showed delayed eye opening, a classic milestone of postnatal neurological maturation. More dramatically, pubertal onset was delayed in males but not in females, pointing to a sex-specific disruption of the neuroendocrine machinery that initiates reproductive maturation. Puberty is orchestrated by a finely tuned hypothalamic-pituitary-gonadal axis, and its timing is increasingly recognized as a sensitive indicator of developmental perturbation. A delay confined to one sex implies that the biological variables governing that axis, including hormonal milieu and possibly the differential tissue burdens of mercury, interact to shape vulnerability in ways that a single-sex study would entirely miss.

Growth trajectories also diverged by sex in ways that hint at lasting metabolic programming. Males exposed prenatally to the high dose of methylmercury weighed less during late adolescence, while their female counterparts weighed more. The placenta offered an early clue to these divergent paths: high-dose exposure reduced placental weight but increased placental efficiency, a measure of how effectively the organ supports fetal growth per unit of tissue. The concept of developmental programming holds that stressors during critical windows can permanently recalibrate metabolic setpoints, and the opposing adolescent weight patterns observed here are consistent with sex-specific recalibration of energy balance, body composition or endocrine regulation that only becomes visible long after the exposure itself.

Blood-based biomarkers measured at puberty deepened the picture of persistent internal disruption. The researchers used MILLIPLEX magnetic bead assays to profile plasma liver injury markers and a panel of cytokines and chemokines, and an advanced oxidation protein products assay to quantify circulating oxidized proteins. Markers of hepatic function, including arginase 1, sorbitol dehydrogenase, aspartate aminotransferase and 5-prime nucleotidase, were altered in patterns that depended on both sex and dose. Given that males preferentially sequestered mercury in the liver, the hepatic signal in that sex is particularly coherent with the toxicokinetic data, suggesting the organ bearing the greatest mercury burden also shows the clearest functional disturbance.

The inflammatory profile told a parallel story. Cytokines including tumor necrosis factor alpha, interleukin-2, interleukin-1 alpha, interleukin-17A and interleukin-6 were differentially altered by sex and methylmercury dose, indicating that prenatal exposure had imprinted a durable dysregulation on immune signaling that persisted into puberty. Chronic low-grade inflammation is a known contributor to a wide range of adult diseases, from cardiovascular disease to metabolic syndrome, and developmental immunology has increasingly emphasized that early-life exposures can set immune trajectories for life. The finding that a brief gestational exposure to a dietary contaminant can shift circulating inflammatory chemistry months later, and differently in each sex, underscores how far the consequences of prenatal toxicology can reach.

For public health, the implications are twofold. First, the doses used here were calibrated to real-world advisory levels rather than extreme laboratory exposures, which strengthens the argument that current guidance deserves continued scrutiny, particularly for populations that rely heavily on fish as a dietary staple. Fish remains an excellent source of protein and omega-3 fatty acids, and the study does not suggest that fish should be avoided altogether; rather, it reinforces the rationale behind advisories steering pregnant individuals toward low-mercury species. Second, and perhaps more broadly, the work is a forceful demonstration of why sex must be treated as a critical biological variable in developmental toxicology. Every endpoint the team examined, from mercury biodistribution to pubertal timing, growth and immune signaling, showed sex-dependent effects that a male-only or female-only design would have obscured or misrepresented.

The study, which was approved by the University of North Texas Health Science Center’s Institutional Animal Care and Use Committee and funded in part by the National Institutes of Health, arrives at a moment when regulatory science is actively wrestling with how to incorporate sex as a biological variable into risk assessment. As the authors conclude, environmentally relevant prenatal methylmercury exposure disrupts developmental trajectories and induces long-lasting, sex-specific alterations in growth, hepatic function and inflammatory signaling. Translating that conclusion from rats to humans will require further work, but the core lesson travels well: the developing fetus is exquisitely sensitive to its chemical environment, the effects of that environment may not declare themselves until adolescence, and assuming that males and females respond identically is no longer a defensible default in environmental health research.

Subject of Research: Sex-specific developmental toxicity of prenatal methylmercury exposure in rats

Article Title: Prenatal methylmercury exposure disrupts developmental trajectories and induces sex-specific toxicity in pubertal rats

Article References: Bradshaw, J. L., Wilson, E. N., Mabry, S., Gardner, J. J., Grief, A., Soulen, B. K., Ortega-Rodriguez, C. L., Armstrong, T. D., Lund, A. K., Roberts, A. P., & Cunningham, R. L. (2026). Prenatal methylmercury exposure disrupts developmental trajectories and induces sex-specific toxicity in pubertal rats. Biology of Sex Differences. https://doi.org/10.1186/s13293-026-00987-6

Image Credits: AI Generated

DOI: 10.1186/s13293-026-00987-6

Keywords: methylmercury, prenatal exposure, developmental toxicology, sex differences, puberty, placental efficiency, hepatic biomarkers, inflammation, toxicokinetics, developmental programming, public health, rats