Summary: Opioid use prior to pregnancy raises the risk that male offspring will develop type 2 diabetes and metabolic syndrome, a new rat study finds.
Source: Tufts University
New research from scientists at Cummings School of Veterinary Medicine at Tufts University suggests opioid use before pregnancy—even if not used during pregnancy itself—could result in a higher likelihood that a mother’s male offspring will develop type 2 diabetes and metabolic syndrome, conditions that increase the risk of heart disease and stroke.
The current studies are in rats exposed to opioids over a 10-day period several weeks before mating, and have yet to be studied in humans. The results suggest, however, that even if moms stop opioid use before becoming pregnant, the effects on future generations could lead to significant health problems.
More than 142 million opioid prescriptions were dispensed in the U.S. in 2020, with an estimated 1 in 3 Americans using prescription opioids and 11.5 million misusing them. In 3.6 percent of U.S. counties, enough opioid prescriptions were dispensed in 2020 for every person to have one, according to the Centers for Disease Control and Prevention.
In many circumstances prescription opioids such as oxycodone, hydrocodone, and morphine can be an important component of overall pain management. But the current epidemic misuse of opioids leading to addiction has resulted in a crisis in the U.S., destroying lives and families regardless of income level, race, age, or gender.
“The percentage of the population exposed to prescription opioids has exploded in recent years,” says Cummings School professor and neuroscientist Elizabeth Byrnes.
“Addiction and overdose deaths have been the biggest and most important focus of our public health efforts to combat the misuse of opioids thus far. Yet perhaps what hasn’t been as widely appreciated is that opioids may also have significant effects on the immune and neuroendocrine systems and can also affect metabolism in those who take these drugs.”
“What our research suggests is that these effects may also be passed down to future generations, even if the mother stops taking the drugs before pregnancy,” Byrnes says. “We as a society may not fully understand all the potential consequences of widespread prescription opioid use and misuse,” she says.
This recent research from Byrnes and colleagues at Cummings School and the Department of Computer Science at Tufts University was published in the journal Scientific Reports. Byrnes and computer science professor Donna Slonim were co-principal investigators, and it builds on an earlier study published in Addiction Biology in 2019. The lead author on both studies is Anika Toorie, who was a postdoctoral researcher under Byrnes and is now an assistant professor at Rhode Island College.
What Rats Tell Us About Human Biology
Researchers examine the effects of opioid use on addiction and other health consequences in rats as a gateway to better understanding the drugs’ effect in humans. They do so because rats have similar biological and reward systems as humans, and because they can look in the laboratory, under tightly controlled conditions, to discover changes in the rat brain, in metabolism, and in organ systems in response to opioid use, misuse, addiction, and withdrawal. Findings deemed worthy of further exploration can then be studied in humans.
In the studies published in Addiction Biology and Scientific Reports, the researchers looked at male rats born to mothers who were exposed to morphine (opioids) for 10 days as adolescents but who were drug free for at least three weeks prior to mating, so their male offspring were not exposed in utero. The control group of offspring were born to mothers who received a saline solution, rather than morphine.
For the Addiction Biology paper, male offspring rats from both groups of mothers were fed a high fat-sugar diet for six weeks. The males born to mothers who had been exposed to morphine consumed more food, gained more weight, and developed fasting-induced hyperglycemia (high blood sugars) and hyperinsulinemia (high circulating levels of insulin). This indicates the rats were becoming less able to regulate how their body converts food into energy, which can lead to obesity, type 2 diabetes, and a variety of other health problems that type 2 diabetes causes.
“What we essentially saw is that the limited morphine exposure in female rats prior to conception increased the risk of metabolic disorders, including type 2 diabetes in the males in the next generation,” said Byrnes.
For the paper in Scientific Reports, researchers compared both an eight and twelve-week administration of high fat-sugar diet or a controlled diet in both the males whose mothers had been exposed to morphine and those who had received only saline. The results for males whose mothers had been exposed to morphine and were given the high fat-sugar diet supported previous findings—they gained more weight and displayed higher levels of fasting blood sugars and higher levels of circulating insulin when compared to males whose mothers had received saline and were fed the high fat-sugar diet.
By extending the feeding regiment even longer, the researchers found that the male rats in both the controlled and high-fat diet group whose mothers had been exposed to morphine pre-conception also developed impaired glucose tolerance, which is an early sign of type 2 diabetes. They also had liver and other abnormalities.
“Even if the offspring are not exposed to a high fat-sugar diet, the risks for developing diabetes and other health problems are there, though they may take longer to emerge,” Byrnes said.
The researchers plan to next examine what the effects of morphine were on the female offspring, to see if the effects are similar or different than those on the male offspring.
Obesity, metabolic syndrome, and type 2 diabetes are linked to increased risks of heart disease, stroke, kidney disease, and other ailments. “With such widespread use of opioids, we need think about all the ways that these drugs are affecting not only the current generation, but how they will impact future generations,” says Byrnes.
Intergenerational effects of preconception opioids on glucose homeostasis and hepatic transcription in adult male rats
Adolescence represents a period of significant neurodevelopment during which adverse experiences can lead to prolonged effects on disease vulnerability, including effects that can impact future offspring.
Adolescence is a common period for the initiation of drug use, including the use of opioids. Beyond effects on central reward, opioids also impact glucose metabolism, which can impact the risk of diabetes. Moreover, recent animal models suggest that the effects of adolescent opioids can effect glucose metabolism in future offspring. Indeed, we demonstrated that the adult male offspring of females exposed to morphine for 10 days during adolescence (referred to as MORF1 males) are predisposed to the adverse effects of an obesogenic diet.
As adults, MORF1 males fed a high fat moderate sucrose diet (FSD) for just 6 weeks had increased fasting glucose and insulin levels when compared to age-matched offspring of females exposed to saline during adolescence (SALF1 males). Clinically, a similar profile of impaired fasting glucose has been associated with hepatic insulin resistance and an increased risk of non-alcoholic fatty liver disease.
Thus, in the current study, we used RNA sequencing to determine whether adult MORF1 males demonstrate significant alterations in the hepatic transcriptome suggestive of alterations in metabolism. Age-matched SALF1 and MORF1 males were fed either FSD or control diet (CD) for 8 weeks. Similar to our previous observations, FSD-maintained MORF1 males gained more weight and displayed both fasting hyperglycemia and hyperinsulinemia when compared to FSD-maintained SALF1 males, with no significant effect on glucagon.
No differences in bodyweight or fasting-induce glucose were observed in control diet (CD)-maintained F1 males, although there was a trend for CD MORF1 males to display elevated levels of fasting insulin. Unexpectedly, transcriptional analyses revealed profound differences in the hepatic transcriptome of CD-maintained MORF1 and SALF1 (1686 differentially expressed genes) with no significant differences between FSD-maintained MORF1 and SALF1 males.
As changes in the hepatic transcriptome were not revealed under 8 weeks FSD conditions, we extended the feeding paradigm and conducted a glucose tolerance test to determine whether impaired fasting glucose observed in FSD MORF1 males was due to peripheral insulin resistance. Impaired glucose tolerance was observed in both CD and FSD MORF1 males, and to a more limited extent in FSD SALF1 males.
These findings implicate intergenerational effects of adolescent morphine exposure on the risk of developing insulin resistance and associated comorbidities, even in the absence of an obesogenic diet.