New Pathway May Explain BPA Exposure, Autism Link

Higher prenatal exposure to the chemical bisphenol A (BPA) is associated with a greater risk for autism spectrum disorder (ASD) in men, potentially via the disruption of a key enzyme in the developing brain.
BPA is a potent endocrine disruptor found in polycarbonate plastics and epoxy resins and has been banned by the US Food and Drug Administration for use in baby bottles, sippy cups, and infant formula packaging.
“Exposure to BPA has already been shown in some studies to be associated with subsequent autism in offspring,” lead researcher Anne-Louise Ponsonby, PhD, The Florey, Heidelberg, Australia, said in a statement.
“Our work is important because it demonstrates one of the biological mechanisms potentially involved. BPA can disrupt hormone-controlled male fetal brain development in several ways, including silencing a key enzyme, aromatase, that controls neurohormones and is especially important in fetal male brain development. This appears to be part of the autism puzzle,” she said.
Brain aromatase, encoded by CYP19A1, converts neural androgens to neural estrogens and has been implicated in ASD. Postmortem analyses of men with ASD also show markedly reduced aromatase activity.
The findings were published online on August 7 in Nature Communications.
New Biological Mechanism
For the study, the researchers analyzed data from the BIS in 1067 infants in Australia. At age 7-11 years, 43 children had a confirmed ASD diagnosis, and 249 infants with Child Behavior Checklist (CBCL) data at age 2 years had an autism spectrum problem score above the median.
The researchers developed a CYP19A1 genetic score for aromatase activity based on five single nucleotide polymorphisms associated with lower estrogen levels. Among 595 children with prenatal BPA and CBCL, those with three or more variants were classified as “low aromatase activity” and the remaining were classified as “high.”
In regression analyses, boys with low aromatase activity and high prenatal BPA exposure (top quartile > 2.18 µg/L) were 3.5 times more likely to have autism symptoms at age 2 years (odds ratio [OR], 3.56; 95% CI, 1.13-11.22).
The odds of a confirmed ASD diagnosis were six times higher at age 9 years only in men with low aromatase activity (OR, 6.24; 95% CI, 1.02-38.26).
The researchers also found that higher BPA levels predicted higher methylation in cord blood across the CYP19A1 brain promoter PI.f region (P = .009).
To replicate the findings, data were used from the Columbia Centre for Children’s Health Study-Mothers and Newborns cohort in the United States. Once again, the BPA level was associated with hypermethylation of the aromatase brain promoter PI.f (P = .0089).
In both cohorts, there was evidence that the effect of increased BPA on brain-derived neurotrophic factor hypermethylation was mediated partly through higher aromatase gene methylation (P = .001). 
To validate the findings, the researchers examined human neuroblastoma SH-SY5Y cell lines and found aromatase protein levels were more than halved in the presence of BPA 50 µg/L (P = .01).
Additionally, mouse studies showed that male mice exposed to BPA 50 µg/L mid-gestation and male aromatase knockout mice — but not female mice — had social behavior deficits, such as interacting with a strange mouse, as well as structural and functional brain changes.
“We found that BPA suppresses the aromatase enzyme and is associated with anatomical, neurological, and behavioral changes in the male mice that may be consistent with autism spectrum disorder,” Wah Chin Boon, PhD, co-lead researcher and research fellow, also with The Florey Institute, said in a statement.
“This is the first time a biological pathway has been identified that might help explain the connection between autism and BPA,” she said.
“In this study, not only were the levels of BPA higher than most people would be exposed to but in at least one of the experiments, the mice were injected with BPA directly, whereas humans would be exposed via food and drink,” observed Oliver Jones, PhD, MSc, professor of chemistry, RMIT University, Melbourne, Australia. “If you ingest the food, it undergoes metabolism before it gets to the bloodstream, which reduces the effective dose.”
Jones said further studies with larger numbers of participants measuring BPA throughout pregnancy and other chemicals the mother and child were exposed to are needed to be sure of any such link. “Just because there is a possible mechanism in place does not automatically mean that it is activated,” he said.
Ponsonby pointed out that BPA and other endocrine-disrupting chemicals are “almost impossible for individuals to avoid” and can enter the body through plastic food and drink packaging, home renovation fumes, and sources such as cosmetics.
Fatty Acid Helpful? 
Building on earlier observations that 10-hydroxy-2-decenoic acid (10HDA) may have estrogenic modulating activities, the researchers conducted additional studies suggesting that 10HDA may be effective as a competitive ligand that could counteract the effects of BPA on estrogen signaling within cells.
Further, among 3-week-old mice pups prenatally exposed to BPA, daily injections of 10HDA for 3 weeks showed striking and significant improvements in social interaction. Stopping 10HDA resulted in a deficit in social interaction that was again ameliorated by subsequent 10HDA treatment.
“10-hydroxy-2-decenoic acid shows early indications of potential in activating opposing biological pathways to improve autism-like characteristics when administered to animals that have been prenatally exposed to BPA,” Boon said. “It warrants further studies to see whether this potential treatment could be realized in humans.”
Reached for comment, Jones said “the human studies are not strong at all,” in large part because BPA levels were tested only once at 36 weeks in the BIS cohort.
“I would argue that if BPA is in the urine, it has been excreted and is no longer in the bloodstream, thus not able to affect the child,” he told Medscape Medical News. “I’d also argue that a single measurement at 36 weeks cannot give you any idea of the mother’s exposure to BPA over the rest of the pregnancy or what the child was exposed to after birth.”
The study was funded by the Minderoo Foundation, the National Health and Medical Research Council of Australia, the Australian Research Council, and numerous other sponsors. Boon is a co-inventor on “Methods of treating neurodevelopmental diseases and disorders” and is a board member of Meizon Innovation Holdings. Ponsonby is a scientific advisor to Meizon Innovation Holdings. The remaining authors declared no competing interests.
 
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