Alert! How Bisphenol A exposure during pregnancy might result in autism in boys

A recent study found that boys born to mothers who were exposed to higher levels of Bisphenol A (BPA), a chemical commonly used in the production of many plastics and resins, during pregnancy had autism. According to this study published in Nature Communications, exposure to plastic chemicals that cause autism spectrum disorder (ASD) affects a key enzyme vital for brain development in the male foetus, highlighting the need to reassess policies regarding the use of BPA in the production of food-grade plastics, in particular for young children and expectant mothers.

The possible association of BPA with autism disorder was known earlier, “Our work is important because it demonstrates one of the biological mechanisms potentially involved. BPA can disrupt hormone controlled male foetal brain development in several ways, including silencing a key enzyme, aromatase, which controls neurohormones and is especially important in foetal male brain development,” says a key author of the paper, Anne-Louise Ponsonby, professor at The Florey Institute of Neuroscience and Mental Health, Australia, in a press release.

Studying the effect of BPA on mice foetuses, researchers found that a key enzyme, aromatase, is suppressed by the BPA. This resulted in "anatomical, neurological and behavioural changes in the male mice that may be consistent with autism spectrum disorder", said Wah Chin Boon, School of BioSciences, The University of Melbourne, Australia and a co-author in a statement to the press. "This is the first time a biological pathway has been identified that might help explain the connection between autism and BPA,” she added.

What is ASD

Autism Spectrum Disorder (ASD) refers to a broad range of clinically identified neurodevelopmental issues. Children with ASD have particular challenges with social interaction and communication. They struggle to understand non-verbal clues, including grins, frowns, and tone of voice. Other characteristics include unusual activity and behaviour patterns, such as difficulty transitioning from one activity to another, preoccupation with small details, and unexpected reactions to senses. Autism affects boys more than girls, with a male-female ratio of approximately 3:1. Which is one puzzle that has yet to be fully understood.

According to the World Health Organization (WHO), one out of every hundred persons globally suffers from autism. According to researchers, the prevalence of Autism Spectrum Disorder in India ranges between 0.1% and 1.4%.

Cohort studies

Initially, the researchers looked into the link between BPA and ASD in select epidemiological studies. Since 2010, the Barwon Infant Study (BIS) has collected biological samples from the prenatal stage to the maturation of the children from about 1074 children and mothers in south-east Australia. The researchers analysed the levels of BPA in the maternal urine collected at 36 weeks of pregnancy. The Columbia Center for Children's Environmental Health Study – Mothers and Newborns (CCCEH-MN) collected data from 727 women and their children in Northern Manhattan and the South Bronx, New York City, between 1998 and 2006. The researchers examined the data and discovered a clear relationship between elevated BPA levels in maternal urine samples and the development of ASD in children.

Boys born to women with higher BPA levels present in their urine are 3.5 times more likely to display autism symptoms by age 2 and six times more likely to have a confirmed autism diagnosis by age 11 than those born to mothers with lower BPA levels during pregnancy, says Professor Anne-Louise Ponsonby.

The genetic mechanism

The cytochrome P450 19A1 (CYP19A1) gene, located on human chromosome 15, instructs cells to generate aromatase, an enzyme that converts androgens to estrogen. Researchers discovered elevated quantities of the aromatase enzyme in the male amygdala during fetal development. Studies have shown that ASD is associated with decreased aromatase activity in male fetuses.

The researchers analysed the human cord blood of children diagnosed with ASD from the BIS and CCCEH-MN surveys. They discovered that greater BPA levels in maternal urine correlated with CYP19A1 methylation in male children. Methylation can either activate or deactivate a gene. This showed that higher BPA inhibited the typical function of CYP19A1, resulting in decreased aromatase activity in the pregnancy and the onset of ASD as the child matured.

Laboratory studies

Like laboratory mice, scientists employ clones of nerve cells produced from a bone marrow biopsy in 1970, known as SH-SY5Y human neuroblastoma cell lines, to research neurodegenerative illnesses such as ASD. The researchers artificially cultured these cells in a test tube, dosed them with BPA, and watched the results. Cells exposed to BPA produced half as much aromatase protein as normal cells.

Next, the researchers also exposed the pregnant mice to BPA during the mid-gestation phase. The baby male mice displayed social behaviour deficiencies, including timidity when engaging with a stranger mouse. When they investigated the brain's anatomy, they discovered structural and functional changes.

Subsequently, they also knocked off the CYP19A1 gene, which produces aromatase and investigated the outcomes. Only male mice, not female mice, demonstrated ASD-like symptoms as well as structural and functional brain alterations when the CYP19A1 gene was yanked. This demonstrated the necessity of aromatase for normal brain growth in the male fetus.

Biological mechanism

Together, these investigations identified a plausible biological pathway by which higher BPA exposure during pregnancy causes autism in male children. BPA mimics estrogen and binds to its receptors and alter the endocrine system, similar to how sugar and salt might be mistaken for each other during cooking. The study of the impact of BPA on nerve cells and pregnant mice has shown that bisphenols limit aromatase expression via methylating the aromatase gene. This reduces cellular expression and lowers estrogen levels in the male embryonic brain, which eventually leads to ASD.

Possible antidote

According to this study, bisphenols operate as a 'rogue' hormone, disrupting the development of the unborn male brain. The researchers also aimed to mitigate BPA's adverse effects on the aromatase system.

Previous research revealed that 10-hydroxy-2-decenoic acid (10HDA), a kind of fatty acid present in honeybee royal jelly, inhibits BPA's effects on estrogen signalling within cells.

Could 10-hydroxy-2-decenoic acid (10HDA) be the answer? To test its potential as a treatment, the researchers fed it to 3-week-old mouse pups exposed to BPA during pregnancy. After three weeks of medication, the mice's interaction with others improved significantly. When the researchers stopped giving the mice 10HDA, they relapsed and showed autism-like signs again. However, when the researchers gave 10HDA once again, the ASD-like symptoms faded.

"10-hydroxy-2-decenoic acid shows early indications of potential in activating opposing biological pathways to improve autism-like characteristics", Boon said in the press statement. "It warrants further studies to see whether this potential treatment could be realised in humans", she added.

Scepticism

Manufacturers employ BPA in the production of polycarbonate plastics and epoxy resins. BPA from plastic packaging, bags, and container linings may leach into food and enter our digestive tracts. Because of the risks, food-grade plastics producers are replacing BPA with other plasticisers.

Other experts, however, believe we should avoid being overly concerned. "While BPA is considered an environmental estrogen, it is between 10,000 to 100,000 times weaker," says Dr Ian Musgrave, Senior Lecturer in the Faculty of Medicine at the University of Adelaide, in an interview with the Australian Science Media Centre. Furthermore, he pointed out that the body efficiently metabolises and excretes BPA, which enters the digestive system through food and water. However, the researchers injected BPA into pregnant mice during the experiment. This, he argues, is a major weakness in the study.

However, the findings have sparked a public debate about using BPA in food-grade plastics and other products. The Bureau of Indian Standards (BIS) phased out bisphenols from baby feeding bottles about ten years ago. Still, it does not restrict their usage in other food-grade plastics.

“The FDA still considers BPA safe at current levels in food packaging," says Mahamuni Durai, Assistant Professor, Dept. of Environmental Sciences, PSG College of Arts and Science, Coimbatore. Nevertheless, the European Food Safety Authority has recently drastically reduced the tolerable daily intake (TDI) from 4 µg/kg to 0.2 ng/kg body weight—a 2000-fold decrease.

India does not appear to have a regulatory framework for BPA. "In India, the BIS drafted a policy in 2013 to regulate BPA in food-contact plastics, but the 2018 Food Safety and Standards regulations did not include specific BPA migration limits. Recently, BIS called for developing standards to assess BPA in food packaging and kitchenware," he adds.