Exploring the mixture effects of PFAS exposure and medicines used to treat pregnant HIV patients is at the heart of research led by Janine Santos, Ph.D., of the NIEHS Division of Translational Toxicology (DTT). Santos, and collaborators at Duke University, will be the first to conduct studies examining how real-life exposure to antiretroviral therapy (ART) and a group of chemicals known as PFAS, often described as forever chemicals, influence the cardiovascular system.

Thanks to a recent one-year $750,000 Innovation Award from the Office of AIDS Research at the National Institutes of Health, Santos’ team will model exposures to ART and PFAS, which stands for per- and polyfluoroalkyl substances, in pregnant rats. They will assess risk of cardiovascular disease, a leading cause of maternal morbidity and mortality in pregnant women and the HIV population.

“The Innovation Award will allow Dr. Santos to conduct groundbreaking research and develop knowledge aligned with real-world public health needs of women with HIV,” said DTT Scientific Director Heather Patisaul, Ph.D.

Preliminary data from Santos’ team suggest some of the health effects observed in the hearts of pregnant animals being studied are akin to changes in electrocardiogram parameters in patients exposed to ART. In addition, the researchers found PFAS exposure led to high blood pressure during pregnancy in an animal model.

“Our ultimate goal is to start looking at the health of a patient more holistically, so that if we do find that the combination of exposures might be a problem, we can identify easy fixes,” Santos explained. “For example, maybe filtering water to decrease PFAS contamination, or a different therapy combination, will reduce side effects in a pregnant woman.”

New focus on maternal health

Although the number of pregnant women taking ART is increasing, most research studies have focused on how the therapy affects the developing fetus in terms of size and neurodevelopmental effects.

“If you review the literature, it's all about the fetus, and the mom is a vehicle just carrying it without concern for the pregnant woman’s health before or after birth,” Santos explained.

In contrast, this study will be the first to explore how ART plus an environmental exposure affects maternal health in an animal model.

“The cardiovascular system of a woman goes through tremendous remodeling during pregnancy — the amount of blood and the volume of the pregnant body is a huge stress on the heart,” Santos said. “We’re trying to understand what happens when you combine that stress with HIV drugs and PFAS, and whether we see unintended effects in the pregnant heart.”

Mixture effects

Given most people in the U.S. have measurable levels of PFAS in their blood, Santos seeks to learn whether people should worry about the combined effects of PFAS and HIV drugs, and whether pregnancy is a time of particular concern in the context of co-exposures.

“People are exposed to PFAS and ART, and we really don't understand whether they work together or how they interfere with each other to determine whether they might together worsen health outcomes,” Santos said.

She added that unintended side effects in mitochondria, which have broad effects at the cellular level from energy production in the heart to immunity, may play a role. One class of ART drugs called nucleotide reverse transcriptase inhibitors has been found to induce some mitochondrial toxicity.

“Nowadays, people live with HIV as a chronic condition, so they’re exposed to these drugs for 20, 30, 40 years,” Santos explained. “We need to study whether chronic mitochondrial toxicity, even in small amounts, may eventually lead to an adverse health effect.”