Biological value (BV) is a measure of the proportion of absorbed protein
from a food which becomes incorporated into the proteins of the
organism's body. It captures how readily the digested protein can be
used in protein synthesis in the cells of the organism. Proteins are the major source of nitrogen
in food. BV assumes protein is the only source of nitrogen and measures
the amount of nitrogen ingested in relation to the amount which is
subsequently excreted. The remainder must have been incorporated into
the proteins of the organisms body. A ratio of nitrogen incorporated into the body over nitrogen absorbed gives a measure of protein "usability" – the BV.
Unlike some measures of protein usability, biological value does not take into account how readily the protein can be digested and absorbed (largely by the small intestine). This is reflected in the experimental methods used to determine BV.
BV uses two similar scales:
The true percentage utilization (usually shown with a percent symbol).
The percentage utilization relative to a readily utilizable protein source, often egg (usually shown as unitless).
The two values will be similar but not identical.
The BV of a food varies greatly, and depends on a wide variety of
factors. In particular the BV of a food varies depending on its
preparation and the recent diet of the organism. This makes reliable
determination of BV difficult and of limited use — fasting prior to
testing is universally required in order to ascertain reliable figures.
BV is commonly used in nutrition science in many mammalian organisms, and is a relevant measure in humans. It is a popular guideline in bodybuilding in protein choice.
Determination of BV
For accurate determination of BV:
the test organism must only consume the protein or mixture of proteins of interest (the test diet).
the test diet must contain no non-protein sources of nitrogen.
the test diet must be of suitable content and quantity to avoid use of the protein primarily as an energy source.
These conditions mean the tests are typically carried out over the
course of over one week with strict diet control. Fasting prior to
testing helps produce consistency between subjects (it removes recent
diet as a variable).
There are two scales on which BV is measured; percentage
utilization and relative utilization. By convention percentage BV has a
percent sign (%) suffix and relative BV has no unit.
Percentage utilization
Biological value is determined based on this formula.
BV = ( Nr / Na ) * 100
Where:
Na = nitrogen absorbed in proteins on the test diet
Nr = nitrogen incorporated into the body on the test diet
However direct measurement of Nr is essentially impossible. It will typically be measured indirectly from nitrogen excretion in urine. Faecal
excretion of nitrogen must also be taken into account - this part of
the ingested protein is not absorbed by the body and so not included in
the calculation of BV. An estimate is used of the amount of the urinary
and faecal nitrogen excretion not coming from ingested nitrogen. This
may be done by substituting a protein-free diet and observing nitrogen
excretion in urine or faeces, but the accuracy of this method of
estimation of the amount of nitrogen excretion not coming from ingested
nitrogen on a protein-containing diet has been questioned.
Ne(f) = (nitrogen excreted in faeces whilst on the test diet) - (nitrogen excreted in faeces not from ingested nitrogen)
Ne(u) = (nitrogen excreted in urine whilst on the test diet) - (nitrogen excreted in urine not from ingested nitrogen)
Note:
Nr = Ni - Ne(f) - Ne(u)
Na = Ni - Ne(f)
This can take any value from 0 to 100, though reported BV could be
out of this range if the estimates of nitrogen excretion from
non-ingested sources are inaccurate, such as could happen if the
endogenous secretion changes with protein intake. A BV of 100% indicates
complete utilization of a dietary protein, i.e. 100% of the protein
ingested and absorbed is incorporated into proteins into the body. The
value of 100% is an absolute maximum, no more than 100% of the protein
ingested can be utilized (in the equation above Ne(u) and Ne(f) cannot go negative, setting 100% as the maximum BV).
Relative utilization
Due to experimental limitations BV is often measured relative to an easily utilizable protein. Normally egg protein is assumed to be the most readily utilizable protein and given a BV of 100. For example:
Two tests of BV are carried out on the same person; one with the
test protein source and one with a reference protein (egg protein).
relative BV = ( BV(test) / BV(egg) ) * 100
Where:
BV(test) = percentage BV of the test diet for that individual
BV(egg) = percentage BV of the reference (egg) diet for that individual
This is not restricted to values of less than 100. The percentage BV
of egg protein is only 93.7% which allows other proteins with true
percentage BV between 93.7% and 100% to take a relative BV of over 100.
For example, whey protein takes a relative BV of 104, while its percentage BV is under 100%.
The principal advantage of measuring BV relative to another
protein diet is accuracy; it helps account for some of the metabolic
variability between individuals. In a simplistic sense the egg diet is
testing the maximum efficiency the individual can take up protein, the
BV is then provided as a percentage taking this as the maximum.
Conversion
Providing
it is known which protein measurements were made relative to it is
simple to convert from relative BV to percentage BV:
BV(reference) = percentage BV of reference protein (typically egg: 93.7%).
BV(percentage) = percentage BV of the test protein
While this conversion is simple it is not strictly valid due to the
differences between the experimental methods. It is, however, suitable
for use as a guideline.
Factors that affect BV
The
determination of BV is carefully designed to accurately measure some
aspects of protein usage whilst eliminating variation from other
aspects. When using the test (or considering BV values) care must be
taken to ensure the variable of interest is quantified by BV. Factors
which affect BV can be grouped into properties of the protein source and
properties of the species or individual consuming the protein.
Properties of the protein source
Three major properties of a protein source affect its BV:
Amino acid composition, and the limiting amino acid, which is usually lysine
Preparation (cooking)
Vitamin and mineral content
Amino acid composition is the principal effect. All proteins are made
up of combinations of the 21 biological amino acids. Some of these can
be synthesised or converted in the body, whereas others cannot and must
be ingested in the diet. These are known as essential amino acids
(EAAs), of which there are 9 in humans. The number of EAAs varies
according to species (see below).
EAAs missing from the diet prevent the synthesis of proteins that
require them. If a protein source is missing critical EAAs, then its
biological value will be low as the missing EAAs form a bottleneck in
protein synthesis. For example, if a hypothetical muscle protein
requires phenylalanine
(an essential amino acid), then this must be provided in the diet for
the muscle protein to be produced. If the current protein source in the
diet has no phenylalanine in it the muscle protein cannot be produced,
giving a low usability and BV of the protein source.
In a related way if amino acids are missing from the protein
source which are particularly slow or energy consuming to synthesise
this can result in a low BV.
Methods of food preparation also affect the availability of amino
acids in a food source. Some of food preparation may damage or destroy
some EAAs, reducing the BV of the protein source.
Many vitamins and minerals are vital for the correct function of
cells in the test organism. If critical minerals or vitamins are missing
from the protein source this can result in a massively lowered BV. Many
BV tests artificially add vitamins and minerals (for example in yeast extract) to prevent this.
Properties of the test species or individual
Under test conditions
Variations in BV under test conditions are dominated by the metabolism
of the individuals or species being tested. In particular differences
in the essential amino acids (EAAs) species to species has a significant
effect, although even minor variations in amino acid metabolism
individual to individual have a large effect.
The fine dependence on the individual's metabolism makes measurement of BV a vital tool in diagnosing some metabolic diseases.
In everyday life
The
principal effect on BV in everyday life is the organism's current diet,
although many other factors such as age, health, weight, sex, etc. all
have an effect. In short any condition which can affect the organism's
metabolism will vary the BV of a protein source.
In particular, whilst on a high protein diet the BV of all foods
consumed is reduced — the limiting rate at which the amino acids may be
incorporated into the body is not the availability of amino acids but
the rate of protein synthesis possible in cells. This is a major point
of criticism of BV as a test; the test diet is artificially protein rich
and may have unusual effects.
Factors with no effect
BV
is designed to ignore variation in digestibility of a food — which in
turn largely depends on the food preparation. For example, compare raw
soy beans and extracted soy bean protein. The raw soy beans, with tough cell walls
protecting the protein, have a far lower digestibility than the
purified, unprotected, soy bean protein extract. As a foodstuff far more
protein can be absorbed from the extract than the raw beans, however
the BV will be the same.
The exclusion of digestibility is a point of misunderstanding and leads to misrepresentation of the meaning of a high or low BV.
Advantages and disadvantages
BV
provides a good measure of the usability of proteins in a diet and also
plays a valuable role in detection of some metabolic diseases. BV is,
however, a scientific variable determined under very strict and
unnatural conditions. It is not a test designed to evaluate the
usability of proteins whilst an organism is in everyday life — indeed
the BV of a diet will vary greatly depending on age, weight, health,
sex, recent diet, current metabolism, etc. of the organism. In addition
BV of the same food varies significantly species to species. Given these
limitations BV is still relevant to everyday diet to some extent. No
matter the individual or their conditions a protein source with high BV,
such as egg, will always be more easily used than a protein source with
low BV.
In comparison to other methods known
There are many other major methods of determining how readily used a protein is, including:
These all hold specific advantages and disadvantages over BV, although in the past BV has been held in high regard.
In animals
The
Biological Value method is also used for analysis in animals such as
cattle, poultry, and various laboratory animals such as rats. It was
used by the poultry industry to determine which mixtures of feed were
utilized most efficiently by developing chicken.
Although the process remains the same, the biological values of
particular proteins in humans differs from their biological values in
animals due to physiological variations.
Typical values
Common foodstuffs and their values: (Note: this scale uses 100 as 100% of the nitrogen incorporated.)
Common foodstuffs and their values: (Note: These values use "whole egg" as a value of 100, so foodstuffs
that provide even more nitrogen than whole eggs, can have a value of
more than 100. 100, does not mean that 100% of the nitrogen in the food
is incorporated into the body, and not excreted, as in other charts.)
Whey protein concentrate: 104
Whole egg: 100
Cow milk: 91
Beef: 80
Casein: 77
Soy: 74
Wheat gluten: 64
By combining different foods it is possible to maximize the score, because the different components favor each other:
85 % rice and 15 % yeast: 118
55 % soy and 45 % rice: 111
55 % potatoes and 45 % soy: 103
52 % beans and 48 % corn: 101
Criticism
Since
the method measures only the amount that is retained in the body
critics have pointed out what they perceive as a weakness of the
biological value methodology. Critics have pointed to research that indicates that because whey
protein isolate is digested so quickly it may in fact enter the
bloodstream and be converted into carbohydrates through a process called
gluconeogenesis
much more rapidly than was previously thought possible, so while amino
acid concentrations increased with whey it was discovered that oxidation
rates also increased and a steady-state metabolism, a process where
there is no change in overall protein balance, is created. They claim that when the human body consumes whey protein it is absorbed so rapidly that most of it is sent to the liver for oxidation. Hence they believe the reason so much is retained is that it is used for energy production, not protein synthesis. This would bring into question whether the method defines which proteins are more biologically utilizable.
A further critique published in the Journal of Sports Science and Medicine
states that the BV of a protein does not take into consideration
several key factors that influence the digestion and interaction of
protein with other foods before absorption, and that it only measures a
protein's maximal potential quality and not its estimate at requirement
levels. Also, the study by Poullain et al., which is often cited to demonstrate
the superiority of whey protein hydrolysate by marketers, measured
nitrogen balance in rats after three days of starvation, which
corresponds to a longer period in humans. The study found that whey protein hydrolysate led to better nitrogen
retention and growth than the other proteins studied. However the
study's flaw is in the BV method used, as starvation affects how well
the body will store incoming protein (as does a very high caloric
intake), leading to falsely elevated BV measures.
So, the BV of a protein is related to the amount of protein
given. BV is measured at levels below the maintenance level. This means
that as protein intake goes up, the BV of that protein goes down. For
example, milk protein shows a BV near 100 at intakes of 0.2 g/kg. As
protein intake increases to roughly maintenance levels, 0.5 g/kg, BV
drops to around 70. Pellet et al., concluded that "biological measures of protein quality
conducted at suboptimal levels in either experimental animals or human
subjects may overestimate protein value at maintenance levels." As a
result, while BV may be important for rating proteins where intake is
below requirements, it has little bearing on individuals with protein
intakes far above requirements.
This flaw is supported by the FAO/WHO/UNU, who state that BV and
NPU are measured when the protein content of the diet is clearly below
that of requirement, deliberately done to maximize existing differences
in quality as inadequate energy intake lowers the efficiency of protein
utilization and in most N balance studies, calorie adequacy is ensured.
And because no population derives all of its protein exclusively from a
single food, the determination of BV of a single protein is of limited
use for application to human protein requirements.
Another limitation of the use of Biological Value as a measure of
protein quality is that proteins which are completely devoid of one essential amino acid
(EAA) can still have a BV of up to 40. This is because of the ability
of organisms to conserve and recycle EAAs as an adaptation of inadequate
intake of the amino acid.
Lastly, the use of rats for the determination of protein quality
is not ideal. Rats differ from humans in requirements of essential amino
acids. This has led to a general criticism that experiments on rats
lead to an over-estimation of the BV of high-quality proteins to man
because human requirements of essential amino acids are much lower than
those for rats (as rats grow at a much faster rate than humans). Also,
because of their fur, rats are assumed to have relatively high
requirements of sulphur-containing amino acids (methionine and
cysteine).
The causes of autism, including environmental and genetic factors, are a subject of scientific research, but understanding of the etiology of autism is incomplete. It is influenced by a complex interplay of genetic, epigenetic,
prenatal, perinatal, and environmental factors. Genetics play a major
role, with heritability estimates ranging from 60–90%. De novo mutations—including copy number variations
and gene-disrupting mutations—contribute to approximately 30–40% of
cases. However, most autism cases involve complex interactions among
multiple inherited genetic variants, many of which are still unknown.
Prenatal risk factors include advanced parental age, maternal metabolic or autoimmune disorders, infections, and prenatal stress, while perinatal risks involve preterm birth, low birth weight, and birth complications. Postnatal mechanisms have been proposed, including immune dysregulation, gastrointestinal abnormalities, oxidative stress, and neural circuit
differences, though these remain largely unproven and are the focus of
ongoing research. Some Neanderthal-derived genetic variants may
influence susceptibility. Current high-quality evidence shows no causal
link between prenatal use of paracetamol and autism.
Genetic factors may be the most significant cause of autism. Early studies of twins had estimated heritability to be over 90%, meaning that genetics explains over 90% of whether a child will develop autism. This may be an overestimation, as later twin studies estimate the heritability at between 60 and 90%. Evidence so far still suggests a strong genetic component, with one of
the largest and most recent studies estimating the heritability at 83%. Many of the non-autistic co-twins had learning or social disabilities.
For adult siblings the risk for having one or more features of the
broader autism phenotype might be as high as 30%.
In spite of the strong heritability, most cases of autism occur
sporadically with no recent evidence of family history. It has been
hypothesized that spontaneous de novo mutations in the sperm or egg contribute to the likelihood of developing autism. Additionally, mutations of the Fragile X Messenger Ribonucleoprotein 1 (FMR1) which cause fragile X syndrome,
the most common cause of intellectual disabilities such as autism, have
been linked to the early cessation of reproductive functions of female
carriers in the gene. This substantiates the notion that those with
autism are more likely to be infertile, weakening the heritability of
the disorder. Also, the likelihood of having a child develop autism generally
increases with advancing parental age, and mutations in sperm gradually
accumulate throughout a man's life.
The first genes to be definitively shown to contribute to risk
for autism were found in the early 1990s by researchers looking at
gender-specific forms of autism caused by mutations on the X chromosome.
An expansion of the CGG trinucleotide repeat in the promoter of the gene FMR1
in boys causes fragile X syndrome, and at least 20% of boys with this
mutation have behaviors consistent with autism spectrum disorder. Mutations that inactivate the gene MECP2 cause Rett syndrome, which is associated with autistic behaviors in girls, and in boys the mutation is embryonic lethal.
Besides these early examples, the role of de novo mutations in autism first became evident when DNA microarray technologies reached sufficient resolution to allow the detection of copy number variation (CNV) in the human genome. CNVs are the most common type of structural variation in the genome, consisting of deletions and duplications of DNA that range in size from a kilobase to a few megabases. Microarray analysis has shown that de novo
CNVs occur at a significantly higher rate in sporadic cases of autism
as compared to the rate in their typically developing siblings and
unrelated controls. A series of studies have shown that gene disrupting de novo CNVs occur approximately four times more frequently in autism than in controls and contribute to approximately 5–10% of cases. Based on these studies, there are predicted to be 130–234 autism-related CNV loci. The first whole genome sequencing study to comprehensively catalog de novostructural variation
at a much higher resolution than DNA microarray studies has shown that
the mutation rate is approximately 20% and not elevated in autism
compared to sibling controls. Structural variants in individuals with autism are much larger and four
times more likely to disrupt genes, mirroring findings from CNV
studies.
CNV studies were closely followed by exome sequencing studies, which sequence the 1–2% of the genome that codes for proteins (the "exome"). These studies found that de novo
gene inactivating mutations were observed in approximately 20% of
individuals with autism, compared to 10% of unaffected siblings,
suggesting the etiology of autism is driven by these mutations in around
10% of cases.There are predicted to be 350-450 genes that significantly increase susceptibility to autism when impacted by inactivating de novo mutations. A further 12% of cases are predicted to be caused by protein altering missense mutations that change an amino acid but do not inactivate a gene. Therefore, approximately 30% of individuals with autism have a spontaneous de novo
large CNV that deletes or duplicates genes, or mutation that changes
the amino acid code of an individual gene. A further 5–10% of cases have
inherited structural variation at loci known to be associated with autism, and these known structural variants may arise de novo in the parents of affected children.
Tens of genes and CNVs have been definitively identified based on
the observation of recurrent mutations in different individuals, and
suggestive evidence has been found for over 100 others. The Simons Foundation Autism Research Initiative (SFARI) details the evidence for each genetic locus associated with autism.
These early gene and CNV findings have shown that the cognitive
and behavioral features associated with each of the underlying mutations
is variable. Each mutation is itself associated with a variety of
clinical diagnoses, and can also be found in a small percentage of
individuals with no clinical diagnosis. Thus the genetic disorders that comprise autism are not
autism-specific. The mutations themselves are characterized by
considerable variability in clinical outcome and typically only a subset
of mutation carriers meet criteria for autism. This variable expressivity
results in different individuals with the same mutation varying
considerably in the severity of their observed particular trait.
The conclusion of these recent studies of de novo mutation is that the spectrum of autism is breaking up into quanta of individual disorders defined by genetics.
One gene that has been linked to autism is SHANK2. Mutations in this gene act in a dominant fashion and appear to cause hyperconnectivity between the neurons.
A study conducted on 42,607 autism cases has identified 60 new
genes, five of which had a more moderate impact on autistic symptoms.
The related gene variants were often inherited from the participant's
parents.
Epigenetic
mechanisms may increase the risk of autism. Epigenetic changes occur as
a result not of DNA sequence changes but of chromosomal histone
modification or modification of the DNA bases. Such modifications are
known to be affected by environmental factors, including nutrition,
drugs, and mental stress. Interest has been expressed in imprinted regions on chromosomes 15q and 7q.
Most data supports a polygenic, epistatic
model, meaning that the disorder is caused by two or more genes and
that those genes are interacting in a complex manner. Several genes,
between two and fifteen in number, have been identified and could
potentially contribute to disease susceptibility. An exact determination of the cause of ASD has yet to be discovered and
there probably is not one single genetic cause of any particular set of
disorders, leading many researchers to believe that epigenetic
mechanisms, such as genomic imprinting or epimutations, may play a major
role.
Epigenetic mechanisms can contribute to disease phenotypes. Epigenetic modifications include DNA cytosine methylation and post-translational modifications to histones.
These mechanisms contribute to regulating gene expression without
changing the sequence of the DNA and may be influenced by exposure to
environmental factors and may be heritable from parents. Rett syndrome and fragile X syndrome
(FXS) are single gene disorders related to autism with overlapping
symptoms that include deficient neurological development, impaired
language and communication, difficulties in social interactions, and
stereotyped hand gestures. It is not uncommon for a patient to be
diagnosed with both autism and Rett syndrome or FXS. Epigenetic
regulatory mechanisms play the central role in pathogenesis of these two
disorders.
Genomic imprinting
may also contribute to the development of autism. Genomic imprinting is
another example of epigenetic regulation of gene expression. In this
instance, the epigenetic modification(s) causes the offspring to express
the maternal copy of a gene or the paternal copy of a gene, but not
both. The imprinted gene is silenced through epigenetic mechanisms.
Candidate genes and susceptibility alleles for autism are identified
using a combination of techniques, including genome-wide and targeted
analyses of allele sharing in sib-pairs, using association studies and
transmission disequilibrium testing (TDT) of functional or positional
candidate genes and examination of novel and recurrent cytogenetic
aberrations. Results from numerous studies have identified several
genomic regions known to be subject to imprinting, candidate genes, and
gene-environment interactions. Particularly, chromosomes 15q and 7q
appear to be epigenetic hotspots in contributing to autism. Also, genes
on the X chromosome may play an important role, as in Rett syndrome.
An important basis for autism causation is also the over- or underproduction of brain permanent cells (neurons, oligodendrocytes, and astrocytes) by the neural precursor cells during fetal development.
Prenatal environment
The development of autism is associated with several prenatal
risk factors, including advanced age in either parent, diabetes,
bleeding, and maternal use of antibiotics and psychiatric drugs during
pregnancy. Autism has been linked to birth defect agents acting during the first eight weeks from conception, though these cases are rare. If the mother of the child is dealing with autoimmune conditions or
disorders while pregnant, it may have an effect on the child's
development of autism. All of these factors can cause inflammation or impair immune signaling in one way or another.
Obstructive sleep apnea in pregnancy
Sleep apnea can result in intermittent hypoxia and has been increasing in prevalence due in part to the obesity
epidemic. The known maternal risk factors for autism diagnosis in her
offspring are similar to the risk factors for sleep apnea. For example,
advanced maternal age, maternal obesity, maternal type 2 diabetes and maternal hypertension all increase the risk of autism in her offspring. Likewise, these are all known risk factors for sleep apnea.
One study found that gestational sleep apnea was associated with
low reading test scores in children and that this effect may be mediated
by an increased risk of the child having sleep apnea themselves. Another study reported low social development scores in 64% of infants
born to mothers with sleep apnea compared to 25% of infants born to
controls, suggesting sleep apnea in pregnancy may have an effect on
offspring neurodevelopment. There was also an increase in the amount of snoring the mothers with
sleep apnea reported in their infants when compared to controls. Children with sleep apnea have "hyperactivity, attention problems,
aggressivity, lower social competency, poorer communication, and/or
diminished adaptive skills". One study found significant improvements in ADHD-like symptoms,
aggression, social problems and thought problems in autistic children
who underwent adenotonsillectomy for sleep apnea. Sleep problems in autism have been linked in a study to brain changes,
particularly in the hippocampus, though this study does not prove
causation. A common presentation of sleep apnea in children with autism is insomnia. All known genetic syndromes which are linked to autism have a high
prevalence of sleep apnea. The prevalence of sleep apnea in Down's
Syndrome is 50% - 100%. Sleep problems and OSA in this population have been linked to language development. Since autism manifests in the early developmental period, sleep apnea
in Down's Syndrome and other genetic syndromes such as Fragile X start
early (at infancy or shortly after), and sleep disturbances alter brain
development, it's plausible that some of the neurodevelopmental differences seen in
these genetic syndromes are at least partially caused by the effects of
untreated sleep apnea.
Infectious hypotheses
One hypothesis suggests that prenatal viral infection may contribute to the development of autism. Prenatal exposure to rubella or cytomegalovirus activates the mother's immune response and may greatly increase the risk for autism in mice. Congenital rubella syndrome is the most convincing environmental cause of autism. Infection-associated immunological events in early pregnancy may affect
neural development more than infections in late pregnancy, not only for
autism, but also for psychiatric disorders of presumed
neurodevelopmental origin, notably schizophrenia.
A 2021 meta-analysis of 36 studies suggested a relationship
between mothers recalling an infection during pregnancy and having
children with autism.
Environmental agents
Teratogens are environmental agents that cause birth defects.
Some agents that are theorized to cause birth defects have also been
suggested as potential autism risk factors, although there is little to
no scientific evidence to back such claims. These include exposure of
the embryo to valproic acid, thalidomide or misoprostol. These cases are rare. Questions have also been raised whether ethanol (grain alcohol) increases autism risk, as part of fetal alcohol syndrome or alcohol-related birth defects. All known teratogens appear to act during the first eight weeks from
conception, and though this does not exclude the possibility that autism
can be initiated or affected later, it is strong evidence that autism
arises very early in development.
Autoimmune and inflammatory diseases
Maternal inflammatory and autoimmune diseases can damage embryonic and fetal tissues, aggravating a genetic problem or damaging the nervous system.
Other maternal conditions
Thyroid problems that lead to thyroxine
deficiency in the mother in weeks 8–12 of pregnancy have been
postulated to produce changes in the fetal brain leading to autism.
Thyroxine deficiencies can be caused by inadequate iodine in the diet, and by environmental agents that interfere with iodine uptake or act against thyroid hormones. Possible environmental agents include flavonoids in food, tobacco smoke, and most herbicides. This hypothesis has not been tested.
Diabetes during pregnancy is a significant risk factor for autism. Gestational diabetes doubles the risk that the baby will have autism. The mechanism by which this happens is unknown.
Maternal diagnoses of polycystic ovary syndrome was found to associated with higher risk of autism.
Maternal obesity during pregnancy may also increase the risk of autism, although further study is needed.
Maternal malnutrition during preconception and pregnancy influences fetal neurodevelopment. Intrauterine growth restriction is associated with autism, in both term and preterm infants.
Other in utero
It has been hypothesized that folic acid taken during pregnancy could play a role in reducing cases of autism by modulating gene expression through an epigenetic mechanism. This hypothesis is supported by multiple studies.
Prenatal stress,
consisting of exposure to life events or environmental factors that
distress an expectant mother, has been hypothesized to contribute to
autism, possibly as part of a gene-environment interaction. Autism has
been reported to be associated with prenatal stress both with
retrospective studies that examined stressors such as job loss and
family discord, and with natural experiments involving prenatal exposure
to storms; animal studies have reported that prenatal stress can
disrupt brain development and produce behaviors resembling symptoms of
autism. Other studies cast doubt on this association, notably population based
studies in England and Sweden finding no link between stressful life
events and autism.
The fetal testosterone theory hypothesizes that higher levels of testosterone in the amniotic fluid
of mothers pushes brain development towards improved ability to see
patterns and analyze complex systems while diminishing communication and
empathy, emphasizing "male" traits over "female", or in E-S theory
terminology, emphasizing "systemizing" over "empathizing". One project
has published several reports suggesting that high levels of fetal
testosterone could produce behaviors relevant to those seen in autism.
Based in part on animal studies, diagnostic ultrasounds
administered during pregnancy have been hypothesized to increase the
child's risk of autism. This hypothesis is not supported by
independently published research, and examination of children whose
mothers received an ultrasound has failed to find evidence of harmful
effects.
Some research suggests that maternal exposure to selective serotonin reuptake inhibitors
during pregnancy is associated with an increased risk of autism, but it
remains unclear whether there is a causal link between the two. There is evidence, for example, that this association may be an artifact of confounding by maternal mental illness.
On 24 September 2025, the World Health Organization stated there is no conclusive scientific evidence linking paracetamol (acetaminophen) use during pregnancy to autism.
Very large population-based studies indicate that prenatal
paracetamol use is not linked to autism, ADHD, or intellectual
disability, and studies comparing siblings suggest that earlier reported
links were likely due to other factors, not paracetemol itself.
Perinatal environment
Autism is associated with some perinatal and obstetric
conditions. Infants that are born pre-term often have various
neurodevelopmental impairments related to motor skills, cognition,
receptive and expressive language, and socio-emotional capabilities. Pre-term infants are also at a higher risk of having various
neurodevelopmental disorders such as cerebral palsy and autism, as well
as psychiatric disorders related to attention, anxiety, and impaired
social communication. It has also been proposed that the functions of the
hypothalamic-pituitary-adrenal axis and brain connectivity in pre-term
infants may be affected by NICU-related stress resulting in deficits in
emotional regulation and socio-emotional capabilities. A 2019 analysis of perinatal and neonatal risk factors found that autism was associated with abnormal fetal positioning, umbilical cord complications, low 5-minute Apgar score, low birth weight and gestation duration, fetal distress, meconium aspiration syndrome,
trauma or injury during birth, maternal hemorrhaging, multiple birth,
feeding disorders, neonatal anemia, birth defects/malformation,
incompatibility with maternal blood type, and jaundice/hyperbilirubinemia. These associations do not denote a causal relationship for any individual factor. There is growing evidence that perinatal exposure to air pollution
may be a risk factor for autism, although this evidence has
methodological limitations, including a small number of studies and
failure to control for potential confounding factors. One published paper concluded more study is needed of the association between autism and the use of paracetamol (acetaminophen) in infants and young children. This association does not necessarily demonstrate a causal relationship.
Postnatal environment
A wide variety of postnatal contributors to autism have been
proposed, including gastrointestinal or immune system abnormalities,
allergies, and exposure of children to drugs, infection, certain foods,
or heavy metals. The evidence for these risk factors is anecdotal and
has not been confirmed by reliable studies.
Amygdala neurons
This theory hypothesizes that an early developmental failure involving the amygdala cascades on the development of cortical areas that mediate social perception in the visual domain. The fusiform face area of the ventral stream
is implicated. The idea is that it is involved in social knowledge and
social cognition, and that the deficits in this network are instrumental
in causing autism.
Autoimmune disease
This theory hypothesizes that autoantibodies that target the brain or
elements of brain metabolism may cause or exacerbate autism. It is
related to the maternal infection
theory, except that it postulates that the effect is caused by the
individual's own antibodies, possibly due to an environmental trigger
after birth. It is also related to several other hypothesized causes;
for example, viral infection has been hypothesized to cause autism via an autoimmune mechanism.
Interactions between the immune system and the nervous system begin early during embryogenesis,
and successful neurodevelopment depends on a balanced immune response.
It is possible that aberrant immune activity during critical periods of
neurodevelopment is part of the mechanism of some forms of autism. A small percentage of autism cases are associated with infection,
usually before birth. Results from immune studies have been
contradictory. Some abnormalities have been found in specific subgroups,
and some of these have been replicated. It is not known whether these
abnormalities are relevant to the pathology of autism, for example, by
infection or autoimmunity, or whether they are secondary to the disease
processes. As autoantibodies are found in diseases other than autism, and are not always present in autism, the relationship between immune disturbances and autism remains unclear and controversial.[104]
A 2015 systematic review and meta-analysis found that children with a
family history of autoimmune diseases were at a greater risk of autism
compared to children without such a history.
When an underlying maternal autoimmune disease is present,
antibodies circulating to the fetus could contribute to the development
of autism spectrum disorders.
A 2016 review concludes that enteric nervous system
abnormalities might play a role in several neurological disorders,
including autism. Neural connections and the immune system are a pathway
that may allow diseases originated in the intestine to spread to the
brain. A 2018 review suggests that the frequent association of gastrointestinal disorders and autism is due to abnormalities of the gut–brain axis.
The "leaky gut syndrome" hypothesis developed by Andrew Wakefield, known for his fraudulent study on another cause of autism, is popular among parents of children with autism. It is based on the idea that defects in the intestinal barrier produce an excessive increase in intestinal permeability, allowing substances present in the intestine (including bacteria, environmental toxins, and food antigens)
to pass into the blood. The data supporting this theory are limited and
contradictory, since both increased intestinal permeability and normal
permeability have been documented in people with autism. Studies with
mice provide some support to this theory and suggest the importance of intestinal flora,
demonstrating that the normalization of the intestinal barrier was
associated with an improvement in some of the autism-like behaviors. Studies on subgroups of people with autism showed the presence of high plasma levels of zonulin, a protein that regulates permeability opening the "pores" of the intestinal wall, as well as intestinal dysbiosis (reduced levels of Bifidobacteria and increased abundance of Akkermansia muciniphila, Escherichia coli, Clostridia and Candida fungi that promote the production of proinflammatory cytokines, all of which produces excessive intestinal permeability. This allows passage of bacterial endotoxins from the gut into the bloodstream, stimulating liver cells to secrete tumor necrosis factor alpha (TNFα), which modulates blood–brain barrier
permeability. Studies on ASD people showed that TNFα cascades produce
proinflammatory cytokines, leading to peripheral inflammation and
activation of microglia in the brain, which indicates neuroinflammation. In addition, neuroactive opioid peptides
from digested foods have been shown to leak into the bloodstream and
permeate the blood–brain barrier, influencing neural cells and causing
autistic symptoms. (See Endogenous opiate precursor theory)
After a preliminary 1998 study of three children with autism treated with secretin
infusion reported improved GI function and dramatic improvement in
behavior, many parents sought secretin treatment and a black market for
the hormone developed quickly. Later studies found secretin clearly ineffective in treating autism.
In 1979, a possible association between autism and opioids
was proposed, it was noted that injecting small amounts of opiates into
young laboratory animals resulted in symptoms similar to those seen in
autistic children. The possibility of a relationship between autism and the consumption of gluten and casein was first articulated by Kalle Reichelt in 1991.
Opiate theory hypothesizes that autism is the result of a metabolic disorder in which opioid peptides gliadorphin (aka gluteomorphin) and Casomorphin,
produced through metabolism of gluten (present in wheat and related
cereals) and casein (present in dairy products), pass through an
abnormally permeable intestinal wall and then proceed to exert an effect
on neurotransmission through binding with opioid receptors. It has been
postulated that the resulting excess of opioids affects brain
maturation and causes autistic symptoms including: behavioral difficulties, attention problems, and alterations in communicative capacity and social and cognitive functioning.
Although high levels of these opioids are eliminated in the
urine, it has been suggested that a small part of them cross into the
brain causing interference of signal transmission and disruption of
normal activity. Three studies have reported that urine samples of
people with autism show an increased 24-hour peptide excretion. A study with a control group found no appreciable differences in opioid
levels in urine samples of people with autism compared to controls. Two studies showed an increased opioid levels in cerebrospinal fluid of people with autism.
The theory further states that removing opiate precursors from a
child's diet may allow time for these behaviors to cease, and
neurological development in very young children to resume normally. As of 2021, reliable studies have not demonstrated the benefit of gluten-free diets in the treatment of autism. In the subset of people who have gluten sensitivity there is limited evidence that suggests that a gluten-free diet may improve some autistic behaviors.
Nutrition-related factors
There have been multiple attempts to uncover a link between various
nutritional deficiencies such as vitamin D and folate and autism risk. Although there have been many studies on the role of vitamin D in the
development of autism, the majority of them are limited by their
inability to assess the deficiency prior to an autism diagnosis. A meta-analysis on the association between vitamin D and autism found
that individuals with autism had significantly low levels of serum
25-hydroxy vitamin D than those without autism. Another analysis showed significant differences in levels of zinc
between individuals with and without autism. Although studies showed
significant differences protein intake and calcium in individuals with
autism, the results were limited by their imprecision, inconsistency,
and indirect nature. Additionally, low levels of 5-methyltetrahydrofolate (5-MTHF) in the brain can result in cerebral folate deficiency (CFD) which has been shown to be associated with autism.
Toxic exposure
Multiple studies have attempted to study the relationship between
toxic exposure and autism, despite limitations related to the
measurement of toxic exposure the methods for which were often indirect
and cross-sectional. Systematic reviews have been conducted for numerous
toxins including air pollution, thimerosal, inorganic mercury, and
levels of heavy metals in hair, nails, and bodily fluids.
Environmental exposure to inorganic mercury may be associated
with higher autism risk, with high levels of mercury in the body being a
valid disease-causing agent for autism.
Significant evidence has not been found of an association between
autism and the concentration of copper, cadmium, selenium, and chromium
in the hair, nails, and bodily fluids. Levels of lead were found to be significantly higher in individuals with autism. The precision and consistency of results were not maintained across studies and were influenced by an outlier study. The atypical eating behaviors of autistic children, along with habitual mouthing and pica, make it hard to determine whether increased lead levels are a cause or a consequence of autism.
Locus coeruleus–noradrenergic system
This theory hypothesizes that autistic behaviors depend at least in
part on a developmental dysregulation that results in impaired function
of the locus coeruleus–noradrenergic
(LC-NA) system. The LC-NA system is heavily involved in arousal and
attention; for example, it is related to the brain's acquisition and use
of environmental cues.
Oxidative stress
Oxidative stress, oxidative DNA damage and disruptions of DNA repair have been postulated to play a role in the etiopathology of both ASD and schizophrenia. Physiological factors and mechanisms influence by oxidative stress are
believed to be highly influential to autism risk. Interactions between
environmental and genetic factors may increase oxidative stress in
children with autism. This theory hypothesizes that toxicity and oxidative stress
may cause autism in some cases. Evidence includes genetic effects on
metabolic pathways, reduced antioxidant capacity, enzyme changes, and
enhanced biomarkers for oxidative stress. One theory is that stress damages Purkinje cells in the cerebellum after birth, and it is possible that glutathione is involved. Polymorphism of genes involved metabolization of glutathione is
evidenced by lower levels of total glutathione, and higher levels of
oxidized glutathione in autistic children. Based on this theory, antioxidants may be a useful treatment for autism. Environmental factors can influence oxidative stress pre, peri, and
postnatally and include heavy metals, infection, certain drugs, and
toxic exposure from various sources including cigarette smoke, air
pollutants, and organophosphate pesticides.
Social construct
Beyond the genetic, epigenetic, and biological factors that can
contribute to an autism diagnosis are theories related to the "autistic
identity". It has been theorized that perceptions towards the characteristics of
autistic individuals have been heavily influenced by neurotypical
ideologies and social norms.
The social construct
theory says that the boundary between normal and abnormal is subjective
and arbitrary, so autism does not exist as an objective entity, but
only as a social construct. It further argues that autistic individuals
themselves have a way of being that is partly socially constructed.
Mild and moderate variations of autism are particular targets of
the theory that social factors determine what it means to be autistic.
The theory hypothesizes that individuals with these diagnoses inhabit
the identities that have been ascribed to them, and promote their sense
of well-being by resisting or appropriating autistic ascriptions.
Lynn Waterhouse suggests that autism has been reified, in that
social processes have endowed it with more reality than is justified by
the scientific evidence.
Although social construction of the autistic identity can have a
positive impact on the well-being and treatment of autistic individuals,
that is not always the case when the individuals in question belong to
historically marginalized populations.
Viral infection
Many studies have presented evidence for and against association of
autism with viral infection after birth. Laboratory rats infected with Borna disease virus
show some symptoms similar to those of autism but blood studies of
autistic children show no evidence of infection by this virus. Members
of the herpes virus family
may have a role in autism, but the evidence so far is anecdotal.
Viruses have long been suspected as triggers for immune-mediated
diseases such as multiple sclerosis
but showing a direct role for viral causation is difficult in those
diseases, and mechanisms, whereby viral infections could lead to autism,
are speculative.
Reconstruction of the upper Palaeolithic human Oase 2 with around 7.3% Neanderthal DNA (from an ancestor 4–6 generations back)
One theory on the evolutionary and biological origins of autism traits in Homo sapiens
that has gained recent attention in the 2010s and 2020s is that some
genes linked to autism may have originated from early humans
crossbreeding with Neanderthals, an extinct group of archaic humans (generally regarded as a distinct species, Homo neanderthalensis, though some regard it as a subspecies of Homo sapiens, referred to as H. sapiens neanderthalensis) who lived in Eurasia until about 40,000 years ago.
A possible link between autism spectrum disorders (ASDs) and Neanderthal DNA was identified in 2009, pending genome sequencing.
The first Neanderthal genome sequence was published in 2010, and
strongly indicated interbreeding between Neanderthals and early modern
humans. The genomes of all studied modern populations contain Neanderthal DNA. Various estimates exist for the proportion, such as 1–4% or 3.4–7.9% in modern Eurasians, or 1.8–2.4% in modern Europeans and 2.3–2.6% in modern East Asians. Pre-agricultural Europeans appear to have had similar, or slightly higher, percentages to modern East Asians, and the numbers may have decreased
in the former due to dilution with a group of people which had split off
before Neanderthal introgression.
Typically, studies have reported finding no significant levels of
Neanderthal DNA in Sub-Saharan Africans, but a 2020 study detected
0.3-0.5% in the genomes of five African sample populations, likely the
result of Eurasians back-migrating and interbreeding with Africans, as
well as human-to-Neanderthal gene flow from dispersals of Homo sapiens preceding the larger Out-of-Africa migration, and also showed more equal Neanderthal DNA percentages for European and Asian populations. Such low percentages of Neanderthal DNA in all present day populations indicate infrequent past interbreeding, unless interbreeding was more common with a different population of
modern humans which did not contribute to the present day gene pool. Of the inherited Neanderthal genome, 25% in modern Europeans and 32% in modern East Asians may be related to viral immunity. In all, approximately 20% of the Neanderthal genome appears to have survived in the modern human gene pool.
Due to their small population and resulting reduced effectivity
of natural selection, Neanderthals accumulated several weakly harmful
mutations, which were introduced to and slowly selected out of the much
larger modern human population; the initial hybridised population may
have experienced up to a 94% reduction in fitness compared to
contemporary humans. By this measure, Neanderthals may have
substantially increased in fitness. A 2017 study focusing on archaic genes in Turkey found associations with coeliac disease, malaria severity and Costello syndrome.
Nonetheless, some genes may have helped modern East Asians adapt
to the environment; the putatively Neanderthal Val92Met variant of the
MC1R gene, which may be weakly associated with red hair and UV radiation
sensitivity, is primarily found in East Asian, rather than European, individuals. Some genes related to the immune system appear to have been affected by introgression, which may have aided migration, such as OAS1, STAT2, TLR6, TLR1, TLR10, and several related to immune response. In addition, Neanderthal genes have also been implicated in the structure and function of the brain, keratin filaments, sugar metabolism, muscle contraction, body fat distribution, enamel thickness and oocytemeiosis. Nonetheless, a large portion of surviving introgression appears to be non-coding ("junk") DNA with few biological functions.
A 2016 study indicated that human-Neanderthal gene variance may be involved in autism, with chromosome 16 section 16p11.2 deletions playing a large role.
A 2017 study reported finding that the more Neanderthal DNA a
person has in their genome, the more closely the brain of the individual
would resemble that of a Neanderthal. The study also found that parts
of the Neanderthal brain related to tool use and visual discrimination
may have also experienced evolutionary or adaptational "trade-offs" with
the "social brain", as also found in scientific studies on autism. A 2023 study also found evidence that Neanderthal single nucleotide polymorphisms (SNPs) likely play a "significant role" in autism susceptibility and heritability in autism populations across the United States.
According to the study, "Although most studies on autism genomics focus
on the deleterious nature of variants, there is the possibility some of
these autism-associated Neanderthal SNPs have been under weak positive selection. In support, recent studies have identified genetic variants implicated in both autism and high intelligence. Meanwhile, autistic people often perform better on tests of fluid intelligence than neurotypicals."
Another 2017 study that analyzed 68 genes associated with neurodevelopmental disorders, including autism, found that these disorders were also affected by natural selection and interbreeding between Homo sapiens and other archaic human species. The study also recommended further research into the link between Neanderthal single nucleotide polymorphisms (SNPs) and neurodevelopmental disorders, including autism, in modern-day humans.
A 2021 study confirmed these findings, noting that "the protective allele of rs7170637(A) CYFIP1, [one of the genes associated with autism spectrum disorder
(ASD)], was present in primates to Neanderthals, and reemerged in
modern humans, while absent in early modern humans"; "identified
significant positive selection signals in 18 ASD risk SNPs"; that
"ancient genome analysis identified de novo mutations...representing genes involved in cognitive function...and conserved evolutionary selection clusters"; and that "relative enrichment of the ASD risk SNPs from the respective evolutionary cluster or biological interaction networks may help in addressing the phenotypic diversity in ASD", with "cognitive genomic tradeoff signatures impacting the biological networks [explaining] the paradoxical phenotypes in ASD".
Psychologist Bruno Bettelheim
believed that autism was linked to early childhood trauma, and his work
was highly influential for decades both in the medical and popular
spheres. In his discredited theory, he blamed the mothers of individuals
with autism for having caused their child's condition through the
withholding of affection. Leo Kanner, who first described autism, suggested that parental coldness might contribute to autism. Although Kanner eventually renounced the theory, Bettelheim put an
almost exclusive emphasis on it in both his medical and his popular
books. Treatments based on these theories failed to help children with
autism, and after Bettelheim's death, his reported rates of cure (around
85%) were found to be fraudulent.
Vaccines
The most recent scientific research has determined that changes to
brain structures correlated with the development of autism can already
be detected while the child is still in the womb, well before any
vaccines are administered. Furthermore, scientific studies have consistently refuted a causal relationship between vaccinations and autism.
Despite this, some parents believe that vaccinations cause
autism; they therefore delay or avoid immunizing their children (for
example, under the "vaccine overload" hypothesis that giving many vaccines at once may overwhelm a child's immune system and lead to autism, even though this hypothesis has no scientific evidence and is biologically implausible).
Diseases such as measles can cause severe disabilities and even death,
so the risk of death or disability for an unvaccinated child is higher
than the risk for a child who has been vaccinated. Despite medical evidence, antivaccine
activism continues. A developing tactic is the "promotion of irrelevant
research to justify the science underlying a questionable claim."
The MMR vaccine as a cause of autism is one of the most extensively debated hypotheses regarding the origins of autism. Andrew Wakefieldet al. reported a study of 12 children who had autism and bowel symptoms, in some cases reportedly with onset after MMR. Although the paper, which was later retracted by the journal,
concluded that there was no association between the MMR vaccine and
autism, Wakefield nevertheless suggested a false notion during a 1998
press conference that giving children the vaccines in three separate
doses would be safer than a single dose. Administering the vaccines in three separate doses does not reduce the
chance of adverse effects, and it increases the opportunity for
infection by the two diseases not immunized against first.
In February 2010, The Lancet, which published Wakefield's study, fully retracted it after an independent auditor found the study to be flawed. In January 2011, an investigation published in the journal BMJ described the Wakefield study as the result of deliberate fraud and manipulation of data.
Perhaps the best-known hypothesis involving mercury and autism involves the use of the mercury-based compound thiomersal, a preservative that has been phased out from most childhood vaccinations in developed countries including the US and EU. There is no scientific evidence for a connection between thiomersal and
autism, but parental concern about a relationship between thiomersal and vaccines led to decreasing rates of childhood immunizations and increasing likelihood of disease outbreaks in the 1990s. In 1999, the U.S. Public Health Service recommended that thiomersal be removed from childhood vaccines. By 2002, the flu vaccine
was the only childhood vaccine using thiomersal. The removal of
thiomersal did not decrease autism rates in any country that removed
thiomersal from their childhood vaccines.
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