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Scientists have reported it for decades: Overpopulation can impair reproduction.

Crowded chickens lay fewer eggs. Crowded mice have smaller broods. In humans, several studies have associated increased population density with reduced fertility.��

External factors, such as resource scarcity and social influences, undoubtedly play a role. But researchers have long suspected that intrinsic, biological mechanisms may also be at play as an evolutionary tool to keep populations in check.��

New �鶹��Ѱ�����Boulder research, published this month in the journal , identifies one key mechanism.��

It found that overcrowded animals secrete a chemical messenger that can damage eggs, impair embryos and cause genetic mutations in offspring for generations to come.

“It has been well documented that population density has a direct and negative impact on human and animal fertility, but the underlying mechanisms have been elusive,” said senior author Ding Xue, professor of molecular, cellular and developmental biology at �鶹��Ѱ�����Boulder. “Our study provides novel insights into how��overpopulation can cause various developmental defects, including��reduced fertility and increased��mortality.”��

The study comes as the world population nears 8.3 billion—three times what it was in 1950. Meanwhile, the authors note, birth rates are on the decline. Worldwide, the fertility rate has gone from five births per woman in 1950 to 2.3 births in 2021. According to the World Health Organization,�� experience infertility (defined as the inability to achieve a pregnancy after 12 months of trying).

“Overpopulation and crowding stress have emerged as major challenges in contemporary societies, especially in urban cities, where two-thirds of the world population live,” said Xue. “Our study may provide important molecular insights into the underlying health problems that can come with it.”

What radiation and overcrowding have in common��

Xue’s team stumbled upon the findings serendipitously while studying a phenomenon known as radiation induced bystander effect (RIBE).

RIBE occurs in cancer patients receiving radiation therapy, when untreated, healthy cells outside a radiated site are also affected and damaged, leading to side effects like hair loss, fatigue and reproductive issues. Due in part to concerns about RIBE, pregnant women are advised to avoid radiation exposure.

In a 2017 study, , Xue discovered what drives this bystander effect in the C. elegans��worm: Cells stressed by radiation release a protein called cysteine protease related 4 (CPR-4), which travels to other healthy cells around the body and damages their DNA.

Other species across the animal kingdom, including humans and mice, have a similar chemical messenger called Cathepsin B cysteine protease.

Years later, in a follow-up study, Xue’s team noticed that, even in the absence of radiation, if worms lived in extremely crowded conditions, they emitted the protein.

At the molecular level, Xue said, the crowded animals looked a lot like they had been exposed to radiation.��

Mutations passed through generations

For the new study, the team compared worms living in various-sized colonies. They found the worms typically didn’t secrete CPR-4, but once their colony exceeded 3,000 individuals, they did. The more overcrowded they were, the more of the enzyme they secreted, and the enzyme damaged their DNA. Experiments in mice showed similar results.

On average, those living in crowded conditions had 87% more genetic mutations in germ cells (reproductive cells). The animals had significantly fewer offspring. Also, the surviving offspring often had visible defects.��

Genome sequencing showed some of those genetic mutations were passed on through generations, suggesting that overcrowding may drive genome evolution.��

When the researchers silenced the protein in animals, it prevented the adverse effects of crowding. This suggests the enzyme plays a critical role in reproductive problems.

More research is necessary to determine whether the findings have implications for humans and other animals.

Xue has already developed and patented a compound that can inhibit the Cathepsin B cysteine protease enzyme in animals and has a good safety profile.

He believes such inhibitors could someday be used in agriculture, for example, to increase egg or fish production. The findings could also inform new approaches to helping humans struggling to have a family.