Young & Restless: BPA, Circadian Rhythms, and Hyperactivity

From obesity to autism, the effects of bisphenol A (BPA) during pregnancy and childhood are well known. However, new research shows that BPA exposure during pregnancy at levels once considered safe could disrupt circadian rhythms as well as lead to hyperactivity later in life.

Bisphenol A (BPA) is, unfortunately, everywhere – a seemingly indelible substance in the environment, leaching into food through plastic containers and cans or into homes through equipment designed to abate dangers and neutralize threats. BPA appears in the National Institute of Environmental Health Sciences’s list of environmental agents that may cause adverse effects alongside arsenic and lead and pesticides. California’s Proposition 65 includes BPA in its list of “chemicals known to cause cancer, birth defects, or other reproductive harm.”

BPA has been implicated in obesity, non-alcoholic fatty liver disease, and even autism. Infants and children appear to be the most vulnerable, and recent mouse studies have shown the profound impact BPA can have on fetuses, even at low “safe” levels. Last year, at ENDO 2018 in Chicago, Deborah Kurrasch, PhD, associate professor at the University of Calgary in Calgary, Canada, presented her team’s mouse study that showed BPA can alter brain development and behavior later in life. The researchers found that neurons were born too early in BPA-exposed brains, which meant these neurons could migrate to the wrong places and form incorrect connections.

“The public is becoming well educated on the debate surrounding BPA safety, as well as other chemicals,” Kurrasch said at the time. “Although there is still work to be done to translate these findings in rodents to human pregnancy, this research could provide expectant mothers with important information that they might consider when thinking about what to avoid during pregnancy.”

Kurrasch and her team’s work indeed continued, and they returned for ENDO 2019 in New Orleans to present a new mouse study showing BPA also disrupts circadian rhythms, which can lead to hyperactivity. Kurrasch says that as they’ve studied BPA’s affects on the developing hypothalamus – in zebrafish, mice, and now even human cohorts – and tried to understand how maternal exposure to BPA can alter connectivity in the fetal brain, they have found that hyperactivity later in life is often a result of exposure to BPA.

“We have also found that the hypothalamus appears to be specifically susceptible to developmental disruption even with extremely low doses of BPA,” Kurrasch says. “Given that the hypothalamus contains the suprachiasmatic nucleus, the brain region important for controlling circadian signalling, investigating whether BPA can alter circadian rhythms was a clear next step in our research.”

Mouse Trap

Kurrasch and her team a few years ago established an experimental paradigm for these studies, tailoring a diet for mice that results in measurable elevation in BPA that’s in range of what’s been measured in humans, and they feed this diet to pregnant dams during gestation only. “We do this to control the amount and duration of BPA exposure to ascertain the specific effects of maternal transfer to the developing fetus,” Kurrasch says.

“The field is rapidly transitioning to using lower doses and conducting more precise measurements to elucidate exactly what organs and systems are most susceptible to BPA disruption. This understanding is critical to properly evaluating the BPA risk profile and ensuring that the regulations we have in place are appropriate for the potential effects.” — Deborah Kurrasch, PhD, associate professor, University of Calgary, Canada

For this study, the researchers placed three- to four-month-old mice pups in special cages fitted with an exercise wheel to gauge activity, and the team modified the mice’s sleep/wake cycles, starting the pups out on a normal 12 hours of light and 12 hours of dark for four weeks and then transitioning the mice to 24 hours of dark for four weeks. During the 24-hour dark cycle, the pups were subjected to light pulses to examine their ability to adjust their rhythms in response to unexpected stimuli. “We found a number of changes as a result of BPA exposure,” says Dinu Nesan, a postdoctoral researcher in the Kurrasch Lab.

The researchers observed almost twice as much daily activity in BPA-exposed mice during the normal light cycle, especially in the last third of the dark period. Mice are nocturnal creatures, so they of course were active just after darkness fell, and Kurrasch and her team found that BPA-exposed pups were more active during the dark period than the control mice. Disruptions of circadian rhythms were exaggerated during the all-dark conditions, with BPA-exposed mice remaining far more active for far longer than controls and acting as if their intrinsic “day” was shorter.

“Finally we found that BPA-exposed mice entrain more quickly to altered light conditions, both in the change from light/dark to dark/dark and when we exposed them to transient light pulses after acclimation to total darkness, suggesting that their suprachiasmatic nucleus is more responsive and/or sensitive to light exposure,” Nesan says.

“Overall,” the authors write in their ENDO abstract, “we conclude that low-dose gestational BPA exposure alters circadian rhythms under various conditions, the first such finding in a mammalian model in vivo, and that this may be a contributing factor to the observed hyperactivity in BPA-exposed mice.”

Unpredictable Doses

And yet, the effects of low-dose BPA remain underappreciated. North American and European governments continue to view low doses of the endocrine-disrupting chemical as “safe” and “acceptable,” while the body of evidence suggesting otherwise continues to grow. “The field is rapidly transitioning to using lower doses and conducting more precise measurements to elucidate exactly what organs and systems are most susceptible to BPA disruption,” Kurrasch says. “This understanding is critical to properly evaluating the BPA risk profile and ensuring that the regulations we have in place are appropriate for the potential effects.”

But here’s where things get complicated. BPA doesn’t follow the normal dose response observed for other chemicals. For most toxicants, the dose and the subsequent harmful effects share a linear relationship – the higher the dose ingested, the more harmful the effects. Kurrasch says that this leads to experiments where a minimal threshold is identified and then government agencies can proclaim a dose lower than that threshold safe.

But BPA and some other endocrine-disrupting chemicals aren’t as predictable. “Instead BPA and other EDCs exhibit non-monotonic dose curves, which can be unpredictably shaped with multiple peaks or with a u-shape where extremely low doses may have more pronounced effects than higher doses,” Kurrasch says. “Studies like ours will help to better understand these dose curves and allow for more nuanced regulations to better protect the public.”

Regulatory Upgrades 

Kurrasch and her team will next study the specific changes to the suprachiasmatic nucleus that can cause these effects, looking especially at the alterations in hypothalamic structure and/or expression of neuropeptides and other factors that are changed by gestational BPA exposure. “Our plan is to gain as complete of an understanding as possible of the mechanistic effects of BPA on the developing hypothalamus,” she says.

For now, Kurrasch says that this current study is further evidence that BPA might be harmful on developing as well as mature brains. This study is an indictment of even very low doses of BPA, since the researchers here administered doses far below what North American and European government agencies consider safe. “Although we recognize that regulatory policy is complex and has to take in a variety of factors,” Kurrasch says, “we believe that the current regulations are not taking into account the large and growing body of research evidence that low-dose BPA exposure has harmful effects and that safety guidelines should be re-examined.”

Bagley is the senior editor of Endocrine News. He wrote about the link between unhealthy snacking and screen time to obesity in the July issue. 

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