Summary: New rat research shows that opioid use before pregnancy can increase the risk that male offspring will develop type 2 diabetes and metabolic syndrome.
Source: Tufts University
Researchers at the Cummings School of Veterinary Medicine at Tufts University report that exposure to opioids prior to conception—even when discontinued weeks before pregnancy—may raise the likelihood that male offspring develop metabolic disorders such as type 2 diabetes and metabolic syndrome. These conditions increase long-term risks for heart disease and stroke.
The findings come from controlled studies in rats and have not yet been confirmed in humans. Still, the results raise concern that opioid exposure before pregnancy could have lasting effects on future generations, even when use stops before conception.
Opioid prescriptions remain common: in 2020, more than 142 million opioid prescriptions were dispensed in the United States. Estimates suggest one in three Americans uses prescription opioids and millions misuse them. The Centers for Disease Control and Prevention reported that, in some counties, enough prescriptions were written in 2020 for every resident to receive one.
Prescription opioids—such as oxycodone, hydrocodone, and morphine—are important tools for managing pain when used appropriately. However, widespread misuse and addiction have created a public health crisis, affecting people across income levels, races, ages, and genders.
“The percentage of the population exposed to prescription opioids has exploded in recent years,” says Elizabeth Byrnes, neuroscientist and professor at Cummings School. “Public health efforts have rightly focused on addiction and overdose, but opioids also influence immune and neuroendocrine systems and can alter metabolism.”
Byrnes adds that their research suggests such metabolic effects may be transmitted to the next generation even if mothers stop using opioids before becoming pregnant. “We may not yet appreciate all the long-term consequences of widespread prescription opioid use and misuse,” she says.
The studies were published in the journal Scientific Reports and build on earlier work published in Addiction Biology. Co-principal investigators include Byrnes and Donna Slonim from Tufts’ Department of Computer Science. Anika Toorie, the lead author on both papers, conducted the work as a postdoctoral researcher and is now an assistant professor at Rhode Island College.
Why rats are used to study human biology
Rats are commonly used to model human biological responses, including how the brain and metabolic systems respond to drugs. Under controlled laboratory conditions, researchers can measure changes in brain function, metabolism, and organ systems after opioid exposure. These findings can then guide further research in humans where appropriate.
In these experiments, female rats were given morphine for a 10-day period during adolescence and then allowed to remain drug-free for at least three weeks before mating, ensuring offspring were not exposed in utero. Control females received a saline injection. Researchers then monitored the male offspring into adulthood to evaluate metabolic outcomes.
In the Addiction Biology study, male offspring born to morphine-exposed mothers consumed more food, gained more weight, and developed fasting hyperglycemia (elevated fasting blood sugar) and hyperinsulinemia (high circulating insulin) after six weeks on a high fat-sucrose diet. These changes indicate impaired glucose regulation, a precursor to obesity and type 2 diabetes.
“What we essentially saw is that limited morphine exposure in female rats prior to conception increased the risk of metabolic disorders, including type 2 diabetes, in male offspring,” Byrnes explained.
The Scientific Reports study extended these observations. Male offspring were maintained on either a high fat-sucrose diet or a control diet for eight and twelve weeks. Males born to morphine-exposed mothers and given the high fat-sugar diet showed greater weight gain, higher fasting blood glucose, and increased circulating insulin compared with offspring of saline-exposed mothers on the same diet.
When researchers prolonged the feeding period, they found that male offspring of morphine-exposed mothers developed impaired glucose tolerance—even when maintained on the control diet—an early indicator of type 2 diabetes. They also observed liver and other tissue abnormalities in these males.
“Even if offspring are not fed an obesogenic diet, they still face higher risks of developing diabetes and related health problems, although those risks may take longer to appear,” Byrnes said.
The research team plans to investigate whether female offspring show similar or different metabolic effects from maternal preconception opioid exposure.
Obesity, metabolic syndrome, and type 2 diabetes increase the risk of cardiovascular disease, stroke, kidney disease, and other serious conditions. Given the prevalence of opioid use, researchers emphasize the need to consider not only immediate harms such as addiction and overdose, but also potential long-term and intergenerational metabolic consequences.
About this neurodevelopment research news
Author: Patrick Collins
Source: Tufts University
Contact: Patrick Collins – Tufts University
Image: The image is in the public domain
Original Research: Open access.
“Intergenerational effects of preconception opioids on glucose homeostasis and hepatic transcription in adult male rats” by Anika M. Toorie, Fair M. Vassoler, Fangfang Qu, Donna Slonim, Christopher M. Schonhoff & Elizabeth M. Byrnes. Scientific Reports
Abstract
Intergenerational effects of preconception opioids on glucose homeostasis and hepatic transcription in adult male rats
Adolescence is a critical period of neurodevelopment during which adverse experiences can increase vulnerability to disease later in life and may also affect future offspring. Adolescence is a common time for the initiation of drug use, including opioids. Beyond their effects on central reward pathways, opioids impact glucose metabolism and may raise diabetes risk. Recent animal models suggest adolescent opioid exposure can alter glucose regulation in subsequent generations.
Previous work showed that adult male offspring of females exposed to morphine for 10 days during adolescence (referred to as MORF1 males) are more sensitive to the negative metabolic effects of an obesogenic diet. In that study, MORF1 males fed a high fat-moderate sucrose diet for six weeks had higher fasting glucose and insulin compared to offspring of saline-exposed females (SALF1 males). These clinical features are associated with hepatic insulin resistance and increased risk of non-alcoholic fatty liver disease.
In the current study, the researchers used RNA sequencing to assess whether MORF1 males display lasting changes in liver gene expression related to metabolism. MORF1 and SALF1 males were fed either a high fat-sucrose diet or a control diet for eight weeks. Consistent with earlier findings, MORF1 males on the high fat-sucrose diet gained more weight and showed fasting hyperglycemia and hyperinsulinemia compared to SALF1 males on the same diet, with no significant changes in glucagon.
Surprisingly, transcriptional analysis revealed substantial differences in the hepatic transcriptome of MORF1 versus SALF1 males maintained on the control diet (1,686 differentially expressed genes), while differences were not seen between the groups on the high fat-sucrose diet at eight weeks. Extending the feeding period and performing glucose tolerance tests showed impaired glucose tolerance in MORF1 males on both diets, and to a lesser extent in SALF1 males on the high fat-sucrose diet.
These results indicate that adolescent morphine exposure in mothers can have intergenerational effects that increase the risk of insulin resistance and related metabolic disorders in offspring, even in the absence of an obesogenic diet.