High levels of prenatal exposure to bisphenol A, a plastic commonly found in water bottles and containers and known to leach into our food and beverages, is linked to autism spectrum disorder in boys, according to a new study. The biological mechanism underlying this link has also been identified.
The risks of exposure to bisphenol A (BPA), an industrial chemical used in plastic manufacturing and found in a wide variety of plastic products, are well documented. Known to leach from plastics and find its way into the foods and beverages we consume, BPA has been linked to health problems, primarily because it mimics the structure and function of the hormone estrogen, disrupting body processes such as growth, cell repair, fetal development, energy levels and reproduction.
It has also been linked to neurodevelopmental disorders such as ADHD and autism, also called autism spectrum disorder (ASD). In a new study, researchers from the Florey Institute of Neuroscience and Mental Health (The Florey) in Melbourne, Australia, found a possible link between autism and exposure to BPA in the womb.
“Exposure to plastic chemicals during pregnancy has been shown in some studies to be associated with later autism in the offspring,” says Professor Anne-Louise Ponsonby, who led the study with Dr Wah Chin Boon, head of Florey’s neuroepidemiology research group and a research associate. “Our study is important because it shows one of the biological mechanisms potentially involved.”
ASD is a clinically diagnosed neurodevelopmental condition that affects the way people interact with others, communicate, learn and behave. According to the World Health Organisation (WHO), ASD affects around one in 100 children worldwide. Figures released this year by the US Centres for Disease Control and Prevention (CDC) found that around one in 36 American children have the condition, and it is around four times more common in boys than girls. The prevalence had increased from one in 54 recorded in 2016. In 2018, Autism Spectrum Australia (Aspect) revised autism prevalence rates from one in 100 to an estimated one in 70 Australians on the autism spectrum, an increase of around 40%.
Although increased awareness and more advanced diagnostic methods have a major share in the spread of autism spectrum disorder, possible causal factors such as genetic and environmental factors in early life and the interaction of these two factors also remain important.
In the current study, the researchers focused on the aromatase enzyme, which converts neuroandrogens, a class of male sex hormones found in the brain, into neuroestrogens, or female sex hormones. During fetal development, males have high levels of aromatase expression in the brain. Studies have shown that exposure to bisphenols, including BPA, can disrupt brain aromatase function.
“BPA may disrupt hormone-controlled male fetal brain development in a number of ways, including silencing a key enzyme called aromatase, which controls neurohormones and is particularly important in fetal male brain development,” Ponsonby said. “This appears to be a piece of the autism puzzle.”
To examine the interaction of prenatal BPA, aromatase function and gender with ASD symptoms and diagnosis, researchers collected data from two large cohorts: the Barwon Infant Study (BIS) in Australia and the Columbia Children's Center for Environmental Health – Mothers and Newborns Study (CCCEH-MN) in the USA.
They found that the link between BPA and ASD was particularly pronounced in the top fifth of boys who were sensitive to the chemical’s endocrine-disrupting properties — in other words, those with low aromatase levels. In this group, boys born to mothers with higher levels of BPA in their urine in late pregnancy were 3.5 times more likely to show symptoms of ASD by age two and six times more likely to have a confirmed diagnosis of ASD by age 11 than those born to mothers with lower levels of BPA in their urine during pregnancy.
In both the BIS and CCCEH-MN cohorts, evidence has shown that higher BPA levels overall are associated with epigenetic suppression of the aromatase enzyme. Epigenetic changes are DNA modifications that regulate whether genes are turned on or off. In this case, the CYP19A1 gene, which provides instructions for producing aromatase.
The researchers then went on to examine the effects of prenatal BPA on mice.
“We found that BPA suppresses the aromatase enzyme and is associated with anatomical, neurological and behavioral changes in male mice that may be consistent with autism spectrum disorder,” Boon said. “This is the first time a biological pathway has been identified that may help explain the link between autism and BPA.”
The researchers’ findings understandably drew comments from others in the scientific community, some of whom were impressed by the researchers’ identification of the biological pathway thought to influence ASD.
“What's really new about their results is that they were able to link the effect to a biological pathway that's important in brain development,” said Professor Ian Rae, an expert in environmental chemicals at the University of Melbourne's School of Chemistry. “In other words, BPA is acting as a 'rogue' hormone to compete with the natural hormone that's usually involved in this pathway.”
Others approached the results with varying degrees of skepticism.
“In mouse studies where mothers were given 50 µg/kg BPA daily for about four days in mid-pregnancy, there were changes in the number and structure of brain cells in male offspring,” said Dr Ian Musgrave, senior lecturer in the School of Medical Sciences at the University of Adelaide in Australia. “However, there was a large overlap between treated and untreated in many of the changes, and while statistically significant, it is not clear whether this is biologically significant. Furthermore, the doses were the maximum allowable doses and most people would not be exposed to this.
“Furthermore, the doses were administered subcutaneously, which bypasses the metabolic systems that BPA encounters when ingested orally,” Musgrave continued. “Since most human exposure is oral, and humans efficiently metabolize and excrete ingested BPA, mice would have higher BPA exposure than humans.”
Professor Elisa Hill-Yardin, Head of the Gut-Brain Axis Laboratory at RMIT University, said: “Future studies should carefully measure bisphenol A levels over time during pregnancy to clarify these findings… The effects of diet may also be important in these findings.”
“This is an interesting study that deserves further investigation, but it is important to understand that there are many other genetic variations with similar amounts of evidence that may contribute to autism,” Hill-Yardin explained. “Ultimately, we still do not know for sure what causes autism in most people, and normal healthy diet and lifestyle advice should be followed during pregnancy.”
The study was published in the journal Nature Communications.
Source: The Florey, Scimex