How extreme exposure to a common plasticizer might be affecting male fertility

by | Aug 25, 2023

Using mouse embryos, scientists explore the impact of high exposure to a common plasticizer on male fertility, but caution: the dose makes the poison.
Purple disposable coffee cups

DEHP or di(2-ethylhexyl)phthalate is a member of the phthalate family and is one of the most widely used plasticizers, helping to make plastics more flexible and durable. Although highly effective in plastic manufacturing processes, DEHP leaches easily from the materials it is incorporated into, leading to its widespread presence in a number of domains, including hospital equipment, food packaging, airborne dust, and the broader environment.

This has prompted scientists to evaluate its health effects, namely in populations most vulnerable to it, such as fetuses and developing children. Some studies have begun to show that exposure to high levels of DEHP might lead to negative effects, such as preterm birth, altered timing of puberty in boys and girls, delayed mental development, and testicles that do not descend properly.

A recent study carried out by researchers from the Sun Yat-Sen University found that exposure to DEHP during pregnancy caused genital defects, poor semen quality, and reduced testosterone in male mice. The results, published in Advanced Biology, showed that reproductive problems in male mice were linked to the premature aging of the testicles induced by high level exposure to DEHP.

“Our study revealed the significance of prenatal exposure to [high levels of] DEHP in the development of testicular aging,” said Xie Qigen, pediatric surgeon at the First Affiliated Hospital of the Sun Yat-Sen University and first author of the paper. According to Qigen, preventing testicular damage during pregnancy is very important to maintain reproductive health.

”Fetuses and children are certainly more vulnerable to phthalates and other endocrine-disrupting chemicals,” explained Anderson J. Martino Andrade, associate professor of the Federal University of Paraná in Brazil, who is an expert in reproductive toxicology and pharmacology and was not involved in the study. “This publication shows that various adverse reproductive effects may persist and/or be manifested in later life.”

DEHP and testicular toxicity

As we grow older, we experience systemic aging, which represents a deterioration of tissues and organs with the passage of time. At the cellular scale, the “aging” of the cells is known as cellular senescence, a physiological process by which cells lose the capacity to divide.

However, while cellular senescence serves, among other functions, as a mechanism to prevent damaged cells from dividing in an uncontrolled way, essentially acting as an anti-cancer mechanism, when it becomes accelerated, it has been shown to lead to early organ failure and disease.

The researchers found that DEHP induced a degree of senescence in a type of cells called leydig cells in mice, the cells within the testis that oversee the production of testosterone, a primary male hormone. Aged leydig cells, as a consequence of the exposure to the chemical agent during pregnancy, produced less than half the testosterone than healthy leydig cells, causing poor development of the genital system in mouse pups, including reduced testes where sperm is formed.

Furthermore, pups showed reduced epididymis, where sperm is stored and matured, and reduced seminal vesicles, which secret the fluid that ultimately becomes semen. These developmental defects, together with the poor semen quality, and the lifelong testicular toxicity caused by the exposure of mice to high concentration of DEHP, would harm male fertility in the adulthood.

But it wasn’t just the male pups that were at risk. Qigen told Advanced Science News that they are finishing a parallel study that they say would soon provide evidence that the plasticizer affects also female gonad development and fertility.

The dose makes the poison

An important element of toxicology is dosage. A chemical can be considered harmful, but only at certain levels of exposure. An example of this is ethanol, an ingredient in alcoholic beverages, which can have both short-term and long-term effects on the body.

At low to moderate levels of consumption, such as having a glass of wine with dinner, the body can metabolize the alcohol effectively, and the effects might be minimal. However, excessive and chronic alcohol consumption can lead to serious health issues like liver damage, addiction, and an increased risk of various diseases.

The same applies to DEHP exposure.

The most common exposure to DEHP comes through food. Two recent studies published in 2021 and 2022 detected low amounts of several chemicals of concern, including DEHP in food samples. In one of the studies, DEHP was present in the 80% of the 60 different food and drinks containers analyzed. Fast food — heavily processed, packaged and handled — is specially exposed to plasticizer and, indeed, 70% of the items analyzed (19 samples from hamburgers, fries, chicken nuggets, chicken burritos and cheese pizza) contained DEHP at a concentration above the limit of detection.

“DEHP is known to induce antiandrogenic effects [block androgen hormones] and reproductive toxicity [in rodents],” said Martino Andrade. “However, it is important to bear in mind that the results in animal models are not readily translated to humans.”

According to the toxicologist, the main limitation of the study published by Qigen and collaborators is the use of a high DEHP dose, which is less relevant for the levels of exposure people would get on a daily basis. The results represent the adverse effects of an amount of DEHP that was about 100,000 times higher than the estimated average consumption per day per person, which is only about 0.25 milligrams.

We should therefore not expect that the toxic effects of DEHP observed in the study would be the same when exposed to low concentrations.

“[However], certain epidemiological data — which are non-experimental observations in the population — indicate [that there are] associations between maternal phthalate exposure, including DEHP, and disrupted androgen-dependent development in boys,” added Martino Andrade.

The question remains then, what is a an acceptable level of exposure to DEHP? “Although human exposure to DEHP and other phthalates is usually lower than the doses inducing reproductive adverse effects in animal models,” said Martino Andrade, “many studies have provided evidence that these chemicals can have cumulative effects when combined — the so-called cocktail effect.”

The European Union and the United States have restricted the use of several phthalates, including DEHP, in commercial products precisely because of the potential risk of their toxic effects during childhood development and reproduction.

However, there is a parallel rise in exposure to phthalate substitutes. “Although these substitutes are generally considered to be less toxic than phthalates, there is a need for continuing toxicological research to assure their safety,” added Martino Andrade.

In addition, there are geographic differences in phthalate exposure in developing countries, where the pace of phthalate restrictions and replacement with safer alternatives seems to be slower.

What action should be taken?

When asked about what kind regulations we should put in place, Qigen is blunt. “We must restrict the use of this plasticizer […] to protect the environment and human health.” At the individual level, “we should avoid plasticizer exposure as much as possible […] and we should preserve food and water using products that have no DEHP,” he said.

Martino Andrade, on the other hand, thinks that “there should be both individual and collective measures to minimize exposures in vulnerable populations — fetuses and children.”

These measures include the adoption of lifestyle habits to reduce the use of plastics, cosmetics, and processed food by pregnant women and children, as well as governmental actions to restrict or ban the use of certain chemicals in food and consumer products.

This would be in the benefit of the population as a whole since, as Martino Andrade pinpointed, “although fetuses and children are more susceptible to these chemicals, exposure throughout life can further increase the risks of infertility and other health problems in the population.”

Reference: Xie Qigen et al., Prenatal DEHP Exposure Induces Premature Testicular Aging by Promoting Leydig Cell Senescence through the MAPK Signaling Pathways, Advanced Biology (2023). DOI: 10.1002/adbi.202300130

Feature image credit: Layne Harris on Unsplash

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