Timing, Synergy, Cumulative Effects, and Genetic Predisposition Play a Role in Damage
For years scientific evidence has been gravitating towards an epigenetic etiology of autism spectrum disorder (ASD) and moving away from a genetics alone causation theory. A study from 2012, demonstrates this scientific shift. In the paper, the authors describe autism as “a family of diseases with common phenotypes linked to a series of genetic anomalies that are responsible for no more than 2-3% of cases. The total fraction of ASD attributable to genetic inheritance may be about 30-40%.” This study goes on further to discuss the extremely sensitive period of brain development that occurs during the embryonic and fetal stages. It refers to this critical period as “windows of vulnerability” in which early exposures of toxic chemicals and other environmental insults can prove extremely harmful. If this research is correct, up to 60% of cases of autism are due to an unlucky mix of genes, environment, and timing.
Interestingly, this summer has produced numerous scientific articles investigating the link between autism, environmental influences (including toxins) that occur during a specific time period (prenatal and neonatal developmental stages). In this weeks’ SafeMinds Shares, we will examine and summarize each of these nine papers.
The first paper titled “Physiological mediators of prenatal environmental influences in autism spectrum disorder” is a scientific literature review designed to search for common prenatal environmental factors associated with ASD. Specifically, the research team was interested in looking at the factors associated with inflammation, oxidative stress, and mitochondrial dysfunction, conditions often found co-occurring with autism. The authors were also concerned with medical factors during pregnancy and delivery, as well as sex factors and psychological factors. Overall, the review demonstrated that the leading prenatal environmental factors and insults associated with ASD are air pollution, pesticides, microbiome issues, and epigenetics. The review found that air pollution was more likely to be associated with inflammation. Mitochondrial dysfunction was more often linked to pesticide exposures. The team additionally discovered other external environmental factors such as the importance of folate intake during pregnancy for mitigating the effect of prenatal exposures to toxins such as phthalates, pesticides, and air pollution. They also found that low concentrations of vitamin D during pregnancy are associated with ASD severity. Furthermore, the team uncovered research which suggests keeping a healthy microbiome for expectant mothers may be protective of childhood disorders and advocated for the use of probiotics during pregnancy. Timing was another key issue included in this review. The team found that different exposures were more detrimental at different vulnerable periods of development. They also discovered that environmental influences are complicated. A single isolated exposure is difficult to translate in the real world when it is most likely a mixture of exposures that work together to influence biology.
The next article, “Gene-Environment Interaction in Developmental Neurotoxicity: a Case Study of Synergy between Chlorpyrifos and CHD8 Knockout in Human BrainSpheres“ aimed to identify how the interaction of genes and environment could contribute to the etiology of autism. The research team achieved this goal by exposing the high-risk autism gene CHD8 (derived from 3D brain organoids) to the organophosphate pesticide, chlorpyrifos (CPF). The authors included an interesting hypothesis in their research. They suggested that a strong genetic background such as carrying a mutation on a high-risk autism gene can trigger ASD alone. However, the team also acknowledged that a certain genetic background can synergize with environmental cofactors and worsen symptoms and severity of ASD. A key finding from this study showed that the synergy between CPF and the mutated CHD8 gene showed interactions that can be linked with ASD disease progression. The study’s authors concluded that for patients who have the CHD8 mutations, the severity of symptoms could be exacerbated if they are exposed to CPF.
Environmental lead was the focus of this next study. “Exposure to lead on expression levels of brain immunoglobulins, inflammatory cytokines, and brain-derived neurotropic factor in fetal and postnatal mice with autism-like characteristics” was designed to examine the risk factors between exposure to environmental lead and autism. The researchers exposed mice that exhibited ASD-like behaviors and control mice to lead during gestation and/or neonatally. They then compared these lead-exposed mice to unexposed and highly social mice to investigate neuroimmunological abnormalities between the three groups. After lead exposure, the mice that exhibited ASD-like behaviors had high levels of immunological reactivity in their brains. The control mice who were also exposed to lead did not show immunological reactivity. As expected, the highly social and unexposed mice did not show brain reactivity either. Due to these findings, the research team concluded that lead exposure could contribute to developmental brain abnormalities associated with ASD, particularly in individuals with a genetic susceptibility to the disorder.
Predicting or identifying autism quickly was the topic of “Placental DNA methylation changes and the early prediction of autism in full-term newborns” which was conducted at Wayne State University in Detroit, Michigan. As the title of the study suggests, this research used the placenta to act as a surrogate tissue to predict ASD by examining potentially problematic methylated markers. The placenta produces neurotransmitters that regulate fetal brain development. It is also the sole organ responsible for the transmission of nutrients to the developing fetus. The study’s authors theorized that placental DNA methylation changes are a feature in the fetal development of the ASD brain. DNA methylation can be influenced by diet, hormones, stress, and chemical exposures. This study consisted of 14 term autism cases (7 males, 7 females) and 10 term ethnicity-matched controls (5 males, 5 females). The children in the autism cohort had been delivered at WSU and each had a placental histology performed at the time of birth. DNA was extracted from their residual placental tissue. DNA was also extracted from the control group’s residual placental tissue. At this point of the study, the research team used artificial intelligence (AI) to analyze and identify methylation markers from the placental DNA. They did this to determine if it was possible to predict which children later developed autism. The results showed that AI analysis combined with inter-and intragenic markers was highly accurate at identifying which children had autism. The research team was pleased with the study’s results. They speculate that if these methylation changes are recognized at birth, autism could be diagnosed years earlier. Subsequently, interventions could start right after birth, leading to better outcomes.
“A prospective study of maternal 25-hydroxyvitamin D (250HD) in the first trimester of pregnancy and second trimester of heavy metal levels” was conducted by researchers from the NIEHS. Their study determined that low levels of vitamin D were associated with elevated levels of certain heavy metals in pregnant women. Specifically, low 250HD in the first trimester of pregnancy was associated with 47% higher lead, 60% higher tin, and higher odds of detectable tungsten in the second trimester of pregnancy. In utero exposure to heavy metals can result in negative health outcomes for the fetus later in life. A longer summary of this study can be found in Environmental Factor.
A Norwegian study titled “Prenatal exposure to per- and polyfluoroalkyl substances (PFAS) and associations with attention-deficit/hyperactivity disorder and autism spectrum disorder in children” examined a different type of environmental insult during pregnancy. PFAS are a group of man-made chemicals that include PFOA, PFOS, and GenX. Around since the 1940s, PFAS can be found in food packaging, commercial household products, drinking water, and living organisms (fish, animals, humans). For this study, levels of PFAS were measured from data obtained from the Medical Birth Registry of Norway (MBRN), which contained blood samples of mothers at 18 weeks of gestation and from mothers and children (umbilical cord) at birth. Researchers were able to link information from the Norwegian Patient Registry on diagnoses of ADHD and ASD among children born in 2002 or later to the blood samples data, they received from the MBRN. The results showed that there was a higher risk for both ASD and ADHD in children prenatally exposed to mid-range levels of PFOA. For children with ASD, boys exposed to PFOA were especially more vulnerable to developing the disorder. A socioeconomic status signal was detected in the research, most likely due to the wealthier mother’s fish consumption during pregnancy.
“Children with perinatal stroke are at increased risk for autism spectrum disorder: Prevalence and co-occurring conditions within a clinically followed sample” is the last paper in our summary. The study’s authors started their research by acknowledging that children with perinatal stroke are at an increased risk of developmental language disorders, learning difficulties, and other mental health conditions. But oddly enough, ASD prevalence in this vulnerable group had never been studied until now. By gaining access to a single-center stroke registry, the study’s authors found 311 children with a history of perinatal stroke. Of those 311, 201 had complete records which could be analyzed. Results showed that of these 201 cases, 23 children were formally diagnosed with ASD (11.4%), a much higher ASD rate than found in the general population (1.85%). Sadly, on average, parents expressed first concerns about their child’s development during toddlerhood (2.66 years). However, the average age of diagnosis for these children was not until 6.26 years, well past the average age of 4.4 years for ASD diagnosis in the United States. Perhaps even more troubling is that the ASD diagnosis was not attained for 3.6 years after parents had shared their first concerns. The study ends with a call for clinicians to be more aware of the increased ASD prevalence and implement screenings as part of routine care for all pediatric patients with perinatal stroke.
These new environmental research papers, in addition to twenty years worth of previous scientific evidence, caught the attention of the American College of Obstetrics and Gynecologists (ACOG). The organization has recently released an opinion paper titled “Reducing Prenatal Exposure to Toxic Environmental Agents”. In their paper, ACOG recommends integrating environmental health into the practice of obstetrics and gynecology. They advocate for obstetric clinicians to be knowledgeable about toxic environmental agents in relation to environmental health risk assessment, exposure reduction, and clinical counseling. ACOG also suggests that obstetricians-gynecologists include questions about environmental exposures in patient history during pre-pregnancy visits and prenatal care. The organization recognizes environmental health history as information on exposures from the workplace, home, and recreational activities. ACOG ultimately believes that incorporating these policies will reduce harmful environmental exposures and will protect the health of pregnant mothers and their offspring.
