Overpopulation Can Affect Fertility: A New Study Explains Why

For decades, scientists have observed that high population density can affect reproduction in numerous animal species. Chickens kept in cramped conditions lay fewer eggs, mice give birth to smaller litters, and several studies in humans also point to a link between high population density and declining fertility. While external factors such as resource scarcity, competition, or social stress undoubtedly play an important role, researchers have long suspected that biological mechanisms might also exist that evolved to limit population growth.

A new study from the University of Colorado Boulder (CU Boulder), published in the journal Nature Communications, now provides evidence of such a mechanism. According to the researchers, under conditions of severe overcrowding, animals release a specific signaling molecule that can damage egg cells, impair embryo development, and even induce genetic changes that are passed on to subsequent generations.

Birth Rates Are Falling Despite a Growing Global Population

“It is well documented that population density has a direct and negative impact on fertility in humans and animals, but the underlying mechanisms have remained unclear until now,” explains study lead author Professor Ding Xue of the Department of Molecular, Cellular, and Developmental Biology at CU Boulder. “Our study provides new insights into how overpopulation can cause various developmental disorders, including reduced fertility and increased mortality.”

The publication of the study comes at a time when the world’s population continues to grow. There are now approximately 8.3 billion people on Earth—about three times as many as in 1950. At the same time, birth rates are trending in the opposite direction. Globally, the average number of births per woman fell from about five children in 1950 to 2.3 children in 2021. In addition, infertility is an increasing health problem worldwide. According to the World Health Organization (WHO), about one in six people is affected by it at some point in their lives. Infertility is defined as the inability to achieve pregnancy within twelve months despite regular unprotected sexual intercourse.

“Overpopulation and the stress caused by cramped living conditions are now among the major challenges facing modern societies—especially in cities, where about two-thirds of the world’s population now lives,” says Xue. The findings presented here could therefore provide important molecular insights into how such environmental conditions affect health in the long term.

A Serendipitous Discovery During Research on Radiation Damage

The current findings arose rather by chance. Originally, Xue’s research group was working on a completely different area of research—the so-called radiation-induced bystander effect (RIBE).

This phenomenon is known from cancer medicine. Although radiation therapy specifically targets tumor cells, healthy cells outside the actual radiation field can also be damaged. These indirect effects are associated with side effects such as fatigue, hair loss, or reduced fertility, among others. For this reason, pregnant women are generally advised to avoid unnecessary radiation exposure.

As early as 2017, Xue’s research group was able to demonstrate in a study published in Nature what triggers this effect in the nematode Caenorhabditis elegans. According to the study, cells stressed by radiation release a protein called cysteine protease-related protein 4 (CPR-4). This protein migrates to other, originally healthy cells, where it can cause DNA damage. Similar molecular messengers also exist in other animal species, including mice and humans. In these species, a related enzyme, cathepsin B cysteine protease, performs comparable functions.

Overcrowding Triggers the Same Biological Mechanism

In a subsequent follow-up study, the scientists made an unexpected observation that steered their research in a new direction. The nematodes under study released the protein CPR-4 not only in response to radiation exposure. Even when the animals lived for extended periods under extremely cramped conditions and the population density rose sharply, the enzyme was released in significantly increased amounts. This discovery suggested that not only radiation but also environmental stress caused by overcrowding can trigger similar molecular reactions in the organism.

Upon closer analysis, the researchers found that the biological changes in the cells of the overcrowded worm colonies differed only slightly from those previously observed following radiation exposure. At the molecular level, both types of stress activated comparable signaling pathways, which ultimately led to DNA damage and impairment of germ cells. According to the scientists, the organism appears to respond to both ionizing radiation and extreme population stress with the same protective or stress response.

This finding surprised the research team, as it was previously unknown that overcrowding could have such a profound impact on cellular processes. It suggests that the protein CPR-4 does not respond exclusively to radiation damage but may be part of a general biological warning system. If population density rises beyond a certain level, the enzyme could be released as a chemical messenger and send signals to other cells, which in turn trigger changes in the genome and in reproduction.

The researchers suspect that an evolutionary adaptation may lie behind this mechanism. By reducing fertility under conditions of extreme overcrowding while simultaneously increasing genetic changes in germ cells, the growth of a population could be naturally curbed. However, further research is needed to determine whether this mechanism actually represents a biological strategy for regulating populations or serves other functions.

More Mutations and Fewer Offspring: Genetic Changes Can Be Inherited

For the current study, the scientists compared worms kept in colonies of varying sizes. They found that under normal conditions, the worms released hardly any CPR-4. However, once the colony exceeded a size of about 3,000 individuals, the release of the protein began to increase significantly. As overcrowding increased, so did the amount of the enzyme.

The consequences were clearly measurable. The protein caused DNA damage in the germ cells—that is, the cells from which egg and sperm cells later develop. At the same time, the number of offspring decreased significantly. In addition, many of the surviving young exhibited visible developmental abnormalities. The researchers also observed similar effects in experiments with mice. On average, animals living in cramped conditions had 87 percent more genetic mutations in their reproductive cells than animals with sufficient space.

The results of the subsequent genome sequencing were particularly noteworthy. It showed that some of the genetic changes triggered by overcrowding were not limited to the animals directly affected but were passed on to subsequent generations. According to the authors, this suggests that overcrowding not only affects fertility but could also potentially alter the genetic development of populations in the long term. The study thus provides evidence that, under certain conditions, environmental stress can even influence evolutionary processes.

Blocked Enzyme Prevents Negative Effects

To better understand the exact role of the protein CPR-4 in the observed changes, the researchers conducted further experiments in which they specifically inactivated the enzyme or inhibited its activity. In this way, they were able to investigate whether CPR-4 is indeed the decisive trigger for the damage caused by overcrowding or whether other factors play a greater role.

The results were clear: When the enzyme was blocked, the previously observed negative consequences of high population density largely failed to materialize. The animals exhibited less DNA damage in their reproductive cells, the number of genetic mutations decreased, and impairments in reproductive capacity were also significantly reduced. Thus, the experiments provided important evidence that CPR-4 is not only associated with the consequences of overcrowding but may also be actively involved in the development of these changes.

According to the scientists, this suggests that cysteine proteases such as CPR-4 or the related enzyme cathepsin B could represent a central interface between environmental stress and biological changes. When an organism is exposed to severe stress caused by high population density, these enzymes could trigger a cascade of processes that ultimately damage the DNA of germ cells and thereby impair fertility.

At the same time, the findings open up new avenues of research. Should this mechanism be confirmed in other animal species and possibly in humans, inhibitors targeting these enzymes could play a role in certain medical or agricultural applications in the future. Nevertheless, the authors emphasize that the findings to date are primarily based on animal models and that further studies are necessary before their applicability to humans can be assessed.

Potential Applications in Medicine and Agriculture

Professor Xue and his team have already developed and patented a compound capable of inhibiting the related enzyme cathepsin B in animals. According to the researchers, the compound has demonstrated a favorable safety profile so far.

Should the current results be confirmed in further studies, this could lead to a variety of potential applications. In agriculture, for example, it might be possible to improve egg production in poultry or reproduction in fish farming through targeted inhibition of the enzyme. At the same time, these findings could, in the long term, open up new therapeutic approaches for people suffering from fertility disorders who wish to start a family of their own.

Until then, however, it remains unclear to what extent the mechanisms observed in worms and mice are actually transferable to humans. Nevertheless, the study provides important evidence that overcrowding could be far more than just a social stressor—it could deeply interfere with fundamental biological processes, influence reproduction, and possibly even contribute to genetic changes across generations.