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Developmental Immunotoxicity, Perinatal Programming, and Noncommunicable Diseases: Focus on Human Studies

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Developmental immunotoxicity (DIT) is a term given to encompass the environmentally induced disruption of normal immune development resulting in adverse outcomes. A myriad of chemical, physical, and psychological factors can all contribute to DIT. As a core component of the developmental origins of adult disease, DIT is interlinked with three important concepts surrounding health risks across a lifetime: (1) the Barker Hypothesis, which connects prenatal development to later-life diseases, (2) the hygiene hypothesis, which connects newborns and infants to risk of later-life diseases and, (3) fetal programming and epigenetic alterations, which may exert effects both in later life and across future generations. This review of DIT considers: (1) the history and context of DIT research, (2) the fundamental features of DIT, (3) the emerging role of DIT in risk of noncommunicable diseases (NCDs) and (4) the range of risk factors that have been investigated through human research. The emphasis on the human DIT-related literature is significant since most prior reviews of DIT have largely focused on animal research and considerations of specific categories of risk factors (e.g., heavy metals). Risk factors considered in this review include air pollution, aluminum, antibiotics, arsenic, bisphenol A, ethanol, lead (Pb), maternal smoking and environmental tobacco smoke, paracetamol (acetaminophen), pesticides, polychlorinated biphenyls, and polyfluorinated compounds.
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Review Article
Developmental Immunotoxicity, Perinatal Programming, and
Noncommunicable Diseases: Focus on Human Studies
Rodney R. Dietert
Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, North Tower Road,
Ithaca, NY 14853, USA
Correspondence should be addressed to Rodney R. Dietert; rrd@cornell.edu
Received  August ; Revised  October ; Accepted  October ; Published  January 
Academic Editor: Gernot Zissel
Copyright ©  Rodney R. Dietert. is is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Developmental immunotoxicity (DIT) is a term given to encompass the environmentally induced disruption of normal immune
development resulting in adverse outcomes. A myriad of chemical, physical, and psychological factors can all contribute to DIT.
As a core component of the developmental origins of adult disease, DIT is interlinked with three important concepts surrounding
health risks across a lifetime: () the Barker Hypothesis, which connects prenatal development to later-life diseases, () the hygiene
hypothesis, which connects newborns and infants to risk of later-life diseases and, () fetal programming and epigenetic alterations,
which may exert eects both in later life and across future generations. is review of DIT considers: () the history and context of
DIT research, () the fundamental features of DIT, () the emerging role of DIT in risk of noncommunicable diseases (NCDs) and
() the range of risk factors that have been investigated through human research. e emphasis on the human DIT-related literature
is signicant since most prior reviews of DIT have largely focused on animal research and considerations of specic categories of risk
factors (e.g., heavy metals). Risk factors considered in this review include air pollution, aluminum, antibiotics, arsenic, bisphenol A,
ethanol, lead (Pb), maternal smoking and environmental tobacco smoke, paracetamol (acetaminophen), pesticides, polychlorinated
biphenyls, and polyuorinated compounds.
1. Introduction
Early-life environmental insults aecting the developing
immune system can have signicant health ramications not
only for the exposed ospring but also potentially extending
to additional generations. Developmental immunotoxicity
(DIT) appears to play a signicant role in the current global
epidemic of non-communicable diseases (NCDs) [,]. is
review of DIT begins with the history of DIT placed in the
context of the area of immunology known as immunotoxicol-
ogy and charts the emergence of recent concepts concerning
early developmental programming as it impacts later-life
health.ItalsodescribesthecurrentstateofthescienceforDIT
and the likely applications of DIT assessment as it may
impact both human health and environmental protection. In
particular, the paper discusses () the history of DIT research,
() the role of critical windows of vulnerability for the
developing immune system, () frequent outcomes of DIT,
() consideration of the microbiome in DIT, () the role of
prenatal epigenetic alterations in immunotoxicity, and () the
connection between DIT, elevated risk of comorbid chronic
diseases, and current epidemic of NCDs.
2. History of DIT Research
2.1. Emergence within Immunotoxicology. Immunotoxicol-
ogy, the study of the adverse impact of environmental con-
ditions (e.g., exposure to food, drugs, chemicals, microbial
agents, and physical and psychosocial factors) on the immune
system, began to gain recognition during the s and early
s [] with the initial focus on use of surrogates for host
resistance in animal models [,] and concern about envi-
ronmentally induced immunosuppression []. e search
for assays and parameters that were predictive of chemical-
or drug-induced immunotoxicity centered on measures that
could replace then cumbersome and costly host challenges
with infectious agents or transplantable cancer cells. Not sur-
prisingly loss of immune protection (i.e., immunosuppres-
sion) and increased susceptibility to infections and/or cancer
were a driving concern. is also coincided with the era in
Hindawi Publishing Corporation
Advances in Medicine
Volume 2014, Article ID 867805, 18 pages
http://dx.doi.org/10.1155/2014/867805
Advances in Medicine
which the HIV-induced immunosuppression associated with
AIDS was an increasing human health challenge [,]. A
coordinated eort to identify the best predictor of immuno-
toxicity resulted in the development of the tier system of
assays providing a strategy of immunotoxicity testing []and
the concept that a limited combination of immune measures
could be eective for identifying immunotoxic chemicals [,
]. In addition to the identication of chemicals that could
produce immunosuppression in humans [], the detection
ofchemicalswithsensitizingpotentialwasanearlysystematic
concern within immunotoxicology [,].
e examination of adverse insults to the developing
immune system, a subsection of immunotoxicology known
as developmental immunotoxicity (DIT), was among the rst
research initiatives within immunotoxicology. As early as
the s, animal studies revealed the persistent nature of
immune problems resulting from early-life insult. Studies
involving drugs [,], heavy metals [,], pesticides [],
mold toxins [], and polycyclic aromatic hydrocarbons
[] suggested that the developmental periods of immune
system formation, dissemination, and acquired host defense
capacities represent developmental windows that need to
be research and public safety priorities. Yet, developmental
studies represented only one of several aspects of immuno-
toxicological research and the term “developmental immuno-
toxicity” was not prevalent in the literature until the mid-
s [,].
DIT did not achieve a priority position for research and
safety evaluation within immunotoxicology until approxi-
mately the late s–early s. Among the important
events were a workshop on childhood health risks coordi-
natedbytheMarchofDimesandEPA[], the publi-
cation of a seminar text on compiling DIT research [], and
the increasing recognition of fetal programming of later-life
health and disease []. Basic features of developmental
immunotoxicity (DIT) have emerged during decades of
research. ese features are shown as follow
DIT
(i) is directly linked with immune dysfunction and
increased risk of NCDs,
(ii) stems from critical developmental windows of
immune vulnerability restricted to the young,
(iii) can happen at lower exposure levels than usually
produce adult-exposure immunotoxicity,
(iv) oen involves a broader spectrum of adverse immune
outcome versus adult-exposure immunotoxicity,
(v) usually produces more persistent eects than those
following adult exposure,
(vi) can lead to latent dysfunction that may be masked
until it is triggered by a later-life event,
(vii) oen manifests as immune dysfunctional imbalances
(suppression of some immune responses along with
the inappropriate enhancement of others),
(viii) may produce dierent sex-based outcomes,
(ix) is not routinely assessed in most required safety
testing protocols to date,
(x) can occur via several dierent biological pathways
(e.g., impaired immune maturation, epigenetic alter-
ation, and immune-microbiome disruption).
e DIT literature is suciently extensive to permit funda-
mental characterizations. is information is derived from
[,,].
2.2. DIT and the Barker Hypothesis. e impetus for a
greater focus on DIT was aided by the ndings of Barker
and colleagues that maternal undernutrition during prenatal
development could increase the risk of cardiovascular disease
(CVD) in the ospring []. is led to what has been
termed the “Barker Hypothesis” []. Originally, the linkage
between fetal environment-adult disease was focused solely
on maternal nutrition and CVD (including both coronary
heart disease and hypertension) as an example linking early
developmental conditions and fetal programming to later-life
adult disease. But it became clear that the same relationship
could exist for many other adult chronic diseases and condi-
tions (e.g., renal disease and type  diabetes, in adult ospring
that were also aected by the fetal nutritional environment)
[,].
2.3. DIT and Developmental Origins of Adult Health and
Disease (DOHaD). As the net was cast beyond just maternal-
fetal nutritional status to include a wide array of environ-
mental conditions and factors, the concept of developmental
origins of health and disease (DOHaD) emerged [,]to
connect critical windows of development with specic child-
hood and adult health risks. Immune damage, dysfunction,
and/or imbalances are now known to persist long aer either
toxicant levels of chemical exposures return to normal or
physical-psychosocial stressors have been removed [,].
In fact, part of the challenge in deciphering pathways result-
ing in DIT and fetal programming of adverse immune status
is that evidence of prior problematic exposure conditions may
remain largely hidden. For this reason, DIT testing usually
requires careful consideration about exposure windows and
immunological assessment tools [,,]. e opportunity
to examine the dierent functional responses of the immune
system in response to various challenges has emerged as a key
component of safety assessment [,,].
3. Fundamental Features of DIT
3.1. Heightened Sensitivity of the Developing Immune System.
One of the hallmarks of the developing immune system is
that it exhibits an increased sensitivity for most environ-
mentally induced toxicity compared with the fully matured
immune system of the adult. Additionally, DIT oen occurs
at exposure doses that are below those producing other
developmental eects []. Luebke et al. []reviewedthe
evidence of comparative age-based sensitivity for ve of the
most extensively studied drugs and environmental chemicals:
diethylstilbestrol (DES), diazepam (DZP), lead (Pb), ,,,-
tetrachlorodibenzo-p-dioxin (TCDD), and tributyltin oxide
(TBO). ey concluded that early development appears to
be a time of increased sensitivity to xenobiotics and risk of
Advances in Medicine
adverse immune outcomes that are likely to persist into later
life.
is increased risk of developmental immune insult
compared with that of the adult has been seen across broad
categories of drugs and chemicals as well as among dierent
dietary and physical/psychological factors [,,]. is
dierential, age-based sensitivity can take dierent forms,
which are reviewed in detail in Dietert and Piepenbrink [].
In many cases, the lowest dose required to produce immune
disruption is several fold to several magnitudes lower in early
life than in the adult []. Additionally, a broader array of
immune parameters are likely to be aected following expo-
sure of the nonadult versus the adult [,]. Prenatal and
early postnatal exposures are more likely to produce persis-
tent adverse immune outcomes [].
3.2. Critical Developmental Windows. e identication and
consideration of both systemic and tissue-oriented develop-
mental vulnerabilities for the immune system have under-
gone progressive evolution since the original series of
immune “critical windows” emerged from a national work-
shop [,]. As was illustrated in Dietert [],formostkey
developmental steps of immune maturation, multiple envi-
ronmental disruptors have been identied. e eect of inhi-
bition or delay of a critical developmental step can increase
the risk of multiple later-life diseases. For example, key
processes of T cell selection in the thymus can be aected by
maternal exposure to certain heavy metals, plasticizers, diox-
ins, polycyclic chlorinated biphenyls, tobacco smoke, and
certain drugs. Not surprisingly, the adverse health outcomes
that have been associated with environmental targeting of
thymus-directed processes are largely restricted to prenatal
development and cover virtually every category of disease
including cancer as well as autoimmune and allergic diseases
and childhood vaccine failures [].
Each immune developmental window has its own unique
vulnerabilities that are best detected via age-relevant safety
screening []. For example, Bunn et al. [] demonstrated
that while Pb was immunotoxic across all windows of prena-
tal developmental, later gestational maternal exposures were
more likely to result in profound T helper - (-) favored
functional skewing in the juvenile rat.
Application of the critical windows concept for enhanced
immune-associated disease prevention has been explored
by Jenmalm and Duch´
en []. ese authors stressed that
dietary interventions capable of aiding prevention of allergy
are most likely to be eective if directed toward specic pre-
natal, perinatal, and early postnatal developmental windows
[].
4. Frequent Outcomes of DIT and Risk of
Noncommunicable Diseases (NCDs)
OneoftheoutcomesoftherecenthumanstudiesonDITand
fetal programming of immune-based disease is an increasing
realization that these processes are major contributors to
the ongoing epidemic of noncommunicable diseases (NCDs)
(most of which are chronic diseases). NCDs are the major
causeofdeathgloballyandincludecardiovasculardiseaseas
well as cancer []. What has become clear is that the vast
majority of NCDs cannot be maintained in the absence of
misregulated (usually unresolving) inammation [,,].
is means that improper immune homeostasis in tissues
is likely to be required for NCD onset and/or maintenance.
Human studies supported by animal model research have
established the importance of the prenatal and early postnatal
environment for maturation of innate immune cells in con-
cert with formation of the microbiomein mucosal tissues and
other sites (e.g., skin).
One of the impediments to recognizing this DIT-NCD
linkage is that historic examination of immunotoxicity oen
focused on changes in primary and secondary immune
organs. However, the majority of immune cells actually reside
outside of these organs in mucosal and other tissues such as
the gut, brain, skin, liver, endocrine, reproductive, urogenital,
and cardiovascular systems. It is these tissues that are most
oen involved with NCDs, and the status of these resident
immune cells is oen at issue relative to tissue pathology. A
shi in focus in immune evaluation to consider the impact of
DIT and later-life status of cells such as skin dendritic cells,
microglia, Kuper cells, and immune cells of the BALT and
GALT should provide a clearer picture of the cause-eect
relationship between DIT and certain NCDs []. Tab l e 
provides examples of environmental factors and conditions
that are thought to contribute to later-life human disease via
DIT and immune dysfunction. NCDs represent the majority
of examples shown in Table .
e signicance of the prevention of DIT as a strategy to
reduce the prevalence of NCDs has been strengthened with
the awareness that NCDs exist as tightly intertwined patterns
of comorbid risks. is paradigm of tightly interlinked
chronic diseases and conditions was described in a series
of papers illustrating the health risk trajectories that exist
when children are diagnosed with a number of dierent
immune-/inammatory-driven conditions: asthma, recur-
rent infections, schizophrenia, autoimmune thyroiditis, celiac
disease, inammatory disease, and psoriasis [,,,].
Cancer is one of the common outcomes in the tissue receiving
the primary inammatory insult []. Even end-stage condi-
tions such as chronic kidney disease and frailty form part of
these interlinked patterns of chronic diseases and conditions
[,].
As an example, one interconnected pattern of comorbid-
ity exists among a triad of autoimmune conditions: type  dia-
betes, celiac disease, and autoimmune thyroiditis. Children
diagnosed with type  diabetes have a predictably greater risk
for developing celiac disease and/or autoimmune thyroiditis
[,]. While the mechanism remains to be elucidated,
childhood asthma, obesity, and sleep disorders are similarly
interlinked in a triad [,]. Tanaka et al. [] and Anders
et al. []havepointedoutthatclinicaldepressionisa
largely immune driven, inammatory-based condition that is
another comorbid outcome intrinsically connected to many
dierent NCDs/chronic diseases.
Advances in Medicine
T:DITandincreasedriskofhumandisease
.
Disease, disorder, or
susceptibility state
Suggested early-life
immune-modulating risk
factor
Reference(s)
Acute myeloid
leukemia Benzene []
Allergic sensitization Polychlorinated biphenyls []
Asthma Maternal paracetamol use []
Atherosclerosis Maternal hypercholesterolemia []
Atopic dermatitis Maternal smoking []
Allergic rhinitis Antibiotics in infancy []
Autism spectrum
disorders Maternal immune activation []
Bipolar disorder Gestational inuenza []
Cardiovascular
disease Childhood abuse []
Celiac disease Elective cesarean delivery []
Crohn’s disease Maternal smoking []
Chronic obstructive
pulmonary disease Smoke from biomass fuels []
Depression Childhood trauma []
Endometriosis Environmental tobacco smoke []
Hypertension Pesticides (DDT) []
Insulin resistance Maternal diet []
Lack of protection
against diphtheria
and tetanus following
childhood
vaccination
Peruorinated pollutants []
Multiple sclerosis Vitamin D insuciency []
Myalgic
encephalomyelitis
(Chronic fatigue
syndrome)
Childhood trauma [,]
Narcolepsy (specic
subpopulation) HN u vaccination [,]
Obesity/overweight
risk Cesarean delivery []
Otitis media Maternal smoking/ETS []
Parkinsons disease Pesticides [,]
Preeclampsia Trac-related air pollution []
Psoriasis Environmental tobacco smoke []
Respiratory infections Polychlorinated biphenyls [,]
Rheumatoid arthritis Maternal smoking []
Schizophrenia Prenatal immune activation [,]
Sudden infant death
syndrome
Maternal smoking and alcohol
consumption []
Typ e  d iab ete s Lack of or short-duration
breastfeeding []
Ulcerative colitis Urban living []
is table includes both noncommunicable and communicable diseases
and conditions. Environmental risk factors are provided to illustrate an
example and are not intended to be an exhaustive listing. e focus is on
human studies and data.
e ramication of these comorbid disease interconnec-
tions is that there is increased value in avoiding fetal program-
ming that results in childhood-onset, immune dysfunction-
based NCDs. ese implications led four immunotoxicolo-
gists to call for required DIT testing of chemicals and drugs
as a step to better protect children from the risk of NCDs [].
5. Human Studies Involving DIT: Alphabetical
List of Risk Factors
Most prior reviews of DIT have focused largely on animal
research. is section examines the wide range of risk factors
for DIT that has been evaluated among human populations.
Evidence supporting the occurrence of DIT among human
populations has been obtained from both exposed popula-
tions as well as via epidemiological studies. e risk factors
are presented alphabetically rather than being grouped into
dierent categories (e.g., chemicals, drugs, physical, and
psychological factors).
In many of these studies antibody titers against either a
common virus or childhood vaccinations have been used as
a biomarker of DIT. While limited as an overall immune mea-
sure, there are signicant benets to this approach: () serum
antibody levels are easily determined, () a majority of chil-
dren will have been vaccinated according to a predictable and
standard schedule, and () the microbial infection or vaccine
challengeofthechildsimmunesystemwillenableadetection
of potential dysfunction in an actively responding immune
system and, based on animal data, these are among the
most sensitive parameters for measuring DIT. Other stud-
ies reach beyond vaccination data to examine associations
between exposure/environmental conditions and immune-
based chronic diseases during childhood. Among the most
commonly used are asthma, allergic rhinitis, atopic dermati-
tis, type  diabetes, celiac disease, and inammatory bowel
disease. Only a portion of these disease-association studies
has overt human immune function associated with them. For
the remainder, there has been a tendency to rely more on
linking DIT immune function animal data with information
on human immune disease-associations.
5.1. Air Pollution. Ambient air pollution including specic
components (e.g., polycyclic aromatic hydrocarbons, par-
ticulate matter) has been implicated in respiratory and
cardiovascular diseases via improperly controlled inamma-
tion. Nadeau et al. [] examined groups of asthmatic and
nonasthmatic children in Fresno, CA, for pollutant exposure,
T regulatory (Treg) cell activity (that would help to control
 mediated asthma symptoms), and DNA methylation.
e researchers found that increased exposure to ambient air
pollutants was associated with increased methylation of CpG
islands at the Foxp locus as well as reduced Foxp expres-
sion []. ey also reported reduced numbers of Foxp+
Treg cells and reduced Treg activity particularly among the
asthmatic children. e authors concluded that increased air
pollutionexposureinchildrenisassociatedwithincreased
asthma morbidity via epigenetic alterations and a possible
immune mechanism [].
Advances in Medicine
Kerkhof et al. [] found evidence in children that trac-
related air pollution (e.g., particulate matter (PM) ., ,
soot, and nitrogen dioxide) increased the prevalence of
doctor-diagnosed asthma by year  particularly among chil-
dren with specic variant alleles for the toll-like receptor
(TLR) genes  and . e investigators suggested that their
results are consistent with the suspected involvement of
innate immune response in the linkage between exposure to
trac pollution and risk of childhood asthma [].
Calder´
on-Garcidue˜
nas et al. []comparedimmune
markers in asymptomatic children from two dierent city
areas (Southwest Mexico City versus Polotitl´
an, Mexico as
a control city) with vastly dierent burdens of urban air
pollution. ey found that children exposed to the severe
air pollution had immune dysregulation with reduced levels
of IFN-𝛾and natural killer cells with evidence of elevated
systemic inammation (elevated C-reactive protein and
prostaglandin E metabolites).
Indoor air pollution, beyond that of environmental
tobacco smoke, which is discussed in a later section, has also
been associated with human DIT. Herberth et al. []studied
the eects of home renovation (e.g., painting, ooring, and
new furniture) on inammatory biomarker proles of six-
year-old children. Signicant increases in serum IL- and
macrophage chemotactic protein  (MCP-) were associated
with home renovation activities. Installation of new wall-to-
wall carpet gave the strongest single activity association with
these markers.
5.2. Aluminum. Aluminum exposure during prenatal and
childhood development can occur via a variety of routes
including via food, certain drugs (aluminum-containing
antacids), drinking water, and air [] including some par-
enteral nutrition products []. e immune system appears
to be a sensitive target for aluminum []. However, a preva-
lent opportunity for repeated exposure is alum (aluminum
oxyhydroxide)-containing vaccines. Alum is an adjuvant
designed to promote a protective immune response, which
may include a component of local inammation (via specic
cytokine release). One of the concerns with aluminum is the
potential to sometimes induce inappropriate inammation
involving innate immune cells such as macrophages. In some
individuals, such as those carrying HLA-DRB, there
appearstobeanelevatedriskofpersistentmacrophagic
myofasciitis [,], and this link has been proposed as one
route to autoimmune/inammatory syndrome induced by
adjuvants (ASIA) [].
ere is evidence to suggest that febrile responses in
children following alum-containing vaccination may rep-
resent an inammation-driven hyperresponse that occurs
in a subset of children, possibly those possessing certain
cytokine gene alleles []. A proposed mechanistic basis for
alum-induction of DIT in a subpopulation of children was
discussed by Terhune and Deth []. ese authors suggested
that the  biasing and inammasome activating eects
of aluminum may present a problem for children carrying
genetic variants of certain cytokine genes (e.g., IL-, IL-
, IL-, and IL-). In some subpopulations of children,
aluminum adjuvants might enhance the production of non-
target directed IgE thereby elevating the risk of allergy and
atopy []. Other investigators have suggested that alum may
playaroleintheinductionofCrohnsdiseaseingenetically
susceptible individuals [].
5.3. Antibiotics. Antibiotic use in early life has been associ-
ated with an elevated risk of immune-based diseases such as
childhood asthma. Raciborski et al. [] found that antibiotic
useduringtherstthreeyearsoflifewasassociatedwithasig-
nicantly elevated risk of asthma by – years of age among
 children in Warszawa, Poland. e highest association
was found between infants who completed three courses of
antibiotic within the rst year of life and later childhood
asthma (OR = ., % CI: .–.) []. Not all authors
agreeonthisassociation.HeintzeandPetersen[]argue
that various forms of bias weaken the literature on perinatal
antibiotic use and risk of childhood asthma. However, the
impact of repeated antibiotic use on the microbiome during
immune development provides a potential mechanistic basis
forDIT,skewing,andmisregulatedinammation[].
Extensive antibiotic use is of particular concern when
viewed in the context of the hygiene hypothesis or the
recently-described “Completed Self” model (i.e., where
unimpeded comaturation of the development immune sys-
tem and infant microbiome is critical) [](seeFigure ).
Under the “Completed Self ” paradigm, successful develop-
ment of a balanced, well-regulated immune system needs co-
maturation with a complete microbiome in the infant. e
developing immune system receives important signals from
the commensal microbes and eventually matures to perceive
self as a combination of the mammalian cells and commensal
microbes. e successful merger of the infant’s mammalian
and microbial components into the fully formed human-
microbial superorganism may well represent the single most
important step distinguishing later-life health from disease.
As a result, any prenatal or postnatal environmental exposure
that interferes with timely and eective self-completion is a
signicant health risk []. is new immunological view of
what constitutes a fully completed infant could impact risk-
benet considerations for antibiotic administration in early
life.
5.4. Arsenic. Arsenic is found in both inorganic and organic
forms. Most of the environmental health concerns have
focused on the inorganic forms of arsenic (e.g., arsenite or
arsenate) with exposure occurring primarily via ingestion of
contaminated food and water and secondarily via inhalation.
Some forms of arsenic (e.g., arsenic trioxide) have been used
in the treatment of leukemias. e topic of arsenic-induced
immunotoxicity was recently reviewed by Dangleben et al.
[]. ese authors stressed the increased vulnerability of
infants and children to arsenic-induced immune dysfunction
and the potential for early-life exposures to produce later-life
health problems.
Studies of exposed human populations also suggest that
arsenic is a major concern for DIT, and several studies
have examined children in Mexico and Bangladesh among
Advances in Medicine
Environmentally induced
epigenetic alterations
Maternal nutrition
and infant feeding
Maternal stress
Developing
immune
system
Prenatal exposure to
environment chemicals and drugs
(disrupted maturation)
Infant
microbiome
Birth delivery
mode
Maternal and
infant infection
Childhood
stress/abuse
Infant exposure to environmental
chemicals and drugs
(disrupted maturation)
Developmental immunotoxicity (DIT) in the context of
the Completed Self model for the human-microbial superorganism
F : is gure depicts a model following the “Completed Self” paradigm [] in which the immune system and infant microbiome
need to comature without interference or disruption to reduce later-life health risks. e categories of environmental risk factors reported to
cause prenatal and/or postnatal disruption are illustrated.
highly exposed populations. Soto-Pe˜
na et al., []foundthat
children in Mexico (– years old) with arsenic exposure
primarily from drinking water (evaluated based on urinary
levels) had peripheral blood mononuclear cells (PBMs) that
were shied in ex vivo stimulated function (proliferation and
cytokine secretion). Rocha-Amador et al. []foundthat
children in Mexico living in an area with high exposure to
arsenic via drinking water had increased apoptosis among
PBMs compared with those from an area with lower exposure
levels. In a study of Bangladeshi children where a signicant
exposure to arsenic can occur via drinking water, Ahmed
et al. [] found that prenatal exposure to arsenic interfered
with thymic function aecting T cell development. e pro-
posed route of insult was via oxidative damage and possible
misregulation of apoptosis. e same investigators demon-
strated that prenatal exposure to arsenic was associated with
increased placental inammation increasing oxidative stress
and altering both T cell and cytokine proles in cord blood
[].
is suggests that, at physiologically-relevant exposures,
arsenic-induced DIT can manifest almost immediately dur-
ing fetal development. is is consistent with the ndings of
arsenic-exposed children in Mexico where increased arsenic
levels were associated with increased basal nitric oxide
production by monocytes and increased superoxide anion
produced by activated monocytes []. Taken together these
studies suggest that a proinammatory state is part of the
prole of arsenic-induced human DIT. Lower resistance to
certain infectious diseases has been associated with early-life
exposure to arsenic. In a prospective population-based
cohort study, , Bangladeshi infants were examined for
both lower respiratory tract and diarrhea-associated infec-
tions and compared versus maternal arsenic levels during
the pregnancy (measured at two time points via urine) [].
Rahman et al. [] found that the highest quadril of maternal
arsenic exposure versus the lowest had a signicantly elevated
risk of both forms of mucosal tissue infections. Lower
respiratory tract infections had a % increased relative risk
for infants of high arsenic exposed mothers adjusted rel-
ative risk (RR = .; % condence interval (CI), .–
.), whereas there was a % increased risk of diarrheal-
associatedinfections(RR=.;%CI,..)amongthe
same groups.
5.5. Bisphenol A. BisphenolA(BPA)isusedinavariety
of food and beverage containers. Most human chemical
exposure occurs via food and beverages although exposure
via air, dust, and water is also possible. Sources of BPA include
food storage containers, water bottles, baby bottles, and poly-
carbonate tableware. BPA has received signicant immune
system evaluation in recent years although the majority of
studies, to date, have been performed in rodents.
Rogers et al. [] recently reviewed the immunotoxico-
logic prole of BPA suggesting that it () increases  polar-
ization of dendritic cells, () alters macrophage inammatory
cytokine production and metabolism but with dierent dose-
dependent eects, () decreases T regulatory cells, () alters
the relative proportions of immunoglobulin (Ig) producing
cells, and () polarizes CD+ T helper () cells although the
Advances in Medicine
direction of polarization (e.g.,  versus ) has diered
among studies.
Human studies for BPA and DIT are comparatively
limited to date. In a National Health and Nutrition Exam-
ination Survey (NHANES) study, children and teens less
than  years of age exhibited an inverse correlation of BPA
exposure (urinary levels of BPA) with antibody levels against
cytomegalovirus []. Kim et al. [] examined the genomic
alteration patterns of Egyptian prepubescent girls (ages –)
relative to both genome-wide methylation and methylation
of genes previously identied as sensitive to BPA exposure.
Among those genes prominently modied were those
involved with immune response and autoimmune thyroid
disease. Taken together, the animal and human studies
suggest that early-life exposure to problematic doses of BPA
produces altered gene expression related to immune function
and inammatory responses. However, more research is
needed to dene the boundaries of these alterations and the
impact on various immune-related diseases in later life.
5.6. Cesarean Section. Cesarean section (CS) can b e a medical
necessity in some circumstances. However, the increased
prevalence of elective CS (versus vaginal delivery (VD)) has
created a public health concern []. CS has been reported
to alter the course of immune development by producing 
skewing, innate immune dysfunction, and an increased like-
lihood of exacerbated inammatory responses (reviewed in
[]). ere are a minimum of four possible factors with
Cesarean delivery that may contribute to subsequent DIT: ()
failuretoproperlyseedthenewbornsmucosaltissueswith
microbiota from the maternal vaginal tract, () the prophy-
lactic use of antibiotics, () other drug administration con-
nected with the Cesarean operation, and () the contrasting
placental immune-stress-hormonal environment between
the two delivery modes.
In the rst category, birth delivery mode can signi-
cantly aect the microbiota and the subsequent immune-
microbiome interactions. In a Canadian study, Azad et al.
[] found that infants delivered by elective Caesarean were
much lower in the bacterial diversity and richness of their
microbiome. In the fourth category from above, the immune
physiology of vaginal delivery (versus CS) appears to create
a strikingly dierent environment for the full-term fetus.
A cross-sectional study of  women in e Netherlands
compared spontaneous, term VDs versus elective CSs for
signs of intrauterine inammation. Houben et al. []found
that measures of placental inammation and amniotic uid
proinammatory cytokines (IL-, TNF-𝛼, and IL-) were
signicantly elevated with VD versus CS. e investigators
suggested that increased sterile inammation during labor
andVDdeliverymayplayacriticalroleinnormalpartu-
rition and facilitate subsequent maturational processes (e.g.,
immune and airway maturation) in the newborn [].
CShasbeenassociatedwithalteredlevelsofimmune
cell populations, cytokines, and chemokines in neonates
leading Cho and Norman []tosuggestthatitshould
not be recommended except where there is a clear medical
indication or a benet over risk estimate including long-
term consideration for the infant child. For example, CS has
been found to skew the infant immune proles toward a 
biased capacity []. Innate immune maturational markers
are also aected. Elective CS without labor was found to be
associated with reduced surface expression of two dierent
toll-like receptors (TLRs): TLR and TLR. In contrast, labor
and vaginal delivery appears to upregulate these TLRs to
adult levels []. Because these TLRs are important in innate
immunity, the authors suggest that labor is an important
component of ongoing immune maturation []. e con-
centrations of the chemokine, RANTES (CCL), a chemokine
important in recruiting immune cells to inammatory sites,
were found to be lower in neonates from CS than VD [].
In a prospective study of full-term deliveries, Malamitsi-
Puchneretal.[] found that VD neonates had elevated levels
of both soluble IL- receptor and TNF-𝛼compared with
CS delivered babies. Taken together, these studies suggest
that neonatal immune proles, including early inammatory
interactions, are locked into a less mature, more-fetal-like
state following CS versus VD deliveries. Not surprisingly, this
appears to have consequences relative to risk of childhood
chronic diseases.
CS with the outcome of low bacterial diversity in the
infant is reported to increase the risk of several immune-
based diseases emerging in children including asthma [,
], atopic dermatitis [], celiac disease [], and type 
diabetes [,]. A meta-analysis of  studies on CS and
asthma estimated that the increased risk associated with this
birth delivery mode was estimated at % []. Of note
is the observation that specic subpopulations may be at
an increased risk for the disease-promoting aspects of CS.
For example, Magnus et al. [] found that the association
between CS and childhood asthma (at  years of age) was
strongest among children of nonatopic mothers.
5.7. Childhood Abuse. In children who experience abuse,
the developing immune system appears to become wired
for dysfunctional responses. In the Nurses’ Health Study II,
Bertone-Johnson [] found that women reporting moder-
atetoseverechildhoodoradolescentabusehadsignicantly
elevated levels of two inammatory markers CRP and IL- as
adults. e authors argued that early-life stress may program
the immune system for dysregulation and that subsequent
immune dysregulation elevates the risk of certain chronic
diseases. Slopen et al. [] make a similar link between
childhood adverse experiences, misregulated inammation,
and risk of cardiovascular disease.
5.8. Diethylstilbestrol. While human immunological stud-
ies on diethylstilbestrol (DES) are limited compared with
other health-related studies, there are reports suggesting that
prenatally-exposed ospring are at a higher risk of immune-
based disease. Overall DES daughters exposed in utero self-
reported an increased risk of all immune-based diseases
(infections, allergies, and autoimmune conditions). Within
specic categories, the women experienced more infectious
diseases than non-DES exposed daughters []. In a separate
Advances in Medicine
study, Strohsnitter et al. [] examined the incidence of
selected autoimmune conditions among DES daughters. ey
found no overall increase in disease associations for rheuma-
toid arthritis (RA), systemic lupus erythematosus (SLE),
optic neuritis (ON), or idiopathic thrombocytopenic purpura
(ITP). However, there was a signicant increase in the
onset of RA by  years of age in the DES-exposed versus
nonexposed groups [].
5.9. Ethanol. ere are substantial data from animals sug-
gesting that developmental exposure to alcohol produces
DIT [,] and can elevate the risk of non-communicable
diseases possibly via inammatory processes []. Mater-
nal consumption of alcohol during pregnancy can produce
immune-related adverse outcomes in the ospring. In fact,
later gestation appears to be particularly sensitive to the eect
of ethanol []. Among the reported long-term eects was
interference with the immune response to inuenza virus
challengeinmice[].
Remarkably, human studies are limited for low-level
ethanol intake and DIT-related outcomes. Most studies fol-
lowing children exposed in utero to alcohol have focused on
growth and behavioral outcomes [,]. Carson et al. []
utilized the COPSAC prospective birth cohort comprising
 children born to asthmatic mothers. e children were
considered full term and lacked congenital abnormality,
systemic illness, or history of mechanical ventilation or lower
airway infection. For this study group, the risk of ospring
atopic dermatitis was reported to be signicantly elevated for
any maternal alcohol consumption during pregnancy (HR
., % CI .–., 𝑃 = 0.024) even aer exclusion of
eects of maternal smoking or atopic dermatitis [].
Two studies reported negative results for maternal alcohol
intake and childhood asthma. Yuan et al. [] examined
the incidence of hospitalization for asthma to age  among
children from , singleton full-term births in Denmark
between the years  and . e authors reported
no signicant associations between alcohol and no alcohol
consumption (HR .; % CI .–.) including dierent
doses of alcohol as well as binge drinking. In a second study,
Shaheen et al. [] examined maternal alcohol consump-
tion during pregnancy relative to risk of childhood atopic
disease (asthma and hayfever) measured at seven years of
age within the Avon Longitudinal Study of Parents and
Children (ALSPAC). ey found no elevated risk for late ges-
tational alcohol consumption with asthma or hayfever and no
dierence among mothers carrying dierent alleles for the
alcohol dehydrogenase gene [].
A case-controlled study in Ireland with infants born in
– examined factors that are potentially involved
with sudden infant death syndrome (SIDS) []. McDonnell
Naughton et al. [] reported that mothers of infants with
SIDS were more likely to have consumed alcohol during
pregnancy than controls (HR ., % CI .–.).
5.10. Lead (Pb). A cadre of heavy metals has been examined
for DIT and associated health risks in both children and
adults.Amongthemostconsistentobservationswithlead
(Pb) are elevated risk of oxidative damage and a skewing
toward -driven responses with elevated levels of IgE. As
an indicator of Pb’s ability to produce misregulated inam-
mation, Pineda-Zavaleta et al. []foundthemacrophages
isolated from Pb-exposed children stimulated in vitro with
lipopolysaccharide overproduced superoxide anion. Kar-
maus et al. [] reported that Pb exposure was associated
with elevatedIgE in children. Li et al. []reportedanegative
correlation between circulating CD+T cells and blood lead
levels. Lutz et al. [] found that combined exposure to Pb
and environmental tobacco smoke was strongly associated
with elevated serum IgE levels in children. e human data
are consistent with the animal studies suggesting that 
skewing, increased oxidative stress and tissue damage, and
misregulated inammation are among the adverse immune
outcomes following developmental exposure to Pb [].
5.11. Maternal Smoking and Environmental Tobacco Smoke.
ere are several suggested developmental risk factors for
asthma. Among these, maternal smoking during pregnancy
and exposure of the infant to environmental tobacco smoke
(ETS) were identied by Selgrade et al. []ashavingthe
most convincing body of evidence connecting environmental
exposure to DIT and risk of childhood asthma. Additionally,
Prescott [] identied early life exposure to tobacco smoke
producing altered immune function as being an important
contributor to risk of allergic diseases. Among the pathways
proposed to be involved is the capacity of maternal smoking
to alter TLR-mediated responses in infant innate immune
cells []. Noakes et al. [] suggest that smoking induced
TLR alterations will aect not only the developing immune
system but also the “hygiene hypothesis” eects of immune-
microbiome interactions in the newborn. e capacity of
DIT to disrupt integrity of the immune-microbiome (the
Completed Self model) is depicted in Figure .
Wilson et al. [] reported that exposure of children to
secondhand smoke produced signicant changes in cytokine
levels particularly reducing the level of IFN-𝛾.Aspreviously
mentioned in the section on Pb, Lutz et al. []reported
an interaction of environmental risk factors in which Pb-
exposed children also exposed to ETS had elevated IgE and
IL- levels and altered T cell populations. Similar results were
obtained by Tebow et al. [] for exposure covering both
prenatal and postnatal periods. ese researchers found that
parental smoking was associated with a disrupted balance of
IFN-𝛾to IL- among children of smokers. While IL- levels
wereunchangedinthecomparisonofchildrenwithparental
smokers versus non-smokers, reduced IFN-𝛾was associated
with parental smoking and a dose response relationship
appeared to exist. erefore, the balance of IFN-𝛾to IL- was
shied toward the latter.
Elevated risk of allergic diseases is not the only immune-
based concern with early-life exposure to tobacco smoke.
Kum-Njietal.[] reviewed t he literature regarding ETS and
childhood infection and concluded that there is no longer a
doubt about this association. Supporting evidence has been
seen using childhood vaccination. In an examination of 
infants with a history of parental allergy, Baynam et al. []
Advances in Medicine
found that, among children with parents who smoked, infants
carryingavariantoftheIL-receptorgene(theIL-Ralpha
 QR/QQ genotype) exhibited signicantly altered immune
responses. ese included reduced IgG responses, reductions
in certain T cell responses (e.g., those associated with IFN-
𝛾production), and altered innate immune (defective TLR-
driven) responses upon vaccination with tetanus toxoid.
ese studies suggest that early-life exposure to smoking
causes immune dysbiosis (targeted inappropriately exagger-
ated responses as well as suppression) that includes both an
elevated risk of certain allergic diseases as well as potentially
impaired responses to childhood vaccination. In keeping with
many other DIT studies involving other risk factors, it also
suggests that some human subpopulations are likely to have
enhanced vulnerability for smoking-related DIT.
Disrupted immune maturation is not the only pathway
throughwhichmaternalsmokingandETSappeartoaect
later-life immune function. Wilhelm-Benartzi []found
that childhood ETS exposure produced epigenetic marks in
genes associated with both immune function and immune
signaling.
5.12. Paracetamol. Prenatal and early infant exposure to
paracetamol (acetaminophen) has been associated with an
increased risk of a variety of wheeze-associated disorders in
the child including asthma. In the case of prenatal exposure,
a study from Denmark examined , singletons born in
northern Denmark in – []. Paracetamol expo-
sure during any trimester of the pregnancy resulted in an
adjusted odds ratio of . (% condence interval: .–
.) for risk of asthma by the end of  []. For infant
exposure, Gonzalez-Barcala et al. [] studied , 
children in Galicia, Spain, and reported that paracetamol use
duringtherstyearoflifeledtoasignicantincreasedriskof
asthma in --year-old children (odds ratio (OR) . (.–
.)). Henderson and Shaheen []recentlyreviewedthe
epidemiological data regarding prenatal and infant exposure
to paracetamol and an increased risk of childhood asthma.
ey argue that the evidence is suciently strong as to
be compelling for this association but also point out that
mechanistic causation remains a signicant data gap.
One of the potential confounding factors is prevalence of
infections and the use of antibiotics, which may coincide with
administration of paracetamol []. Heintze and Petersen
[] argued that failure to distinguish among the confound-
ing eects of these two factors would signicantly weaken the
proposed associations. However, Muc et al. []performed
a cross-sectional study of  primary school children in
Portugal in which they partitioned the factors of paracetamol
in early childhood and antibiotic administration relative to
risk of asthma. Paracetamol use and antibiotic administration
were independently found to increase the risk in children of
current asthma (at the time of evaluation) as well as ever
having asthma. Because frequency of paracetamol use was
connected to increased allergic symptoms, the researchers
suggested that dose-dependent associations may be present
among the data []. Not all studies have reported positive
associations for paracetamol and asthma. However, based on
an understanding of the pathways through which paraceta-
mol is likely to aect ospring immune status and childhood
health, iele et al. [] called for a reconsideration of safety
and dosage recommendation during pregnancy.
For potential infant use, McBride []arguedthatrisk
data combined with the likelihood of glutathione depletion
by paracetamol in the airways suggested that children at risk
for asthma should avoid the use of paracetamol. Selgrade et al.
[] pointed out that accompanying animal data have been
generally lacking in DIT models of the human paracetamol-
asthma linkage. However, these authors also point to the over-
all importance of oxidative stress and inammation as likely
routes for xenobiotic-induced, DIT-related asthma. is
would be consistent with ndings of several research groups.
Evidence from several studies suggests that disruption
of eective oxygen species regulation is a likely route to
theelevatedrisk.Kangetal.[]reportedthatpostnatal
pediatric use of paracetamol was more likely to produce
asthma among children carrying specic genetic alleles
associated with control of oxidative inammation (NAT2,
Nrf2, and GSTP1). Shaheen et al. [] examined the eect of
specic maternal alleles for nuclear erythroid  p-related
factor  (Nrf2) and glutathione S-transferase (GST) poly-
morphisms within data from the Avon Longitudinal Study
of Parents and Children. ey found that maternal Nrf2
allelic dierences had an eect on early gestation exposure
to paracetamol and childhood asthma, while the presence of
the GSTT1 allele was important in late gestational exposure
to paracetamol []. Taken together, these studies suggest
that subpopulation dierences are likely to exist for the
relative risks of association between prenatal exposure to
paracetamol and childhood-onset asthma.
5.13. Pesticides. Pesticides fall into several dierent chem-
ical categories (e.g., organophosphate, organochlorine, and
pyrethroids). However, humans are likely to be exposed to
pesticide mixtures rather than to a single pesticide, and
mixtures may result in unanticipated interactions among the
pesticides at the molecular level []. Human exposure to
certain pesticides at sucient doses has been known to pro-
duce a variety of eects on physiological systems with some
outcomes potentially linked to their endocrine disrupting
activity [] and altered oxidative stress []. In particular,
most of the human ndings primarily concern early life
exposure and childhood neurodevelopmental impairment.
In a prospective longitudinal study conducted in the French
West Indies, Boucher et al. [] reported that exposure to the
organochlorine pesticide, chlordecone, was associated with
impaired neurodevelopment in -month-old infants. e
eects were seen in boys but not girls.
ree epidemiological studies are signicant in pointing
to similar conclusions regarding prenatal pesticide exposure
and later childhood neurodecits. In the Columbia Univer-
sity study, Rauh et al. []foundaninverseassociation
between Working Memory Index and Full-Scale IQ in inner-
city children at age seven and the level of prenatal exposure
to chlorpyrifos, an organophosphate pesticide. In a Mount
Sinai Childrens Environmental Health Study, Engel et al. []
 Advances in Medicine
reported that prenatal exposure to organophosphate pesti-
cides was negatively associated with cognitive function by 
months of age but also continuing later into childhood. In
a multi-institutional California study among predominately
Latino farmworker families, Bouchard et al. []reported
that prenatal exposure to organophosphate pesticides was
associated with reduced intellectual development at age
seven.
Among pesticides, the exposure risks not only involve
childhood-onset conditions but also later-life-appearing dis-
eases (e.g., neurodegenerative). Zhou et al. []found
that early-life exposure of mice to paraquat led to a later
silencing in the gene (PINK) responsible for producing a
neuroprotective peptide. At the same time these pesticides
activated the brains innate immune cell resident microglia
populations to generate excessive oxidative damage among
neurons []. e reduced neuroprotection coupled with the
increased risk of immune-mediated oxidative damage shis
the equilibrium of the aging brain toward neurodegeneration.
ere is a suggestion that pesticide exposure may aect
the risk of immune-driven NCDs. In the U.S. Agricultural
Health Study, Hoppin et al. [] found that exposure to
pesticides elevated the risk for atopic (but not nonatopic)
asthma among farm women. In fact the exposure to pesticides
nullied the benecial eect of growing up on a farm relative
to risk of asthma. In this study, a total of  of  insecticides,
 of  herbicides, and  of  fungicides were associated
with an elevated risk of atopic asthma while permethrin use
was the only pesticide associated with an increased risk of
nonatopic asthma []. e study design []didnotpermit
a comparison of dierential developmental sensitivities and
the potential role of pesticide-induced DIT in risk of asthma.
However,theapparentnullicationofimmune-microbiome
protection against asthma (i.e., hygiene hypothesis) raises
intriguing questions.
Corsini et al. [] recently reviewed the literature on pes-
ticides and immunotoxicity. Based on human studies, these
investigators concluded that the potential role of pesticides
in immunotoxicity is unclear at present. ey pointed out the
serious limitations of most of the available studies including
problems in accessing exposure levels and quite divergent
approaches to assessment. e researchers called for better
studies that would include pre- and postexposure informa-
tionandbedesignedwithappropriatelymatchedcontrols.
Beyond the weaknesses discussed by Corsini et al. [],
other weaknesses include a general lack of data regard-
ing early developmental exposures and information regard-
ing potential hypervulnerability for pesticide-induced DIT
among human subpopulations.
5.14. Polychlorinated Biphenyls. Polychlorinated biphenyls
(PCBs) are in a category of persistent organic pollutants
(POPs) that can present human health challenges long aer
release into the environment. Stølevik et al. [] examined
the eects of exposure to PCBs and dioxin among Norwegian
mother-child pairs and potential immune eects. ey found
that exposure to PCBs and dioxins was associated with
increased incidence of respiratory infections and reduced
antibody response against one (measles) of several childhood
vaccinations. is is consistent with the ndings of Heilmann
et al. [,] who studied perinatal PCB exposure and
immune outcomes among children of the Faroe Islands.
ese researchers reported reduced antibody titers up to age
seventocommonchildhoodvaccinationsfollowinglargely
maternal diet-based perinatal exposure to PCBs. For the
strongest associations, these investigators found that a dou-
blingofserumPCBconcentrationsresultedinanapproxi-
mately % reduction in antibody levels. Approximately %
of the Faroe Islands children were found to be eectively
unprotectedagainstthechildhoodpreventablediseasesbased
on the extent of antibody suppression [,].
SignicantlyforriskofNCDs,Grandjeanetal.[]
found that prenatal and lactational exposure of Faroe Island
children to marine pollutants including PCBs increased the
risk of allergic sensitization. ese ndings are consistent
with the apparent capacity of PCBs to produce disruption
of immune homeostasis with eects including not only
immunosuppression but also inappropriately enhanced and
misdirected immune responses.
5.15. Polyuorinated and Peruorinated Compounds. e
impact of developmental exposure to peruorooctane sul-
fonic acid (PFOS) and peruorooctanoic acid (PFOA) was
examinedinaprospectivecohortbirthstudyintheFaroe
Islands []. e researchers found that a twofold increase
in the levels of PFOS and PFOA at age ve resulted in a
several-fold increased likelihood of being unprotected against
preventable childhood illnesses at age seven. In this case, lack
of protection was dened as being below a protective level of
antibodies against diphtheria and tetanus []. ese nd-
ings have potentially stark implications for the health pro-
tection of children. In fact, the investigators determined that
if benchmark dose (BMD) was calculated for the various
polyuorinated compounds using antibody levels as the
driver and these were converted to safety limits for PFCs, the
current limits may be several hundredfold too high [].
6. Conclusions
DIT and fetal programming are emerging as signicant con-
tributors not only to later-life immune dysfunction and mis-
regulatedinammationbutalsotoincreasedriskofNCDs
and particularly chronic diseases. Given the present epidemic
of NCDs, the interrelated comorbidities that exist among
amyriadofchronicdiseases,andtheroleofNCDsas
the greatest cause of death worldwide, better preventative
strategies are needed.
Animal model research of DIT dates back several decades
andhelpedtoestablishthefundamentalcharacteristicssur-
rounding early-life immune vulnerability for later-life dis-
ease. Recently, human DIT-related data have shown the rele-
vance of the animal model information concerning dose sen-
sitivity, subpopulation vulnerability, and health ramications.
While data gaps still exist for some categories of environmen-
tal risk factors (e.g., bisphenol A, certain pesticides), the way
forward seems clear.
Advances in Medicine 
Better identication of DIT risk and improved pro-
tection of age-, sex-, and genotype-based hypervulnerable
subpopulations are needed. is may well require a dierent
approach to safety testing. With the potential for epigenetic
alterationstobeproducedinuteroandinheritanceofaltered
immune- and inammation-related gene expression across
generations, it is apparent that eorts to reduce the prevalence
of NCDs need to focus on early life. Reducing the prevalence
of DIT is an important rst step in comprehensive eorts to
reduce the prevalence and global impact of NCDs.
Abbreviations
ALSPAC: Avon Longitudinal Study of Parents and
Children
Alum: Aluminum oxyhydroxide
BMD: Benchmark dose
CI: Condence interval
COPSAC: Copenhagen Prospective Study on
Asthma in Childhood
CRP: C-Reactive protein
CS: Cesarean section
CVD: Cardiovascular disease
DES: Diethylstilbestrol
DIT: Developmental immunotoxicity
DOHaD: Developmental origins of health and
disease
DZP: Diazepam
HLA: Human leukocyte antigen
Ig: Immunoglobulin
IgE: Immunoglobulin E
IFN-𝛾: Interferon-gamma
Il-: Interleukin-
IL-: Interleukin-
IL-: Interleukin-
NHANES: National Health and Nutrition
Examination Survey
NCDs: Noncommunicable diseases
Pb: Lead
PFOA: Peruorooctanoic acid
PFOS: Peruorooctane sulfonic acid
POPs: Persistent organic pollutants
RR: Relative risk
: T helper
: T helper 
TBT: Tributyltin oxide
TCDD: ,,,-Tetrachlorodibenzo-p-dioxin
TLR: Toll-like receptor
TNF-𝛼: Tumor necrosis factor-alpha
VD: Vaginal delivery.
Conflict of Interests
e author declares that he has no conict of interests
regarding the publication of this paper.
Acknowledgment
e author thanks Janice Dietert, Performance Plus Consult-
ing, for her editorial suggestions.
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