Papers of the Month
By Adeline Lopez
Gut microbiome helps modulate social behavior and brain health in sex-specific ways
In mice, prenatal exposure to both air pollution and maternal stress led to male-specific deficits in social behavior and changes in the brain’s reward system, according to an NIEHS-funded study. The researchers also found that altering the offspring’s gut microbiome, or microbial composition, restored sociability.
Exposure to air pollution and stress during pregnancy has been linked to neurodevelopmental disorders such as autism. Disruption to the brain’s reward system has also been implicated in autism, which affects four times as many males as females. The reward system — which releases the chemical dopamine in response to pleasing stimuli — is critical to social interactions as well.
The researchers sought to determine whether combined exposures would induce autism-like behaviors in mice, and if so, what underlying mechanisms might be at play. They exposed pregnant mice to diesel exhaust and provoked stress by creating uncomfortable nesting conditions. They then administered tests to the offspring designed to measure sociability, anxiety, and repetitive behavior.
In addition, they analyzed changes to the pups’ dopamine systems and to specialized immune cells called microglia, which play a role in reward system development. The team identified social deficits, alterations in microglia, and changes in dopamine circuitry in progeny of exposed mothers.
In a related experiment, the team allowed unexposed female mice to foster affected offspring. In response, the pups’ gut microbial compositions shifted to resemble that of their foster mother. The researchers found that this shift prevented social deficits and microglial alterations but did not affect dopamine pathways, the researchers found.
The findings suggest that the gut microbiome is an important modulator of both social behavior and microglia in males and could be a target for therapeutic interventions for autism, according to the authors.
Citation: Smith CJ, Rendina DN, Kingsbury MA, Malacon KE, Nguyen DM, Tran JJ, Devlin BA, Raju RM, Clark MJ, Burgett L, Zhang JH, Cetinbas M, Sadreyev RI, Chen K, Iyer MS, Bilbo SD. 2023. Microbial modulation via cross-fostering prevents the effects of pervasive environmental stressors on microglia and social behavior, but not the dopamine system. Mol Psychiatry; doi: 10.1038/s41380-023-02108-w. [Online 17 May 2023].
Mechanism linking PFAS exposure during pregnancy and early birth revealed
NIEHS-funded researchers identified molecular signatures of prenatal exposure to PFAS associated with early birth using a minimally invasive blood sampling technique. This study represents a significant step toward understanding how the pervasive chemicals may contribute to early term birth, a leading cause of infant death in the United States.
The researchers analyzed maternal blood samples and newborn dried blood spots collected from 267 African American mother-infant pairs in Atlanta, Georgia, between 2016 and 2020. Participants predominantly had a high school education or less, public health insurance with Medicaid, and an income level 132% or lower times that of the federal poverty level. Dried blood spots were collected via a simple heel prick within 48 hours of birth as part of normal postnatal screening. Scientists combined untargeted high-resolution mass spectrometry with sophisticated statistical analyses that link environmental exposures and health outcomes to specific groups of metabolic byproducts, called metabolomic profiles. These profiles helped identify key biological changes resulting from environmental exposures that may interfere with fetal development and growth.
Mothers with higher levels of two PFAS, perfluorooctanoic acid and perfluorohexane sulfonic acid, had increased odds of an early birth. The team determined that the effect of PFAS exposure on reduced gestational length was driven by eight pathways and 52 metabolites, based on data from newborn dried blood spots. The researchers explained that these pathways and metabolites are related to tissue formation, neuroendocrine function, and redox homeostasis — an important balance of reactions that regulate biological responses.
According to the authors, this is the first study to use minimally invasive samples from newborns to identify mechanistic molecular signatures linking PFAS exposure with early birth in a socially and economically marginalized population. However, more research is needed to validate these findings in other populations and to understand the potential joint effects of chemical and non-chemical stressors on health outcomes among groups disproportionately exposed to environmental hazards and social stressors.
Citation: Taibl KR, Dunlop AL, Barr DB, Li YY, Eick SM, Kannan K, Ryan PB, Schroder M, Rushing B, Fennell T, Chang CJ, Tan Y, Marsit CJ, Jones DP, Liang D. 2023. Newborn metabolomic signatures of maternal per- and polyfluoroalkyl substance exposure and reduced length of gestation. Nat Commun 14(1):3120.
Prenatal benzene exposure may have lifelong metabolic consequences
Prenatal exposure to benzene may predispose offspring to metabolic diseases later in life, according to an NIEHS-funded study in mice. Benzene is a chemical found in vehicle and industrial emissions, tobacco smoke, and some products such as paints, glues, and detergents.
During the study, pregnant female mice were exposed to benzene at a concentration of 50 parts per million, which is equivalent to levels found in tobacco smoke. Some of the offspring continued to be exposed to benzene during lactation or were later challenged with a high-fat diet in adulthood. At 21 days old, the researchers conducted transcriptomic analyses to evaluate differences in the hypothalamus — the brain region responsible for hormonal production, glucose metabolism, energy regulation, and appetite control.
Among the offspring prenatally exposed to benzene, male mice had altered hypothalamic genes related to metabolic regulation, inflammation, and neurodevelopment. These males also had changes in appetite-regulating neurons and impaired leptin signaling, which normally regulates the feeling of being full after eating. Male mice also exhibited increased inflammation in the hypothalamus, which the team explained is a response to stress by immune cells in the brain.
Subsequent benzene exposure during lactation had no additional effect in males or females. However, when these mice were exposed to a high-fat diet in adulthood, their glucose metabolism was further affected, and hypothalamic inflammation worsened in both males and females compared with mice without prenatal benzene exposure.
According to the authors, benzene exposure early in life may have enduring effects on hypothalamic development and increase susceptibility to metabolic diseases in adulthood, particularly in males or when combined with a high-fat diet.
Citation: Koshko L, Scofield S, Debarba L, Stilgenbauer L, Fakhoury P, Jayarathne H, Perez-Mojica JE, Griggs E, Lempradl A, Sadagurski M. 2023. Prenatal benzene exposure in mice alters offspring hypothalamic development predisposing to metabolic disease in later life. Chemosphere 330:138738
Key gene expression changes in the placenta may predict autism diagnosis
Researchers funded by NIEHS identified key changes in placental gene expression that are associated with the development of autism spectrum disorder (ASD) in children born preterm.
Children born preterm are at heightened risk of neurodevelopmental impairments, such as those observed in ASD. Recent studies have shown a link between inflammation and immune system dysregulation during pregnancy and preterm birth. However, the relationships among inflammation and immune dysregulation during pregnancy, preterm birth, and ASD are complex. The authors highlighted the need to identify specific biomarkers — evidence of biological changes — that could enable earlier ASD predictions.
With a focus on the placenta, the team analyzed multiomic data, including gene expression of messenger RNAs (mRNAs) and epigenetic factors, which control gene expression but not structure. This included evaluating CpG methylation and microRNAs (miRNAs) in the Extremely Low Gestational Age Newborn (ELGAN) cohort. They compared the gene expression profiles of 340 children without ASD and 28 children with ASD at age 10 years to identify differences that could be used to predict diagnosis.
Diagnosis with ASD was associated with changes in the expression levels of 111 genes, many of which play critical roles in immune system regulation and inflammatory response. Within this set of genes, the researchers identified specific mRNAs expressed in the placenta that predicted an ASD diagnosis later in life. The team also identified a subset of the ASD-related genes that were under the control of CpG methylation, and genes that were under miRNA expression control. One gene, called LRRFIP1, was under the control of both CpG methylation and miRNA expression.
According to the authors, certain gene expression changes in the placenta may be used as biomarkers to predict ASD at birth and facilitate more timely and effective interventions.
Citation: Freedman AN, Clark J, Eaves LA, Roell K, Oran A, Koval L, Rager J, Santos HP, Jr., Kuban K, Joseph RM, Frazier J, Marsit CJ, Burt AA, O’Shea TM, Fry RC. 2023. A multi-omic approach identifies an autism spectrum disorder (ASD) regulatory complex of functional epimutations in placentas from children born preterm. Autism Res 16(5):918-934.