The effects of antidepressant exposure during early development can pass down through three generations of offspring—at least in zebrafish. A new study, published today (December 10) in PNAS, reveals that fluoxetine, a commonly used antidepressant that goes by the brand name Prozac, can alter hormone levels and blunt stress responses in an exposed embryo and its descendants.

“The paper is very intriguing,” says Tim Oberlander, a developmental pediatrician at the British Columbia Children’s Hospital who was not involved in this work. The question of whether these medications have a transgenerational effect is “a really important one that requires further study in other animal models, and ultimately, when we have the data, we need to figure out whether it’s also true in humans.”

Fluoxetine is a selective serotonin reuptake inhibitor (SSRI), a class of drugs widely used to treat depression as well as other conditions...

What we think is happening is that by generation three, the fish are already adapting to new low cortisol levels.

—Marilyn Vera-Chang, University of Ottawa

SSRIs are often prescribed as the first-line treatment for pregnant women with depression, and prior studies in humans suggest infants exposed to SSRIs while in the womb may experience developmental disturbances such as delayed motor development and increased levels of anxiety later in childhood. Oberlander, whose research is focused on the influence of prenatal exposure to these medications, notes that it has been unclear whether those correlations represent a direct result of the drugs or if other factors, such as a genetic propensity for those outcomes or growing up with a parent with a mood disorder, may also play a part.

The hints that SSRIs taken by pregnant mothers may affect their children, as well as evidence from animal studies that chemicals such as certain fungicides could cause behavioral disruptions in subsequent generations of offspring, spurred Vance Trudeau, a neuroendocrinologist at the University of Ottawa, and his colleagues to address the question of whether an antidepressant may affect an animal’s descendants. Trudeau’s team had been investigating the effects of fluoxetine on adult fish for years—and wondered whether offspring might be affected as well. 

See “Pregnancy Stress Spans Generations

The researchers exposed embryos of zebrafish (Danio rerio) to fluoxetine for six days, then investigated the physiology and behavior of those fish and three subsequent generations of their offspring. In zebrafish, levels of the hormone cortisol normally increase in response to a stressful event, such as when they’re handled in a net. But the researchers observed that fish exposed to fluoxetine—at concentrations within the range found in umbilical cord blood—as embryos had blunted levels of cortisol, both during rest and in the presence of a stressor. The animals also didn’t explore their environments as much their unexposed peers. These kinds of “exploratory behaviors,” Trudeau says, are important for survival strategies such as escaping from predators and finding food. 

They then injected the drug-treated fish with cortisol, and found that the fish behaved normally after the injection. This confirmed that the behavioral alterations were caused by the changes in cortisol production. 

A zebrafish treated with the antidepressant fluoxetine doesn’t explore its tank as much as control fish.
Movie courtesy of the University of Ottawa
A zebrafish treated with fluoxetine and cortisol will explore its tank like untreated fish.

Examining several generations of the fish, the scientists revealed that the cortisol effects persisted through the exposed animals’ offspring, grand-offspring, and great-grand-offspring—but the behavioral disruptions only continued across two. “What we think is happening is that by generation three, the fish are already adapting to new low cortisol levels,” says coauthor Marilyn Vera-Chang, a biologist who completed her doctoral studies under the co-supervision of Trudeau and Thomas Moon, a retired professor of comparative physiology at the University of Ottawa. “Cortisol is really important in the body—that’s why they’re trying to adapt and survive.” 

The team also found that the effects were more pronounced and consistent in male offspring than in female ones. Trudeau says that it is still unclear why sex differences occur, although it is possible it may simply be due to inherent differences in male and female physiology.

Trudeau notes that there are good reasons to believe that the effects they observed in this study could also occur in humans. After all, he says, humans and zebrafish share similarities in stress-response machinery—for example, cortisol levels will rise in both fish and humans in stressful situations—and researchers have found changes in cortisol levels in infants born to mothers treated with SSRIs during pregnancy. However, it is important to be cautious about the interpretation of these findings, he adds. “A pregnant mother taking antidepressants should not stop taking her therapy. She should talk to her physician and bring this new finding to their attention.” 

While this study raises concerns about the possible generation-spanning effects of antidepressant use, it also revealed a piece of potential good news, Trudeau says. To examine whether the fluoxetine in the environment—as a result of drugs discarded into sewage—could affect aquatic wildlife, the team also subjected the fish to the antidepressant at a lower dose to reflect environmental exposure. This revealed disruptions similar to those observed at higher concentrations, but those changes were less pronounced and shorter-lived. According to Trudeau, “if you could clean up some of the sewage, in a generation or so animals could escape the potential negative effects of the drug in the [environment].”

Trudeau’s team is now conducting additional experiments to examine whether these transgenerational effects are caused by epigenetic changes, such as DNA methylation of key genes in the stress pathway or changes in the levels of microRNAs, small RNA molecules that can modify gene expression.

“We don’t know how these transgenerational effects pass from one generation to the next,” says Neel Aluru, a biologist at the Woods Hole Oceanographic Institution who was not involved in the work but has collaborated with some of the study’s authors in the past. “That’s the million-dollar question that we’re all trying to figure out.”

M.N. Vera-Chang et al, “Transgenerational hypocortisolism and behavioral disruption are induced by the antidepressant fluoxetine in male zebrafish Danio rerio,PNAS, doi:10.1073/pnas.1811695115, 2018.

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