Plastic bottles (credit: Kyle LeBoeuf/Creative Commons)

University of Calgary have found evidence that both BPA in bottles (and elsewhere) and its substitute, BPS, cause alterations in brain development leading to hyperactivity in zebrafish.

Bisphenol A, known as BPA, is produced in massive quantities around the world for use in consumer products, including household plastics. BPA is a ubiquitous endocrine disruptor that is present in many household products.

It has been linked to obesity, cancer, and, most relevant here, childhood neurological disorders such as anxiety and hyperactivity.

In response to public concerns, many manufacturers have replaced BPA with a chemical called bisphenol S (BPS), which is often labeled as “BPA-free” and presumed to be safer.

However, in an open-access study published Monday, Jan. 12 in the Proceedings of the National Academy of Sciences (PNAS), researchers in Deborah Kurrasch’s lab present contrary evidence.

Surprisingly low doses of BPA and BPS linked to hyperactivity

“Strikingly, treatment of embryonic zebrafish with very low-dose BPA (0.0068 μM, 1,000-fold lower than the accepted human daily exposure) and bisphenol S (BPS), a common analog used in BPA-free products, resulted in 180% and 240% increases, respectively, in neuronal birth (neurogenesis) within the hypothalamus, a highly conserved brain region involved in hyperactivity,” the authors write.

“I was actually very surprised at our results. This was a very, very, very low dose, so I didn’t think using a dose this low could have any effect,” says Kurrasch, PhD, a researcher in the University of Calgary’s Cumming School of Medicine and corresponding author on the paper.

For the study, Kurrasch worked with University of Calgary researcher Hamid Habibi, PhD, and Cassandra Kinch, a PhD student, to expose zebrafish embryos to concentrations of the chemicals at levels found in the Bow and Old Man rivers of Alberta, Canada. The researchers found that exposure to BPA and BPS changed the timing of when neurons were formed in the brains of the zebrafish.

‘Problems in how the neurons connect and form circuits’

“These findings are important because they support that the prenatal period is a particularly sensitive stage, and reveal previously unexplored avenues of research into how early exposure to chemicals may alter brain development, ” says Kinch.

“In the second trimester, brain cells become the specialized neurons that make up our brain. What we show is that the zebrafish exposed to BPA or BPS were getting twice as many neurons born too soon and about half as many neurons born later, so that will lead to problems in how the neurons connect and form circuits,” says Kurrasch, a member of the Alberta Children’s Hospital Research Institute and the department of medical genetics.

Researchers discovered the number of neurons generated in the developing zebrafish brains increased by 180 per cent compared with unexposed fish. They also learned that BPS increased the number of neurons by 240 per cent in similar experiments. The result was a change in behavior, with the fish demonstrating greater hyperactivity later in life.

‘Smoking gun’

Another surprise finding was that zebrafish receptors targeted by BPA and BPS were androgen receptors. Numerous reports has postulated that BPA and BPS modulate normal physiology by mimicking the endogenous sex steroid estrogen, and not testosterone.

“Finding the mechanism linking low doses of BPA to adverse brain development and hyperactivity is almost like finding a smoking gun,” says Habibi, a professor of environmental toxicology and comparative endocrinology in the Faculty of Science.

Although further research is needed to explore that link and the potential effect on human brains developing in the womb, Kurrasch says the findings add weight to other studies suggesting pregnant women should try to limit their exposure to items containing both bisphenols. The evidence also supports removing all bisphenols and structurally similar chemicals from consumer products, she says.

Zebrafish are a widely accepted biomedical model for understanding embryonic brain development. About 80 per cent of the genes found in people have a counterpart in zebrafish, and possess developmental processes similar to that of humans.

The Washington Post published Tuesday a selective list of plastic items or products that contain plastic resins that experts say you should limit your exposure to (or sanitize your hands after touching), and a second selective list of safe alternatives.

The study was funded by the Natural Sciences and Engineering Research Council of Canada (NSERC).

Abstract of Low-dose exposure to bisphenol A and replacement bisphenol S induces precocious hypothalamic neurogenesis in embryonic zebrafish

Bisphenol A (BPA), a ubiquitous endocrine disruptor that is present in many household products, has been linked to obesity, cancer, and, most relevant here, childhood neurological disorders such as anxiety and hyperactivity. However, how BPA exposure translates into these neurodevelopmental disorders remains poorly understood. Here, we used zebrafish to link BPA mechanistically to disease etiology. Strikingly, treatment of embryonic zebrafish with very low-dose BPA (0.0068 μM, 1,000-fold lower than the accepted human daily exposure) and bisphenol S (BPS), a common analog used in BPA-free products, resulted in 180% and 240% increases, respectively, in neuronal birth (neurogenesis) within the hypothalamus, a highly conserved brain region involved in hyperactivity. Furthermore, restricted BPA/BPS exposure specifically during the neurogenic window caused later hyperactive behaviors in zebrafish larvae. Unexpectedly, we show that BPA-mediated precocious neurogenesis and the concomitant behavioral phenotype were not dependent on predicted estrogen receptors but relied on androgen receptor-mediated up-regulation of aromatase. Although human epidemiological results are still emerging, an association between high maternal urinary BPA during gestation and hyperactivity and other behavioral disturbances in the child has been suggested. Our studies here provide mechanistic support that the neurogenic period indeed may be a window of vulnerability and uncovers previously unexplored avenues of research into how endocrine disruptors might perturb early brain development. Furthermore, our results show that BPA-free products are not necessarily safer and support the removal of all bisphenols from consumer merchandise.