Toxic PCBs, sex-biased genes and the developing brain

In two new studies, researchers at the UC Davis MIND Institute have clarified how a long-banned group of chemicals, called polychlorinated biphenyls (PCBs) affect genetic activity. The research helps explain how biological systems respond to these exposures, including key differences between males and females.

"PCBs were banned in the 1970s but are still around us," said Janine LaSalle, professor in the Department of Medical Microbiology and Immunology, MIND Institute faculty member and senior author on both studies. "PCB chemicals are decreasing in the environment, but surprisingly, low exposure levels aren't always less hazardous. Higher chemical levels can trigger the body to turn on DNA repair and other stress-related pathways. However, lower levels can slip under the body's radar and have long-term effects."

LaSalle and colleagues used PCBs as a lens to better understand developmental biology. The first paper investigated why girls seem to respond differently than boys to some environmental and genetic exposures linked to neurodevelopmental conditions. The second dissected the combined role the MECP2 gene and PCBs play in Rett syndrome.

Together, the two studies provide a more detailed picture of how PCBs influence gene expression and how the body responds.

X chromosome defenses

Much of this research was built on the MIND Institute's MARBLES study. This long-term investigation follows pregnant women who already have an autistic child. Research has shown these younger siblings are more likely to have autism and other neurodevelopmental conditions.

Among its many findings, MARBLES suggested that girls show traits associated with autism and other neurodevelopmental conditions differently than boys, despite similar exposures to genetic or environmental factors. One of the current studies, published in Genome Biology, dove deeper to identify those mechanisms in female and male mouse models.

"There are well-documented sex differences in many neurodevelopmental conditions, but the biological mechanism is largely unknown," said Pamela Lein, professor and department chair in the Department of Molecular Biosciences in the UC Davis School of Veterinary Medicine and co-author on both papers. "This research suggests the genetic and epigenetic responses to PCBs differ between males and females, contributing to these differences."

The team found PCBs altered many genes, and that influence was highly dependent upon whether the animal model was male or female. When the researchers stratified the data by sex, they saw major differences between males and females - to the point where many genes changed in opposite directions in response to PCBs.

Further investigation led them to female X chromosomes, specifically, a gene called XIST. This gene's main job is silencing one of the two female X chromosomes (females, like males, have a single gene-expressing X); however, it turns out XIST has another important job.

"The amount of XIST produced in the brain is changed in females in response to PCBs," LaSalle said. "So, in addition to silencing an X, it also may be moonlighting to protect against PCBs and possibly other toxins. It protects females because it's a mechanism that males just don't have."

The importance of folic acid

The research also reaffirmed folic acid's protective capabilities. Folic acid is a B vitamin that has been added to food for decades to help prevent neural tube defects, such as spina bifida, but may offer additional benefits. MARBLES and other studies have shown that folic acid supplements are associated with dramatically reduced likelihood of a child developing autism and other neurodevelopmental conditions.

In addition to illuminating XIST's protective effect, the Genome Biology study showed folic acid can mitigate the harmful effects of PCB exposure, particularly in women. Specifically, folic acid helped preserve healthy gene expression.

"Taking folic acid-containing supplements prior to becoming pregnant, and in early pregnancy, has been shown to decrease likelihood of autism by about half," said Rebecca Schmidt, professor in the Department of Public Health Sciences and the MIND Institute and co-author on this paper. "In addition, research has shown that folic acid reduces the likelihood of autism associated with contaminant exposures, such as pesticides. This study points to the genomic changes that could be behind these findings."

PCBs and Rett syndrome

The second paper, published in the journal iScience, examined the relationships between PCBs and the gene MECP2, which is altered in Rett syndrome, autism and other neurological conditions.

Rett syndrome is a rare neurodevelopmental condition that primarily affects women. It is caused by a MECP2 mutation on an X chromosome. The syndrome can lead to a range of symptoms, including impaired hand movements, breathing problems, loss of speech and seizures.

Rett syndrome has a unique impact on the female brain. Because of XIST, patients' cells express both typical and altered MECP2 genes, which work against each other. In other X-linked neurodevelopmental conditions, typical cells are protective, but that's not the case with Rett syndrome. Instead, altered cells disrupt neighboring cells, impairing the typical ones over time. These findings could explain why girls with Rett initially develop normally but then start to regress.

"We see in the models these fluctuations in cellular gene expression, almost like they are seesawing back and forth," LaSalle said. "The conflicting signals mean they can't seem to reach homeostasis, or balance."

PCB exposure adds another factor to the mix, and it may not be entirely negative. PCBs share many functional pathways with MECP2 mutations and may be changing some of the effects associated with the mutated gene.

"The environmental exposures from PCBs and the genetic effects from the MECP2 variants are acting on similar mechanisms and either counteracting or compounding each other," LaSalle explained. "The PCB exposure could be helping the normal cells attempt to reach homeostasis, which is an intriguing relationship that deserves more investigation."

Funding for the the study published in Genome Biology included a National Institutes of Health (NIH) grant (R01ES029213), the UC Davis Intellectual and Developmental Disabilities Research Center (P50HD103526) and the UC Davis Environmental Health Sciences Center (P30ES023513).

Funding for the study published in iScience included the NIH (T32ES007059, R01ES029213, R01AA027075, S10OD010786, U2CES030158, P50HD103526 and U24DK097154) and the Superfund Research Center at The University of Iowa (P42 ES013661).