Biomarkers for tracking metabolic changes pre-post nutritional epigenetics diet/intervention to prevent autism and attention deficit/hyperactivity disorders in children

Abstract

The prevalence of autism and attention deficit/hyperactivity disorders is increasing worldwide. Recent studies suggest the excessive intake of ultra-processed food plays a role in the inheritance of these disorders via heavy metal exposures and nutritional deficits that impact the expression of genes. In the case of the metallothionein (MT) gene, biomarker studies show dietary zinc (Zn) deficits impact MT protein levels in children with autism and are associated with the bioaccumulation of lead and/or mercury in children exhibiting autism/attention deficit/hyperactivity disorders symptomology. The impact of dietary changes on lead and mercury exposures and MT gene behavior could be determined using a randomized test and control group design. Pregnant women serving in the test-group would participate in a nutritional epigenetics education intervention/course designed to reduce ultra-processed food intake and heavy metal levels in blood while increasing whole food intake and MT and Zn levels. Changes in maternal diet would be measured using data derived from an online diet survey administered to the test and control groups pre-post intervention. Changes in maternal lead, mercury, Zn, and MT levels would be measured via blood sample analyses prior to the intervention and after childbirth via cord blood analyses to determine infant risk factors.

Key Words: Mercury; Lead; Autism; Attention deficit/hyperactivity disorder; Metallothionein; Nutritional epigenetics; Zinc

Core Tip: Increasing evidence supports the nutritional epigenetics model for autism and attention deficit/hyperactivity disorders that explains how unhealthy diet contributes to the epigenetic inheritance of these disorders. An unhealthy diet characterized by excessive intake of ultra-processed foods results in heavy metal exposures and deficits in zinc that may impact metallothionein gene function. Metallothionein gene malfunction may result in the bioaccumulation of mercury and/or lead in the blood depending on diet. Nutritional epigenetics education may be used as an intervention to reduce the intake of ultra-processed foods and heavy metals in expectant mothers and prevent the development of autism and attention deficit/hyperactivity disorders in children.

INTRODUCTION

The purpose of this opinion review article is to report the current prevalence trends and issues associated with autism and attention deficit/hyperactivity disorders (ADHD) and consider why it is in the best interest of countries to prevent or mitigate the development of these neurodevelopmental disorders in children. In considering the prevention and mitigation of these disorders, the review focused exclusively on the etiology involving environmental and dietary factors related to heavy metal exposures and nutritional deficits. Using relevant key words, the PubMed database was searched to find articles published over the last ten years on the prevalence of autism and/or ADHD worldwide and recent studies of the role of ultra-processed foods and/or heavy metal exposures in creating conditions for the development of autism and/or ADHD.

PREVALENCE TRENDS, SPECIAL EDUCATION COSTS, LEARNING AND BEHAVIOR, AND HEALTH CONCERNS

The annual additional cost of providing special education services to children with autism in the United States varies by state and can range between 6838 dollars to 23860 dollars per child according to published estimates[1]. Children with autism need special education services because of their highly individualized learning needs that cannot be met in the mainstream general education classroom. Half of children with autism have developmental delays in the acquisition of language and most have difficulty communicating and establishing relationships with others[1]. Other characteristics of children with autism may include delayed cognitive skills, hyperactivity, impulsiveness, inattention, seizures, unusual eating and sleeping habits, gastrointestinal issues, and anxiety[2]. As the autism prevalence rises, costs associated with educating and raising these children will also rise.

The prevalence of autism varies geographically across the world. In the United States, the Centers for Disease Control (CDC) and prevention determines autism prevalence using data gathered by the Autism and Developmental Disabilities Monitoring surveillance program that tracks autism diagnoses among children aged 8 years[3]. In 2000, the autism prevalence estimate from the Autism and Developmental Disabilities Monitoring program was 6.7/1000 or one in 150 children aged 8 years[3]. In 2020, CDC reported the prevalence had nearly tripled with one in 36 children aged 8 years estimated to have the autism diagnosis which is more common in boys[3]. In the United States, approximately 4% of boys and 1% of girls have autism[3]. In China, Jiang et al[4] recently reported the results of a systematic review and meta-analysis of studies on autism prevalence among children aged 0 to 14. Their finding is the prevalence of autism in China from 2017 to 2023 was 7/1000 (0.007) with 1% of boys and 0.2% of girls having the diagnosis[4]. The prevalence of autism in China before 2017 was 2/1000 (0.002)[4]. In Europe, Bougeard et al[5] recently reported the prevalence of autism ranged between 0.004 and 0.015 with evidence supporting an upward trend over time. Along with increasing autism prevalence, it is becoming clear that individuals with autism also commonly suffer from co-morbid disorders with ADHD presenting as a higher risk for boys[5].

ADHD is one of the most common presenting co-morbid conditions in children[6]. In the United States, one in eight children with ADHD is also diagnosed with autism and requires more intervention support[7]. In 2011, the estimated annual cost to society of educating a child with ADHD was 4689 dollars more than the cost of educating a child without ADHD[8]. This cost did not reflect any costs associated with co-morbid conditions (e.g., autism). Children with ADHD in the classroom have difficulty paying attention, staying on task, concentrating, and may exhibit hyperactivity and/or impulsivity[9]. For these reasons, they are often labeled as “troublemakers” and have higher rates of disciplinary referrals[8]. Due to their inability to achieve their learning goals, children with ADHD often receive special education services under the Other Health Impaired category as defined by the United States Department of Education Special Education program[10].

As is the case with autism, the prevalence of ADHD worldwide varies geographically. In the US, the CDC estimates that 11.4% of America’s children between ages 3-17 have been diagnosed with ADHD[11]. The CDC also reported in 2022 that 14.4% of children with ADHD also have an autism diagnosis[11]. Other co-morbid diagnoses that may overlap with ADHD include anxiety, behavioral or conduct disorders, depression, learning disability, developmental delay, speech/language, and intellectual disability[11]. The CDC report states that 44.1% of American children with ADHD also have a behavioral or conduct diagnosis[11]. In China, researchers recently reported the ADHD prevalence was 9.8% in a community sample (n = 2497) of children aged 6-13[12]. In a recent review of the literature, Sayal et al[13] found the community prevalence of ADHD globally is on average about 5% with an additional 5% of children having difficulties with hyperactivity, impulsiveness, and inattention just under the threshold of meeting the diagnostic criteria for ADHD. In addition to exhibiting symptoms that impact learning and behavior in the classroom, youth with ADHD and autism are at risk for premature mortality with suicide rates particularly high in the case of individuals having psychiatric comorbidities[14,15]. As children with these neurodevelopmental disorders grow older, they are at higher risk of developing cardiometabolic diseases, obesity, type-2 diabetes, and other conditions that impact quality of life[16,17]. With such detrimental outcomes associated with the development of autism and ADHD, it would seem prudent that countries take steps to prevent these conditions from occurring in the first place, especially in the case of epigenetic inheritance.

EPIGENETIC INHERITANCE AND SHARED ENVIRONMENTAL AND DIETARY FACTORS

Epigenetic inheritance is the transmission of gene behavior across generations; genes may be turned off or turned on inside the mother and this gene behavior then passes on to the child. An example of epigenetic inheritance includes the following: A woman with gestational diabetes has elevated glucose levels and her fetus is exposed to a hyperglycemic environment in the womb which disrupts its brain derived neurotrophic factor (BDNF) gene expression[18]. The BDNF gene promotes the production of BDNF proteins that engage in child learning and memory[19]. Decreased BDNF levels in male fetuses exposed to a hyperglycemic environment in the womb are also associated with impaired language development[18,20]. While a link between maternal diabetes and the onset of autism has been firmly established[21], evidence is only now emerging for such a link in the development of ADHD[22]. In addition to hyperglycemia’s impact on BDNF gene activity in the womb, specific nutrients and dietary chemical exposures may modify or alter the behavior of other genes associated with the development of autism and ADHD[23-25].

Gene behaviors can be described by DNA methylation patterns. DNA methylation is the addition of a methyl group to a gene which acts as a chemical switch to turn the gene off[26]. DNA methylation patterns are influenced in the womb by individual lifestyle factors (e.g., diet, exercise) and exposures to toxicants (e.g., mercury, lead, organophosphate pesticides) via air, food, and water pollution. An unhealthy diet characterized by an increased intake of ultra-processed foods along with inadequate intake of nutrient-rich whole foods (e.g., fruits, vegetables, nuts, legumes) is associated with alterations in DNA methylation patterns that impact offspring health[27,28]. DNA methylation patterns are inheritable and reversible depending on epigenetic stressors related to prenatal diet[26].

Recent studies shed light on the role of prenatal diet in creating mechanisms for the development of disease in offspring. In a recent review, Nilsson and Ling[27] found a family history of unhealthy diet affects DNA methylation patterns in tissues that create conditions for the development of insulin resistance in offspring that predispose them to type 2 diabetes. Rijlaarsdam et al[28] conducted a study of parents and children enrolled in the Avon Longitudinal Project to determine whether prenatal high-fat and sugar diet is associated with the onset of ADHD or conduct problems in children between the ages of 7-13. Participants completed a food frequency questionnaire that included questions about the frequency of their intake of ultra-processed food products[28]. The more frequently these products were consumed, the higher the participants’ diet score, and the “unhealthier” their diet due to the excessive amounts of fat and sugar included in the ultra-processed foods (e.g., fried food, pastries, chips, chocolate bars, cakes, buns, and biscuits)[28]. The researchers found higher prenatal unhealthy diet scores were associated with the methylation of the insulin-like growth factor 2 gene at birth for children diagnosed with either ADHD or conduct disorder[28]. They concluded higher insulin-like growth factor 2 methylation predicted ADHD symptoms and suggested preventing unhealthy diet in pregnancy could reduce ADHD prevalence in children[28].

The World Federation of ADHD released a consensus statement in 2021 which provided evidence-based conclusions about the etiology of ADHD that may now be considered from the standpoint of epigenetic inheritance[29]. Environmental correlations of ADHD include exposure to toxicants (e.g., maternal smoking, childhood exposure to secondhand cigarette smoke, lead exposure, artificial food colors, organophosphate pesticide exposures, air pollution), nutrient deficiencies, and events during pregnancy with maternal obesity being the greatest risk factor for the development of ADHD in offspring[29]. Similar environmental correlations to the development of autism include food related toxic chemical exposures (e.g., mercury, lead, organophosphate pesticide residues), maternal prenatal diet, and early childhood diet and nutrition[30]. In studying the environmental correlations associated with both autism and ADHD, it becomes clear that factors associated with the western diet are the drivers behind the increasing prevalence of these neurodevelopmental disorders from one generation to the next generation.

A recent study, Horner et al[31] confirmed the significant association between a western dietary pattern in pregnancy and the development of ADHD (P = 0.002), autism (P = 0.002) and the associated symptoms for both (P < 0.001) disorders in offspring. The prospective cohort study examined the pregnancy dietary patterns of 508 mother-child pairs using data derived from self-reported food frequency questionnaires which were administered to the mothers at several points in time during infant gestation and at child ages 6 years and 8 years[31]. The findings of significant association between western dietary pattern in pregnancy and the development of autism and ADHD in the offspring remained consistent after multivariate modeling adjusted for pre-pregnancy maternal BMI, child sex, birth weight, gestational age, pregnancy smoking/antibiotic use, pre-eclampsia, and child western dietary patterns[31].

CHARACTERISTICS OF WESTERN DIETARY PATTERN

The components of the western diet positively associated with the development of autism and ADHD at 32-38 weeks of gestation include deep fried foods, processed meats, margarine, and red meat[31]. The components of the western diet positively associated with autism and ADHD at 10-12 weeks gestation include deep fried foods, processed meats, margarine, red meat, baked goods, added salt, and whole milk dairy foods[31]. Although details on the exact ingredients or molecular makeup of the components of the western diet are not provided, Horner et al[31] provided further description of the categories of food associated with the development of neurodevelopmental disorder, autism, and ADHD. The categories of foods identified by Horner et al[31] are provided in Table 1 and show the western dietary pattern with food intakes associated with the development of any neurodevelopmental diagnosis, autism, and ADHD. Horner et al[31] calculated the P values using principal component analysis on nutrient constituent data collected from food frequency surveys administered to the mothers at 24 weeks of gestation[31].

Table 1 Western prenatal dietary pattern associated with any neurodevelopmental diagnosis (P = 0.002), autism (P = 0.002), and attention deficit/hyperactivity disorders (P = 0.002).

High prenatal intake of ultra-processed foods positively associated with any neurodevelopmental diagnosis	Low prenatal intake of nutrient-rich foods positively associated with any neurodevelopmental diagnosis
Animal fats	Fruit
Refined grains	Fish
High energy drinks	Vegetables
Spices	Dried fruit
High fat dairy	Tomatoes
Snacks	Water
Red meat	Green leafy vegetables
Cheese	Nuts
Fruit syrup and marmalade	Beans, lentils
Processed meat	Shellfish
Potato products	Poultry
Eggs	Whole grains

The higher prenatal intake of ultra-processed foods presented in Table 1 is characteristic of the western dietary pattern. Numerous studies have found a maternal diet high in ultra-processed foods with saturated fats and added sugars (especially those found in carbonated beverages) adversely impact child neurodevelopment[32]. Ultra-processed foods have undergone physical or chemical processes (e.g., frying, hydrogenation) and contain a wide variety of food ingredients (e.g., artificial flavors, vegetable oils, starch, petroleum-based food coloring, high fructose corn syrup (HFCS), maltodextrin, and other added sugars)[33]. Examples include potato chips, fortified breads, crackers, carbonated soft drinks, energy bars, chicken nuggets, powdered baby formulas, candy, energy drinks, syrups, hot dogs, and sausages[33]. Numerous studies show high intake of ultra-processed foods correlate with increased intake of added sugars and fats and decreased intake of fiber, protein, zinc (Zn), calcium, magnesium, potassium, and multiple vitamins[34,35].

Mechanisms by which ultra-processed foods or their ingredients cause harm to health are under study. Evidence suggests consumption of specific food ingredients may impact metabolism and lead to deficits in essential nutrients or mineral imbalances. Several studies have linked Zn losses with the consumption of the following food ingredients: Tartrazine, sunset yellow, and HFCS[36-38]. The most recent finding of Zn loss from the consumption of HFCS was confirmed by Harder et al[38] during a recent clinical trial involving young college students. The students were fed beverages sweetened with glucose (n = 28), fructose (n = 28), HFCS comprised of 55% fructose and 45% glucose (n = 28), or aspartame (control beverage with n = 28), three times a day, for two weeks[38]. Fasting serum samples were collected and analyzed pre and post intervention[38]. Students consuming HFCS showed significant decreases in serum Zn concentrations with post-test adjusted P value: 0.0014[38].

In addition to Zn losses, another mechanism by which ultra-processed food ingredients may cause harm to health is via inorganic mercury exposures. Mercury levels in all types of non-fish food have been found in numerous countries across the world[39]. Studies show significant mercury exposures are likely to occur via the consumption of non-fish ultra-processed foods containing vegetable oils and HFCS [40,41]. Mercury, in any form, is toxic and can negatively impact infant brain development during pregnancy and after birth[42]. There is increasing concern among government regulatory bodies and scientists across the world about the harmful effects of dietary prenatal mercury exposure[39] and heavy metal mixtures that increase risk of neurodevelopmental disorder[43-45]. Recent clinical trials have examined the impact of prenatal co-exposures to heavy metal mixtures[43-45]. In every study, researchers found significant interactions between lead and mercury with prenatal mercury exposures potentiating the harmful effects of lead on infant neurodevelopment[43-45].

In addition to mercury, co-exposures to arsenic, cadmium, and lead are commonly found in ultra-processed foods fed to infants and young children[46]. Hoffman-Pennesi et al[47] recently analyzed data collected by the United States Food and Drug Administration’s total diet study from 2018-2020 and found the ultra-processed food categories contributing most to children’s lead and cadmium exposures included grains/baked goods. Compelling evidence suggests prenatal and child co-exposures to dietary heavy metal residues and Zn loss, or deficits, are the most common western dietary factors associated with the excess consumption of ultra-processed foods that contribute to the development and symptoms of autism and ADHD[36]. Zn losses or deficits resulting from the excess consumption of ultra-processed food ingredients may impact the Zn dependent metallothionein (MT) gene[48].

MT GENE

The MT gene gives the body instructions for producing MT proteins (MTs), which are made up of the amino acid histidine and Zn and copper (Cu) atoms bound to the amino acid cysteine[48]. MTs serve as metal transporter proteins in the body and play a key role in heavy metal detoxification and elimination[48]. The MT molecules can bind with cadmium, mercury (Hg), arsenic, and lead (Pb) atoms via the cysteine molecules which are rich in sulfur. Cu plays a key role in metal detoxification by its interactions with Zn as it regulates the transfer of heavy metals to and from the MT protein molecule. Heavy metals are transported out of the body via urine or feces via the displacement of Zn atoms from within the MT protein[49]. The Zn/Cu ratio is the most important building block of the MT protein. Figure 1 shows three Zn atoms, and one Cu atom bound to yellow cysteine residues which connect to blue histidine molecules. Selenium, represented by red in Figure 1, plays a key role in reducing oxidative stress from the heavy metals that bind with and are transported through the excretion process by MTs[49]. An unhealthy diet high in ultra-processed food intake may lead to Zn losses that impact MT gene function creating conditions for the bioaccumulation of heavy metals in the blood[25,48]. Children with autism and/or ADHD suffer from Zn deficits[50,51] and tend to accumulate mercury and/or lead in their blood[52]. The severity of their symptomology correlates directly to the heavy metal levels in their blood[53]. To prevent symptoms of autism and/or ADHD from developing, it is important to reduce dietary exposures to heavy metals.

Figure 1 Metallothionein protein molecule. Figure shows three zinc atoms, and one copper atom bound to yellow cysteine residues which connect to blue histidine molecules. Selenium, represented by red, plays a key role in reducing oxidative stress from the heavy metals that bind with and are transported through the excretion process by metallothionein proteins. MT: Metallothionein; Zn: Zinc; Cu: Copper; Se: Selenium.

DIETARY HEAVY METAL EXPOSURES

Heavy metal exposures may be reduced through the elimination of dietary chemicals, or ingredients, from the diet that contain allowable, or known, heavy metal residues. Table 2 provides a listing of the food ingredients and chemicals with heavy metal residues found in the ultra-processed food supply[54-61]. Mechanisms of harm, or toxicity, of each chemical may vary depending on dose (dietary intake), allowable heavy metal content, and individual Zn status.

Table 2 Food ingredients with allowable or known heavy metal content.

Potentially harmful dietary ingredients or chemicals	Allowable or known heavy metal content with reference	May contribute to autism and/or ADHD
Bleaching agent for flour (chlorine)	Hg[54]	Autism
HFCS	Hg[41]	Autism
Tartrazine (yellow 5, E-102)	As ≤ 3 ppm[55]	Autism; ADHD
	Pb ≤ 10 ppm[55]
	Hg ≤ 1 ppm[55]
Sunset yellow (yellow 6, E-110)	As ≤ 3 ppm[55]	Autism; ADHD
	Pb ≤ 10 ppm[55]
	Hg ≤ 1 ppm[55]
Sodium benzoate	Pb ≤ 2 ppm[56]	Autism; ADHD
Beta carotene, synthetic	Pb ≤ 10 ppm[57]	Autism; ADHD
	As ≤ 3 ppm[57]
Caramel	As ≤ 3 ppm[58]	Autism; ADHD
	Pb ≤ 10 ppm[58]
	Hg ≤ 0.1 ppm[58]
Sodium nitrite	Pb ≤ 2 ppm[59]	Autism; ADHD
Calcium chloride	Pb ≤ 2 ppm[60]	Autism; ADHD
Carrageenan	As ≤ 3 ppm [61]	Autism; ADHD
	Cd ≤ 2 ppm[61]
	Pb ≤ 5 ppm[61]
	Hg ≤ 1 ppm[61]

ADHD: Attention deficit/hyperactivity disorders; HFCS: High fructose corn syrup; Hg: Mercury; As: Arsenic; Pb: Lead; Cd: Cadmium; ppm: Parts per million.

DIETARY CHANGES REDUCE HEAVY METAL LEVELS

Several studies have shown the relationship between diet and heavy metal levels in blood. In an early study of the blood Pb levels in American children between the ages of one and eleven, Mahaffey et al[62] analyzed data collected by the Second National Health and Nutrition Examination Survey. Blood Pb levels were significantly higher in black children compared to white children who showed significantly higher dietary calcium intake (P < 0.0001)[62]. Dietary calcium intake was inversely associated with blood lead levels regardless of variables analyzed using regression analysis (e.g., race, poverty, urbanization, geographic region)[62]. In a later study of prenatal lead exposures, Ettinger et al[63] evaluated the effect of 1200 mg dietary calcium supplementation on prenatal blood lead levels during each trimester of pregnancy. Dietary calcium intake was associated with significant reductions in blood Pb levels during each trimester of pregnancy relative to the group receiving a placebo[63]. The reduction in maternal blood lead levels was strongest in the second trimester (P < 0.001) with a 14% reduction and among women who were most compliant in taking the calcium supplement (P < 0.001) with a 24% reduction[63]. In addition to calcium, researchers have studied the impact of dietary Zn on blood Pb levels.

Researchers led by Schell et al[64]analyzed data from a study of mother-child pairs in New York to determine the influence of dietary Zn, iron, protein, vitamin D, fat, and calcium on the blood lead level of infants from 3 months to 12 months of age. Although neonates’ blood lead levels were low at birth, by 12 months, 18% of the infants had elevated blood lead levels[64]. At 6 months of age, the researchers observed significant inverse relationships between the infants’ blood lead levels and their intake of Zn, calcium, and iron[64]. At 12 months of age, only low iron intake was associated with higher blood lead levels[64]. More recently, Gulson et al[65] studied the diets of 108 young children over a five-year period and found that as the levels of dietary Zn, calcium, and iron increased, blood lead levels significantly decreased in the children.

While the role of low dietary Zn intake is clearly linked to a reduction in MT protein production and the subsequent bioaccumulation of lead in blood[66], the role of low dietary calcium intake in the bioaccumulation of lead is less understood. The toxic effects of lead exposure in children during critical periods of development are better understood and governments have published guidelines for exposure. The United States CDC now states there is no safe blood lead level and even low levels of lead in blood can be harmful to children[67]. The CDC recommends increasing the dietary intake of calcium and iron in children with any amount of lead detected in their blood[68].

Although many studies have shown the relationship between dietary methylmercury exposure from the consumption of seafood[69], few studies have been conducted to determine the relationship between inorganic mercury exposure from the consumption of ultra-processed foods. Only one study has been conducted thus far to determine how specific dietary changes impact mercury levels in blood[70]. In a clinical trial to determine the impact of inorganic mercury exposure on glucose homeostasis, researchers found total blood mercury levels were influenced by ultra-processed food intake[70]. American Indian college students who completed a nutritional epigenetics course significantly reduced their ultra-processed food intake and had lower inorganic blood mercury and fasting glucose levels compared to students who did not take the nutritional epigenetics course[70]. The role of low-dose mercury exposure in the development of diabetes is an area in need of more research[71]. Well-designed studies that include dietary interventions designed to reduce inorganic mercury levels in blood could shed more light on whether inorganic mercury exposure is a significant risk factor for diabetes[71]. One nutrient known to mitigate the harmful effects of mercury is dietary selenium[39]. Hg and selenium (Se) atoms combine in a 1:1 ratio forming a molecular compound in cells[72]. Tissues having a Se: Hg molar ratio greater than one are protected against the oxidative stress caused by mercury[72]. Pregnant women who are Se deficient have a higher risk of giving birth to children with autism and ADHD traits[73]. In a recent study of 719 mother-child pairs, Demircan et al[73] found three maternal Se biomarkers associated inversely with ADHD traits in children at 5 years of age. Maternal total Se was inversely associated with autism traits in children at 5 years of age[73].

NUTRITIONAL EPIGENETICS

The first nutritional epigenetics model for autism was published in 2009[25]. In a review of the literature, Dufault et al[25] found the excess consumption of HFCS could result in Zn losses which would impede MT gene function and result in the bioaccumulation of Hg in blood exacerbating symptoms in children with autism who were already Zn deficient. In 2019, the model was tested when Meguid et al[74] published the results of an intervention study conducted to determine the impact of Zn supplementation over a three-month period on 30 children with autism between the ages 3-8 years. Meguid et al[74] measured pre- and post-serum MT protein levels in children and determined the genetic expression of MT-1 was higher after the Zn therapy than before the intervention. Although heavy metal levels were not measured, the study showed an increase in cognitive-motor performance among the children following Zn supplementation[74]. The attempt by Meguid et al[74] to affect change in the genetic expression of MT-1 using Zn supplementation clearly exemplifies how nutritional epigenetics research can work to create therapeutic advances.

RECENT TRIAL SUPPORTS NUTRITIONAL EPIGENETICS MODEL FOR AUTISM AND ADHD

In their updated nutritional epigenetics model for autism and ADHD, Dufault et al[53] show how unhealthy diet characterized by high intake of ultra-processed foods leads to heavy metal co-exposures (e.g., inorganic mercury, lead) and dietary deficits in Zn, selenium, and calcium which results in MT gene disruption and the bioaccumulation of inorganic mercury and lead in the bloodstream. Oxidative stress occurs with the bioaccumulation of inorganic mercury and lead in the blood, and this leads to changes in DNA patterns across generations that impact child health and learning[53]. Garí et al[75] conducted a study recently to evaluate the association between prenatal co-exposures to lead, mercury, and cadmium, micronutrients selenium, Zn, and Cu and neurodevelopmental outcomes in school children. The researchers found higher prenatal mercury exposures were associated with lower scores on behavioral tests that measured hyperactivity and inattention in the 436 offspring under study[75]. They also found higher prenatal lead exposures were associated with lower intelligence scores in the school-age children[75]. Prenatal Zn and Se levels in cord blood were inversely associated with emotional difficulties experienced by the children[75]. Zn, selenium, mercury, and lead levels are principal elements of the nutritional epigenetics model for autism and ADHD[53]. In measuring these elements in cord blood (e.g., lead, selenium, Zn) and hair (e.g., mercury), Garí et al[75] found compelling evidence that supports the nutritional epigenetics model for autism and ADHD. Further research is needed to collect additional data to better characterize the dietary factors that play an integral part of the model. For experimental design purposes, the model has been simplified and is shown in Figure 2. Figure 2 shows a simplified version of the nutritional epigenetics model that can be used to design a prenatal nutrition intervention study to better characterize the factors associated with the development of autism and ADHD in offspring. In conducting a new study to further test the nutritional epigenetics model, expectant mothers would be recruited to participate in a nutrition education intervention as test or control subjects. The test group would be given the previously tested intensive nutritional epigenetics instruction focused on reducing the intake of harmful ultra-processed foods and increasing intake of whole, unprocessed, nutrient rich foods[53]. The control group would be given an alternative and limited nutrition education program not focused on reducing ultra-processed food intake but instead following the standard dietary guidelines for pregnancy set forth by the United States government that do not mention ultra-processed food intake[76]. Dietary intake data would be collected pre-post intervention and after childbirth from the participants in both the test and control groups. In addition to collecting dietary intake data, a number of different biomarkers could be collected pre-post intervention and after childbirth to further characterize the elements of the nutritional epigenetics model for autism and ADHD. Suggestions for biomarker collection include MT in maternal serum[74], inorganic mercury and lead in maternal red blood cells and cord blood[52], micronutrient concentrations in maternal and cord blood, especially Zn, Cu, and selenium[75]. The plasma or whole cord blood Zn/Cu ratio could be determined for all sampling events as either biomarker has been useful in evaluating children with autism[77,78]. Breast- and bottle-feeding data could also be collected along with infant and child health, learning, and neurodevelopmental outcomes over a period of six to eight years.

Figure 2 Nutritional epigenetics model for autism and attention deficit/hyperactivity disorders. Figure shows a simplified version of the nutritional epigenetics model. Poor prenatal diet of excessive ultra-processed food intake results in the consumption of food colors, vegetable oils, refined sugars and preservatives. These food ingredients contribute to mercury (Hg) and lead (Pb) exposures and deficits in nutrition such as selenium and zinc losses. Zinc loss and selenium deficits disrupt metallothionein protein production which leads to the bioaccumulation of Hg and Pb in the blood. These heavy metals create oxidative stress and symptoms associated with child behavioral and learning disorders. Oxidative stress impacts DNA methylation patterns creating adverse child health and learning outcomes in the next generation. A healthy diet, free of ultra-processed foods, may reduce Hg and Pb levels and symptoms associated with behavioral and learning disorders (e.g., autism, attention deficit/hyperactivity disorders). MT: Metallothionein; ADHD: Attention deficit/hyperactivity disorders; HFCS: High fructose corn syrup; Zn: Zinc; Se: Selenium; Hg: Mercury; Pb: Lead.

A nutrition intervention study has already been conducted successfully to test the efficacy of nutritional epigenetics instruction in reducing parental intake of ultra-processed foods and increasing parental intake of whole, unprocessed, nutrient rich foods[53]. The study utilized a test and control group pretest-posttest experimental design with participants recruited from parents already having a child with autism or ADHD[53]. The test group participated in a six-week online nutritional epigenetics workshop, while the control group did not[53]. The efficacy of the instruction was determined measuring changes in parental diet pre and post intervention using data derived from an online diet survey questionnaire[53]. Parents who participated in the nutritional epigenetics workshop significantly decreased their intake of ultra-processed foods (P < 0.001) and significantly increased their intake of whole/organic foods (P < 0.05)[53]. Unfortunately, the researchers were not funded to collect biomarker data.

CONCLUSION

Increasing evidence supports the nutritional epigenetics model for autism and ADHD that explains how unhealthy diet contributes to the epigenetic inheritance of these disorders. The link between excessive ultra-processed food consumption and the development of autism and ADHD has been found[31]. An unhealthy diet characterized by excessive intake of ultra-processed foods results in heavy metal exposures, especially mercury and lead, and deficits in nutrition, especially Zn and selenium, which may impact MT gene function. MT gene malfunction results in the bioaccumulation of heavy metals in blood and oxidative stress that impacts DNA methylation patterns and results in adverse child health outcomes. Autism and ADHD prevalence is rising worldwide in populations that overconsume ultra-processed foods. Costs associated with raising, educating, and treating children with autism and ADHD are rising. There is a critical need to conduct further research to determine whether nutritional epigenetics education may be used as an intervention to reduce the intake of ultra-processed foods in expectant mothers and prevent the development of autism and ADHD in children. Reducing the prevalence of autism and ADHD will result in better child health and learning outcomes.

ACKNOWLEDGEMENTS

The author thanks all of the collaborators who have provided support through the years to achieve the goal of informing the research community and public of the problem of heavy metal co-exposures from the consumption of ultra-processed foods.