Slithery Sentinels

From shampoos to food storage containers to pesticides, we touch, ingest and breathe chemicals every day. Despite their ubiquity, the effects of these substances on human reproductive health are largely unknown.

With thousands of chemicals to test, how can researchers quickly zero in on the ones most likely to cause harm?

Help has arrived in an unlikely form: tiny worms known as Caenorhabditis elegans.

In 2013, the lab of Monica Colaiácovo, professor of genetics in the Blavatnik Institute at Harvard Medical School, developed a screening method that flags when a worm’s exposure to a chemical leads to abnormal numbers of chromosomes in its eggs.

In people, such chromosomal abnormalities cause more than 35 percent of miscarriages and 4 percent of stillbirths as well as infertility and conditions such as Down syndrome.

C. elegans share more than 60 percent of their genes with humans, and many discoveries in the worms have been replicated in mice and yielded new insights into cellular processes in humans, making them a standard model organism for investigating biology.

In a new study published in PLoS Genetics, senior author Colaiácovo and team used their worm screen to test 46 common pesticides, phthalates (substances used in many plastics, cosmetics and household products) and byproducts of crude oil processing and hydraulic fracturing, commonly known as fracking.

The screen delivered sobering results: 41 percent of the tested chemicals caused genetic disruptions in egg cells to an equal or greater extent than those caused by bisphenol A (BPA), a plasticizer under investigation for potential harm to fetuses and young children.

The effects included an uptick in DNA damage in cells destined to become eggs, a rise in egg death and a drop in the number of eggs laid.

Among the flagged chemicals was DEET, the most common active ingredient in insect repellents.

Testing each chemical three times in 5,000 worms took just three weeks, providing a swift first pass that should help scientists prioritize which chemicals to study further as possible causes of reproductive health problems in people.

“We can’t avoid all the chemicals in our lives,” said Nara Shin, a postdoctoral fellow in the Colaiácovo lab and first author of the paper. “It’s really important to understand the impact they have on human health and the environment.”

If the worm findings hold true for humans, the repercussions could apply to not only pregnant women, whose female fetuses are forming egg cells while in the womb, said Colaiácovo, but also men, who typically produce sperm for decades. Her team is gearing up to study worm sperm chromosomes next.

The findings likely also extend beyond reproductive health, Colaiácovo said, because the DNA damage her team observed can happen in other cells in the body, not only eggs and sperm.

Chromosome disruption in egg cells “is the canary in the coal mine,” she said. “This may not be all these chemicals are doing.”

The team took a closer look at three of the most damaging chemicals their screen identified:

• Dibutyl phthalate, or DBP, a suspected endocrine disruptor found in products such as nail polish.
• Permethrin, a pesticide used in head lice and scabies treatments, bug sprays and clothes intended to repel insects.
• 2-(thiocyanomethylthio) benzothiazole, or TCMTB, an agricultural pesticide often used on rice, barley, wheat and oat crops.

All three caused problems in meiosis, the type of cell division that produces eggs and sperm, during which chromosomes from the mother and father are recombined.

Shin and colleagues found that some of the chemicals caused excess DNA breaks during meiosis. Compounding the problem, some chemicals hampered the cells’ ability to repair DNA damage.

The team further found that DBP disrupted several genes shared by worms and humans, including an uptick in a gene related to DNA breaks (SPO11) and suppression of a gene involved in DNA repair (MRE11).

In the end, between 22 and 41 percent of eggs had chromosomal abnormalities, leading to the worm equivalents of higher than normal stillbirths and miscarriage rates and lower than normal fertility.

The researchers made sure they weren’t exposing the worms to quantities of each chemical that would be absurd in people. In fact, traces of the chemicals inside the worms’ bodies were, proportionally, “incredibly low—sometimes lower than what you find in human blood and urine,” said Colaiácovo.

The team is now partnering with others to follow up on the most concerning chemicals in mouse models and to study what happens to organisms’ reproductive health when they are exposed to combinations of chemicals.

Despite the physiological gap between worms and humans, the current study findings worry the researchers enough that they hope their insights will enter the public conversation, empowering people to make more informed choices about the products they use and prompting manufacturers and policy makers to consider changes in production and regulation.

“At least some of these changes have to come from the top down,” said Colaiácovo. “Not everyone has access to information about the effects of this or that chemical or can afford to choose which products they buy.”

Source: HMS