When we think about infertility and environmental exposures, we often imagine large epidemiologic studies or animal models linking chemicals like phthalates and BPA to reduced reproductive outcomes. While those remain vitally important, a groundbreaking new tool is stepping onto the stage — and it has the potential to reshape how we study chemical impacts on human fertility.
Traditional toxicology and reproductive biology have relied on either relatively simple cell cultures or whole-animal models to assess how chemicals might interfere with reproductive function. These systems have value, but they fail to fully mimic the complex hormonal crosstalk and tissue-to-tissue communication that characterizes the human female reproductive system. A new generation of microengineered three-dimensional (3D) “organs-on-a-chip” systems promises to change that.¹
A 3D reproductive tract model — sometimes called an organ-on-a-chip — is a microfluidic device that contains tiny cultures of multiple organoid tissues interconnected in a way that simulates the physiologic interactions among reproductive organs over a menstrual cycle. Developed with funding from the National Institute of Environmental Health Sciences (NIEHS), researchers have succeeded in designing a chip that incorporates cells from four critical reproductive organs (the ovaries, fallopian tubes, uterus, and cervix) in a series of connected chambers. Fluids and signals that mimic hormonal fluctuations travel through micro-channels, creating a dynamic environment remarkably similar to the human reproductive tract during a natural cycle.¹
At its core, the system replicates hormonal rhythms and tissue responses over a 28-day period, enabling researchers to observe how tissues interact with one another — and how they respond to chemicals — in a way that conventional static cultures simply cannot. By linking a mini-liver module to the device, scientists can even model how chemicals are metabolized in the liver before they reach the reproductive organs, a key step that traditional in vitro systems often miss.¹
Endocrine-disrupting chemicals (EDCs) are substances that interfere with hormone signaling — sometimes at very low doses — and reproductive tissues are particularly vulnerable to these disruptions.² Until now, researchers studying the reproductive effects of EDCs have been constrained by models that either lack hormonal feedback or oversimplify the organism’s internal environment.
Here’s how the 3D reproductive tract model advances the field:
- Hormonal complexity: By replicating real-world hormone cycles, the system allows scientists to see how EDCs interfere with physiological signaling over time, not just in isolated cells.¹
- Inter-organ communication: Endocrine disruption is not just about one tissue; it involves the interplay between the ovary, uterus, and other organs. The chip enables that real-time interaction.¹
- Metabolism inclusion: With the addition of a liver organoid, researchers can mimic chemical breakdown — crucial because many EDCs are activated or inactivated by liver enzymes before reaching target tissues.¹
- Reduced reliance on animal models: While animal studies will remain important, the chip offers a high-throughput, ethically favorable platform for initial screening of chemical toxicity with human cells.¹
In reproductive toxicology, we care deeply about how exposures affect processes like folliculogenesis, ovulation, embryo transport, and implantation. This model provides an experimental system where:
- Follicular hormone production and ovulatory events can be observed under chemical exposure.¹
- Embryo-maternal interactions and implantation signaling can be perturbed experimentally.¹
- Longer-term exposures, dose responses, and combined chemical mixtures can be investigated.¹
Because of these capabilities, this platform could accelerate toxicity testing for chemicals in commerce, help identify previously unrecognized reproductive hazards, and provide mechanistic insight into how everyday substances may contribute to infertility. For clinicians and researchers alike, it offers a bridge between epidemiologic associations and biological causation.
While traditional models remain indispensable, the advent of 3D reproductive tract systems represents a leap forward in reproductive toxicology. By capturing the dynamic interplay of hormones and tissues that defines human reproduction, these tools allow us to confront one of the central challenges in environmental reproductive health: understanding not just whether chemicals affect fertility, but how and why they do so.
As this technology matures and becomes more widely adopted, it may help refine regulatory testing, focus public health interventions, and inform clinical recommendations tailored to patients seeking to protect their fertility in a world filled with chemical exposures.
- Shuo Xiao, Ph.D., et al., “3D model reveals how exposures affect infertility, reproductive health,” Environmental Factor, National Institute of Environmental Health Sciences, April 2025, https://www.niehs.nih.gov/news/factor/2025/4/science-highlights/exposures-model-infertility.
- National Institute of Environmental Health Sciences, Endocrine Disruptors, NIEHS overview page, accessed 2025.
Dr Marina OBGYN