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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 eects 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 signicant since most prior reviews of DIT have largely focused on animal research and considerations of specic 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 polyuorinated compounds.
1. Introduction
Early-life environmental insults aecting the developing
immune system can have signicant health ramications not
only for the exposed ospring but also potentially extending
to additional generations. Developmental immunotoxicity
(DIT) appears to play a signicant 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
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which the HIV-induced immunosuppression associated with
AIDS was an increasing human health challenge [,]. A
coordinated eort 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 eective for identifying immunotoxic chemicals [,
]. In addition to the identication 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) oen involves a broader spectrum of adverse immune
outcome versus adult-exposure immunotoxicity,
(v) usually produces more persistent eects 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) oen manifests as immune dysfunctional imbalances
(suppression of some immune responses along with
the inappropriate enhancement of others),
(viii) may produce dierent sex-based outcomes,
(ix) is not routinely assessed in most required safety
testing protocols to date,
(x) can occur via several dierent biological pathways
(e.g., impaired immune maturation, epigenetic alter-
ation, and immune-microbiome disruption).
e DIT literature is suciently 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 ospring [–]. 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 ospring
that were also aected 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 specic child-
hood and adult health risks. Immune damage, dysfunction,
and/or imbalances are now known to persist long aer 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 dierent 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 oen occurs
at exposure doses that are below those producing other
developmental eects [–]. 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 dierent
dietary and physical/psychological factors [,,]. is
dierential, age-based sensitivity can take dierent 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 aected 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 identication 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 identied. e eect 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 aected 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 eective if directed toward specic 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) inammation [,,].
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 oen
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
oen involved with NCDs, and the status of these resident
immune cells is oen 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, Kuper cells, and immune cells of the BALT and
GALT should provide a clearer picture of the cause-eect
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 signicance 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 dierent
immune-/inammatory-driven conditions: asthma, recur-
rent infections, schizophrenia, autoimmune thyroiditis, celiac
disease, inammatory disease, and psoriasis [,,,].
Cancer is one of the common outcomes in the tissue receiving
the primary inammatory 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, inammatory-based condition that is
another comorbid outcome intrinsically connected to many
dierent 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 inuenza []
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
Peruorinated pollutants []
Multiple sclerosis Vitamin D insuciency []
Myalgic
encephalomyelitis
(Chronic fatigue
syndrome)
Childhood trauma [,]
Narcolepsy (specic
subpopulation) HN u vaccination [,]
Obesity/overweight
risk Cesarean delivery []
Otitis media Maternal smoking/ETS [–]
Parkinson’s disease Pesticides [,]
Preeclampsia Trac-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 ramication 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
dierent 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 signicant benets 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
challengeofthechild’simmunesystemwillenableadetection
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 inammatory 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 specic
components (e.g., polycyclic aromatic hydrocarbons, par-
ticulate matter) has been implicated in respiratory and
cardiovascular diseases via improperly controlled inamma-
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 Foxp+
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 trac-
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 specic 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
trac pollution and risk of childhood asthma [].
Calder´
on-Garcidue˜
nas et al. []comparedimmune
markers in asymptomatic children from two dierent city
areas (Southwest Mexico City versus Polotitl´
an, Mexico as
a control city) with vastly dierent 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 inammation (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 eects of home renovation (e.g., painting, ooring, and
new furniture) on inammatory biomarker proles of six-
year-old children. Signicant 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 inammation (via specic
cytokine release). One of the concerns with aluminum is the
potential to sometimes induce inappropriate inammation
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/inammatory syndrome induced by
adjuvants (ASIA) [].
ere is evidence to suggest that febrile responses in
children following alum-containing vaccination may rep-
resent an inammation-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 inammasome activating eects
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
playaroleintheinductionofCrohn’sdiseaseingenetically
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
useduringtherstthreeyearsoflifewasassociatedwithasig-
nicantly 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 eective self-completion is a
signicant health risk []. is new immunological view of
what constitutes a fully completed infant could impact risk-
benet 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 shied 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 signicant
exposure to arsenic can occur via drinking water, Ahmed
et al. [] found that prenatal exposure to arsenic interfered
with thymic function aecting 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 inammation increasing oxidative stress
and altering both T cell and cytokine proles 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 proinammatory state is part of the
prole 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 signicantly 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 = .; % condence 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 signicant 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 prole of BPA suggesting that it () increases polar-
ization of dendritic cells, () alters macrophage inammatory
cytokine production and metabolism but with dierent dose-
dependent eects, () 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 diered
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 identied as sensitive to BPA exposure.
Among those genes prominently modied 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 inammatory responses. However, more research is
needed to dene 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 inammatory responses (reviewed in
[–]). ere are a minimum of four possible factors with
Cesarean delivery that may contribute to subsequent DIT: ()
failuretoproperlyseedthenewborn’smucosaltissueswith
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 aect 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 dierent 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 inammation. Houben et al. []found
that measures of placental inammation and amniotic uid
proinammatory cytokines (IL-, TNF-𝛼, and IL-) were
signicantly elevated with VD versus CS. e investigators
suggested that increased sterile inammation 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 benet over risk estimate including long-
term consideration for the infant child. For example, CS has
been found to skew the infant immune proles toward a
biased capacity []. Innate immune maturational markers
are also aected. Elective CS without labor was found to be
associated with reduced surface expression of two dierent
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 inammatory 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 proles, including early inammatory
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 specic 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 inammatory 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 inammation,
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 ospring 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
specic 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 signicant 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 inammatory processes []. Mater-
nal consumption of alcohol during pregnancy can produce
immune-related adverse outcomes in the ospring. In fact,
later gestation appears to be particularly sensitive to the eect
of ethanol []. Among the reported long-term eects was
interference with the immune response to inuenza 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 ospring
atopic dermatitis was reported to be signicantly elevated for
any maternal alcohol consumption during pregnancy (HR
., % CI .–., 𝑃 = 0.024) even aer exclusion of
eects 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 signicant associations between alcohol and no alcohol
consumption (HR .; % CI .–.) including dierent
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
dierence among mothers carrying dierent 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 inam-
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 inammation 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 identied by Selgrade et al. []ashavingthe
most convincing body of evidence connecting environmental
exposure to DIT and risk of childhood asthma. Additionally,
Prescott [] identied 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 aect not only the developing immune
system but also the “hygiene hypothesis” eects 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 signicant 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
shied 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 signicantly 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 . (% condence 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
duringtherstyearoflifeledtoasignicantincreasedriskof
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 suciently strong as to
be compelling for this association but also point out that
mechanistic causation remains a signicant 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 eects of these two factors would signicantly 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 aect ospring 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 inammation 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 eective oxygen species regulation is a likely route to
theelevatedrisk.Kangetal.[]reportedthatpostnatal
pediatric use of paracetamol was more likely to produce
asthma among children carrying specic genetic alleles
associated with control of oxidative inammation (NAT2,
Nrf2, and GSTP1). Shaheen et al. [] examined the eect of
specic 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 dierences had an eect 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 dierences 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 dierent 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 sucient doses has been known to pro-
duce a variety of eects 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
eects were seen in boys but not girls.
ree epidemiological studies are signicant in pointing
to similar conclusions regarding prenatal pesticide exposure
and later childhood neurodecits. 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 Children’s 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 brain’s 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 shis
the equilibrium of the aging brain toward neurodegeneration.
ere is a suggestion that pesticide exposure may aect
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
nullied the benecial eect 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 dierential 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 aer
release into the environment. Stølevik et al. [] examined
the eects of exposure to PCBs and dioxin among Norwegian
mother-child pairs and potential immune eects. 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 eectively
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 eects including not only
immunosuppression but also inappropriately enhanced and
misdirected immune responses.
5.15. Polyuorinated and Peruorinated Compounds. e
impact of developmental exposure to peruorooctane sul-
fonic acid (PFOS) and peruorooctanoic 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 dened 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
polyuorinated 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 signicant 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 ramications.
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 identication of DIT risk and improved pro-
tection of age-, sex-, and genotype-based hypervulnerable
subpopulations are needed. is may well require a dierent
approach to safety testing. With the potential for epigenetic
alterationstobeproducedinuteroandinheritanceofaltered
immune- and inammation-related gene expression across
generations, it is apparent that eorts to reduce the prevalence
of NCDs need to focus on early life. Reducing the prevalence
of DIT is an important rst step in comprehensive eorts 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: Condence 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: Peruorooctanoic acid
PFOS: Peruorooctane 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 conict of interests
regarding the publication of this paper.
Acknowledgment
e author thanks Janice Dietert, Performance Plus Consult-
ing, for her editorial suggestions.
References
[] R. R. Dietert, “Developmental immunotoxicology: focus on
health risks,” Chemical Research in Toxicology,vol.,no.,pp.
–, .
[] R.R.Dietert,J.C.DeWitt,D.R.Germolec,andJ.T.Zeliko,
“Breaking patterns of environmentally inuenced disease for
health risk reduction: Immune perspectives,” Environmental
Health Perspectives,vol.,no.,pp.–,.
[] R. V. House and M. J. Selgrade, “A quarter-century of immuno-
toxicology: looking back, looking forward,” Toxicological Sci-
ences,vol.,no.,pp.–,.
[] J. H. Dean, M. I. Luster, and G. A. Boorman, “Methods and
approaches for assessing immunotoxicity: an overview,” Envi-
ronmental Health Perspectives, vol. , pp. –, .
[] M. K. Selgrade, M. J. Daniels, G. R. Burleson, L. D. Lauer,
and J. H. Dean, “Eects of ,-dimethylbenz[a]anthracene,
benzo[a]pyrene and cyclosporin A on murine cytomegalovirus
infection: studies of resistance mechanisms,” International Jour-
nal of Immunopharmacology, vol. , no. , pp. –, .
[] J. G. Vos, “Immune suppression as related to toxicology,” Journal
of Immunotoxicology, vol. , pp. –, .
[] D. J. Barrett, “Characterization of the acquired immune de-
ciency syndrome at the cellular and molecular level,” Molecular
and Cellular Biochemistry,vol.,no.,pp.–,.
[] H. C. Lane and A. S. Fauci, “Immunologic abnormalities in
the acquired immunodeciency syndrome,” Annual Review of
Immunology,vol.,pp.–,.
[ ] M. I. Luster, C . Port ier, D. G. Pait, and D. R. G ermol ec, “ e
use of animal tests in risk assessment for immunotoxicology,”
Tox i c o l o g y i n Vi t ro,vol.,no.,pp.–,.
[] M.I.Luster,C.Portier,D.G.Paitetal.,“Riskassessmentin
immunotoxicology. I. Sensitivity and predictability of immune
tests,” Fundamental and Applied Toxicology,vol.,no.,pp.
–, .
[] M. I. Luster, C. Portier, D. G. Pait et al., “Risk assessment in
immunotoxicology. II. Relationships between immune and host
resistance tests,” FundamentalandAppliedToxicology,vol.,
no. , pp. –, .
[] J. G. Vos and H. Van Loveren, “Experimental studies on
immunosuppression: how do they predict for man?” Tox i c o l og y ,
vol. , no. , pp. –, .
[] D.A.Basketter,E.Selbie,E.W.Scholes,D.Lees,I.Kimber,and
P. A. Botham, “Results with OECD recommend positive control
sensitizers in the maximization, Buehler and local lymph node
assays,” FoodandChemicalToxicology,vol.,no.,pp.–,
.
[] D. A. Basketter, J. N. Bremmer, M. E. Kammuller et al., “e
identication of chemicals with sensitizing or immunosup-
pressive properties in routine toxicology,” Food and Chemical
Tox i c o l o g y ,vol.,no.,pp.–,.
[] M.I.Luster,R.E.Faith,andJ.A.McLachlan,“Alterationsofthe
antibody response following in utero exposure to diethylstilbe-
strol,” Bulletin of Environmental Contamination and Toxicology,
vol. , no. , pp. –, .
Advances in Medicine
[]M.I.Luster,R.E.Faith,J.A.McLachlan,andG.C.Clark,
“Eect of in utero exposure to diethylstilbestrol on the immune
response in mice,” Toxicology and Applied Pharmacology,vol.,
no. , pp. –, .
[] M. I. Luster, R. E. Faith, and C. A. Kimmel, “Depression of
humoral immunity in rats following chronic developmental
lead exposure,” Journal of Environmental Pathology and Toxicol-
ogy, vol. , no. , pp. –, .
[] R. E. Faith, M. I. Luster, and C. A. Kimmel, “Eect of chronic
developmental lead exposure on cell-mediated immune func-
tions,” Clinical and Experimental Immunology,vol.,no.,pp.
–, .
[]J.M.Spyker-Cranmer,J.B.Barnett,D.L.Avery,andM.F.
Cranmer, “Immunoteratology of chlordane: cell-mediated and
humoral immune responses in adult mice exposed in utero,”
Toxicology and Applied Pharmacology,vol.,no.,pp.–
, .
[] V. Jagadeesan, C. Rukmini, M. Vijayaraghavan, and P. G.
Tulpule, “Immune studies with T- toxin: eect of feeding and
withdrawal in monkeys,” Food and Chemical Toxicology,vol.,
no. , pp. –, .
[] R. R. Dietert, S. E. Bloom, M. A. Qureshi, and U. C. Nanna,
“Hematological toxicology following embryonic exposure to
aatoxin-B,” Proceedings of the Society for Experimental Biology
and Medicine,vol.,no.,pp.–,.
[] R. R. Dietert, M. A. Qureshi, U. C. Nanna, and S. E. Bloom,
“Embryonic exposure to aatoxin-B: mutagenicity and inu-
ence on development and immunity,” Environmental Mutagen-
esis,vol.,no.,pp.–,.
[] P. Urso and N. Gengozian, “Depressed humoral immunity and
increased tumor incidence in mice following in utero exposure
to benzo[a]pyrene,” Journal of Toxicology and Environmental
Health,vol.,no.,pp.–,.
[] M. Schlumpf, E. E. B¨
utikofer,A.A.Schreiber,R.Parmar,H.
R. Ramseier, and W. Lichtensteiger, “Delayed developmental
immunotoxicity of prenatal benzodiazepines,” Tox i c ology in
Vitro,vol.,no.,pp.–,.
[]S.D.HolladayandB.J.Smith,“Alterationsinmurinefetal
thymus and liver hematopoietic cell populations following
developmental exposure to ,- dimethylbenz[a]anthracene,”
Environmental Research,vol.,no.,pp.–,.
[] S. G. Selevan, C. A. Kimmel, and P. Mendola, “Identifying crit-
ical windows of exposure for children’s health,” Environmental
Health Perspectives,vol.,no.,pp.–,.
[] S. D. Holladay and R. J. Smialowicz, “Development of the
murine and human immune system: dierential eects of
immunotoxicants depend on time of exposure,” Environmental
Health Perspectives,vol.,,pp.–,.
[] R. R. Dietert, R. A. Etzel, D. Chen et al., “Workshop to identify
critical windows of exposure for children’s health: immune
and respiratory systems work group summary,” Environmental
Health Perspectives,vol.,no.,pp.–,.
[] S. D. Holladay, Developmental Immunotoxicology,CRCPress,
Boca Raton, Fla, USA, .
[] S. Langley-Evans, “Fetal programming of immune function and
respiratory disease,” Clinical and Experimental Allergy,vol.,
no. , pp. –, .
[] A. M. V. Ward andD. I. W. Phillips, “Fetal programming of stress
responses,” Stress,vol.,no.,pp.–,.
[] D. J. P. Barker, “e developmental origins of insulin resistance,”
Hormone Research,vol.,no.,pp.–,.
[] R.W.Luebke,D.H.Chen,R.Dietert,Y.Yang,M.King,andM.I.
Luster, “e comparative immunotoxicity of ve selected com-
pounds following developmental or adult exposure,” Journal of
Toxicology and Environmental Health B,vol.,no.,pp.–,
.
[] J.C.Dewitt,M.M.Peden-Adams,D.E.Keil,andR.R.Dietert,
“Current status of developmental immunotoxicity: early-life
patterns and testing,” Toxicologic Pathology,vol.,no.,pp.
–, .
[] R. R. Dietert and M. P. Holsapple, “Methodologies for develop-
mental immunotoxicity (DIT) testing,” Methods,vol.,no.,
pp. –, .
[]M.Collinge,L.A.Burns-Naas,G.J.Chellmanetal.,“Devel-
opmental immunotoxicity (DIT) testing of pharmaceuticals:
current practices, state of the science, knowledge gaps, and
recommendations,” Journal of Immunotoxicology,vol.,no.,
pp.–,.
[] A. H. Piersma, E. C. Tonk, S. L. Makris, K. M. Croon, R. R.
Dietert, and H. van Loveren, “Juvenile toxicity testing protocols
for chemicals,” Reproductive Toxicology,vol.,pp.–,
.
[] R. R. Dietert and M. S. Piepenbrink, “Perinatal immunotoxicity:
why adult exposure assessment fails to predict risk,” Environ-
mental Health Perspectives,vol.,no.,pp.–,.
[] R. R. Dietert, J. C. DeWitt, and R. W. Luebke, “Reducing the
prevalence of immune-based chronic dsisease,” in Immunotox-
icity, Immune Dysfunction, and Chronic Disease,R.R.Dietert
andR.W.Dietert,Eds.,pp.–,Humana,NewYork,NY,
USA, .
[] R. R. Dietert, “Role of developmental immunotoxicity and
immune dysfunction in chronic disease and cancer,” Reproduc-
tive Toxicology, vol. , no. , pp. –, .
[] D.J.P.Barker,P.D.Winter,C.Osmond,B.Margetts,andS.J.
Simmonds, “Weight in infancy and death from ischaemic heart
disease,” e Lancet,vol.,no.,pp.–,.
[] D.J.P.Barker,A.R.Bull,C.Osmond,andS.J.Simmonds,“Fetal
and placental size and risk of hypertension in adult life,” British
Medical Journal,vol.,no.,pp.–,.
[] D. J. Barker, “e intrauterine environment and adult cardio-
vascular disease,” Ciba Foundation Symposium,vol.,pp.–
, .
[] N. Paneth and M. Susser, “Early origin of coronary heart
disease (the “Barker hypothesis”). Hypotheses, no matter how
intriguing, need rigorous attempts at refutation,” Briti sh Medical
Journal,vol.,no.,pp.–,.
[] H.WendyE,M.Rees,E.Kile,J.D.Mathews,andZ.Wang,“A
new dimension to the Barker hypothesis: low birthweight and
susceptibility to renal disease,” Kidney International,vol.,no.
, pp. –, .
[] M. J. Holness, M. L. Langdown, and M. C. Sugden, “Early-
life programming of susceptibility to dysregulation of glucose
metabolism and the development of type diabetes mellitus,”
Biochemical Journal,vol.,no.,pp.–,.
[] S. Darney, B. Fowler, P. Grandjean, J. Heindel, D. Mattison, and
W. Slikker Jr., “Prenatal Programming and Toxicity II (PPTOX
II): role of environmental stressors in the developmental origins
of disease,” Reproductive Toxicology,vol.,no.,p.,.
[] R. Barouki, P. D. Gluckman, P. Grandjean, M. Hanson, and
J. J. Heindel, “Developmental origins of non-communicable
disease: implications for research and public health,” Environ-
mental Health,vol.,p.,.
Advances in Medicine
[] J.C.DeWitt,M.M.Peden-Adams,D.E.Keil,andR.R.Dietert,
“Developmental immunotoxicity (DIT): assays for evaluating
eects of exogenous agents on development of the immune
system,” in Current Protocols in Toxicology,chapter,p.,
.
[] G. R. Burleson and F. G. Burleson, “Testing human biologicals
in animal host resistance models,” Journal of Immunotoxicology,
vol.,no.,pp.–,.
[] M. Collinge, M. orn, V. Peachee, and K. White Jr., “Validation
of a Candida albicans delayed-type hypersensitivity (DTH)
model in female juvenile rats for use in immunotoxicity assess-
ments,” Journal of Immunotoxicology,vol.,no.,pp.–,
.
[] E. C. M. Tonk, D. M. G. de Groot, A. H. Penninks et al.,
“Developmental immunotoxicity of methylmercury: the rel-
ative sensitivity of developmental and immune parameters,”
Toxicological Sciences,vol.,no.,pp.–,.
[] E.C.M.Tonk,A.Verhoef,L.J.J.delaFonteyneetal.,“Devel-
opmental immunotoxicity in male rats aer juvenile exposure
to di-n-octyltin dichloride (DOTC),” Reproductive Toxicology,
vol.,no.,pp.–,.
[] E.C.M.Tonk,A.Verhoef,E.R.Gremmer,H.vanLoveren,
andA.H.Piersma,“Relativesensitivityofdevelopmentaland
immune parameters in juvenile versus adult male rats aer
exposure to di(-ethylhexyl) phthalate,” To x i cology and A p plied
Pharmacology,vol.,no.,pp.–,.
[] E.C.Tonk,A.Verhoef,E.R.Gremmer,H.vanLoveren,andA.
H. Piersma, “Developmental immunotoxicity in male rats aer
juvenile exposure to ethanol,” To x i c ology,vol.,pp.–,
.
[]R.R.Dietert,J.-E.Lee,J.Olsen,K.Fitch,andJ.A.Marsh,
“Developmental immunotoxicity of dexamethasone: compari-
son of fetal versus adult exposures,” To x i colog y,vol.,no.-,
pp.–,.
[] B. C. Gehrs, M. M. Riddle, W. C. Williams, and R. J. Smialowicz,
“Alterations in the developing immune system of the F
rat aer perinatal exposure to , , , -tetrachlorodibenzo-p-
dioxin: II. Eects on the pup and the adult,” Tox i c ology,vol.,
pp.–,.
[] T. E. Miller, K. A. Golemboski, R. S. Ha, T. Bunn, F. S. Sanders,
and R. R. Dietert, “Developmental exposure to lead causes
persistent immunotoxicity in Fischer rats,” Toxicological
Sciences, vol. , no. , pp. –, .
[]D.B.Walker,W.C.Williams,C.B.Copeland,andR.J.
Smialowicz, “Persistent suppression of contact hypersensitivity,
and altered T-cell parameters in F rats exposed perinatally to
,,,-tetrachlorodibenzo-p- dioxin (TCDD),” To x icolo g y,vol.
, no. , pp. –, .
[] I. Hussain, M. S. Piepenbrink, K. J. Fitch, J. A. Marsh, and R.
R. Dietert, “Developmental immunotoxicity of cyclosporin-A
in rats: age-associated dierential eects,” Toxicol o g y ,vol.,
no. , pp. –, .
[] T. L. Bunn, P. J. Parsons, E. Kao, and R. R. Dietert, “Exposure
to lead during critical windows of embryonic development:
dierential immunotoxic outcome based on stage of exposure
and gender,” Toxicological Sciences,vol.,no.,pp.–,.
[] M. C. Jenmalm and K. Duch´
en, “Timing of allergy-preventive
and immunomodulatory dietary interventions—are prenatal,
perinatal or postnatal strategies optimal?” Clinical and Exper-
imental Allergy,vol.,pp.–,.
[] D. E. Bloom, E. T. Caero, E. Jan´
e-Llopis et al., e Global Eco-
nomic Burden of Noncommunicable Diseases, World Economic
Forum, Geneva, Switzerland, .
[] R. R. Dietert, “Misregulated inammation as an outcome of
early-life exposure to endocrine-disrupting chemicals,” Reviews
in Environmental Health,vol.,pp.–,.
[] S. L. Prescott, “Early-life environmental determinants of allergic
diseases and the wider pandemic of inammatory noncommu-
nicable diseases,” Journal of Allergy and Clinical Immunology,
vol. , pp. –, .
[] R. R. Dietert and R. W. Dietert, Eds., Immunotoxicity, Immune
Dysfunction, and Chronic Disease, Humana, New York, NY,
USA, .
[] R. R. Dietert and J. T. Zeliko, “Pediatric immune dysfunction
and health risks following early-life immune insult,” Current
Pediatric Reviews,vol.,no.,pp.–,.
[] R. R. Dietert and J. T. Zeliko, “Identifying patterns of immune-
related disease: use in disease prevention and management,”
World Journal of Pediatrics,vol.,no.,pp.–,.
[] R. R. Dietert, “Immune system disorders,” in Aging and Vulner-
ability to Environmental Chemicals: Age-Related Disorders and
eir Origins in Environmental Exposures,B.Weiss,Ed.,Royal
Society of Chemistry, London, UK, .
[] A.Pham-Short,K.C.Donaghue,G.Ambler,A.K.Chan,and
M. E. Craig, “Coeliac disease in Type diabetes from to
: higher incidence in young children aer longer diabetes
duration,” Diabetic Medicine,vol.,pp.e–e,.
[] D. Greco, M. Pisciotta, F. Gambina, and F. Maggio., “Graves’
disease in subjects with type diabetes mellitus: a prevalence
study in western Sicily (Italy),” Primary Care Diabetes,vol.,
no. , pp. –, .
[] C. Papoutsakis, K. N. Priis, M. Drakouli et al., “Childhood
overweight/obesity and asthma: is there a link? A system-
atic review of recent epidemiologic evidence,” Journal of the
Academy of Nutrition and Dietetics, vol. , pp. –, .
[] H. Lazaratou, A. Soldatou, and D. Dikeos, “Medical comor-
bidity of sleep disorders in children and adolescents,” Current
Opinion in Psychiatry,vol.,pp.–,.
[]M.Tanaka,S.Anders,andD.K.Kinney,“Environment,the
immune system, and depression: an integrative review and dis-
cussion of the infection-defense hypothesis,” in Immunotoxicity,
Immune Dysfunction, and Chronic Disease,R.R.DietertandR.
W. Dietert, Eds., Humana, New York, NY, USA, .
[] S. Anders, M. Tanaka, and D. K. Kinney, “Depression as
an evolutionary strategy for defense against infection,” Brain,
Behavior, and Immunity,vol.,pp.–,.
[] K. Nadeau, C. McDonald-Hyman, E. M. Noth et al., “Ambient
air pollution impairs regulatory T-cell function in asthma,”
Journal of Allergy and Clinical Immunology,vol.,no.,pp.
.e–.e, .
[] M. Kerkhof, D. S. Postma, B. Brunekreef et al., “Toll-like
receptor and genes inuence susceptibility to adverse eects
of trac-related air pollution on childhood asthma,” orax,
vol.,no.,pp.–,.
[] L. Calder´
on-Garcidue˜
nas, M. Mac´
ıas-Parra, H. J. Homann et
al., “Immunotoxicity and environment: immunodysregulation
and systemic inammation in children,” Toxicological Pathol-
ogy,vol.,pp.–,.
[] G.Herberth,R.Gubelt,S.R
¨
oder et al., “Increase of inamma-
tory markers aer indoor renovation activities: e LISA Birth
Cohort Study,” Pediatric Allergy and Immunology,vol.,no.,
pp. –, .
Advances in Medicine
[] D. Krewski, R. A. Yokel, E. Nieboer et al., “Human health risk
assessment for aluminium, aluminium oxide, and aluminium
hydroxide,” JournalofToxicologyandEnvironmentalHealthB,
vol.,no.,pp.–,.
[] R. L. Poole, K. P. Pieroni, S. Gaskari, T. Dixon, and J. A.
Kerner, “Aluminum exposure in neonatal patients using the
least contaminated parenteral nutrition solution products,”
Nutrients,vol.,pp.–,.
[] Y. Z. Zhu, D. W. Liu, Z. Y. Liu, and Y. F. Li, “Impact of aluminum
exposure on the immune system: a mini review,” Environmental
Tox i c o l o g y a nd Phar m a c o log y , vol. , pp. –, .
[] E. Israeli, N. Agmon-Levin, M. Blank, and Y. Shoenfeld,
“Macrophagic myofaciitis a vaccine (alum) autoimmune-
related disease,” Clinical Reviews in Allergy and Immunology,
vol.,no.,pp.–,.
[] R. K. Gherardi and F. J. Authier, “Macrophagic myofasciitis:
characterization and pathophysiology,” Lupus,vol.,no.,pp.
–, .
[] O. Vera-Lastra, G. Medina, P. Cruz-Dominguez Mdel, L. J.
Jara, and Y. Shoenfeld, “Autoimmune/inammatory syndrome
induced by adjuvants (Shoenfeld’s syndrome): clinical and
immunological spectrum,” Expert Reviews in Clinical Immunol-
ogy,vol.,pp.–,.
[] T. Nakayama, Y. Kashiwagi, H. Kawashima, T. Kumagai, K. J.
Ishii, and T. Ihara, “Alum-adjuvanted HN whole virion inac-
tivated vaccine (WIV) enhanced inammatory cytokine pro-
ductions,” Vaccin e ,vol.,pp.–,.
[] T. D. Terhune and R. C. Deth, “How aluminum adjuvants could
promote and enhance non-target IgE synthesis in a genetically-
vulnerable sub-population,” Journal of Immunotoxicology,vol.
, pp. –, .
[] A. Lerner, “Aluminum as an adjuvant in Crohn’s disease induc-
tion,” Lupus,vol.,no.,pp.–,.
[] F. Raciborski, A. Tomaszewska, J. Komorowski et al., “e
relationship between antibiotic therapy in early childhood and
the symptoms of allergy in children aged – years—the ques-
tionnaire study results,” International Journal of Occupational
Medicine and Environmental Health,vol.,pp.–,.
[] K. Heintze and K. U. Petersen, “e case of drug causation
of childhood asthma: antibiotics and paracetamol,” European
Journal of Clinical Pharmacology,vol.,pp.–,.
[] R. R. Dietert and J. M. Dietert, “e completed self: an immuno-
logical view of the human-microbiome superorganism and
risk of chronic diseases,” Entropy,vol.,pp.–,.
[] N. L. Dangleben, C. F. Skibola, and M. T. Smith, “Arsenic
immunotoxicity: a review,” Environmental Health,vol.,p.,
.
[] G. A. Soto-Pe˜
na, A. L. Luna, L. Acosta-Saavedra et al., “Assess-
ment of lymphocyte subpopulations and cytokine secretion in
children exposed to arsenic,” FASEB Journal,vol.,no.,pp.
–, .
[] D. O. Rocha-Amador, J. Calder´
on, L. Carrizales, R. Costilla-
Salazar, and I. N. P´
erez-Maldonado, “Apoptosis of peripheral
blood mononuclear cells in children exposed to arsenic and
uoride,” Environmental Toxicology and Pharmacology,vol.,
no. , pp. –, .
[] S. Ahmed, K. B. Ahsan, M. Kippler et al., “In utero arsenic
exposure is associated with impaired thymic function in new-
borns possibly via oxidative stress and apoptosis,” Toxicological
Sciences, vol. , pp. –, .
[] S. Ahmed, S. M.-E. Khoda, R. S. Rekha et al., “Arsenic-
associated oxidative stress, inammation, and immune disrup-
tion in human placenta and cord blood,” Environmental Health
Perspectives,vol.,no.,pp.–,.
[]A.L.Luna,L.C.Acosta-Saavedra,L.Lopez-Carrilloetal.,
“Arsenic alters monocyte superoxide anion and nitric oxide
production in environmentally exposed children,” Toxicol o g y
and Applied Pharmacology,vol.,no.,pp.–,.
[] A. Rahman, M. Vahter, E.-C. Ekstr¨
om, and L.- ˚
A. Persson,
“Arsenic exposure in pregnancy increases the risk of lower
respiratory tract infection and diarrhea during infancy in
Bangladesh,” Environmental Health Perspectives,vol.,no.,
pp.–,.
[] J. A. Rogers, L. Metz, and V. W. Yong, “Review: endocrine
disrupting chemicals and immune responses: a focus on
bisphenol-A and its potential mechanisms,” Molecular Immu-
nology,vol.,pp.–,.
[] E.M.ReesClayton,M.Todd,J.B.Dowd,andA.E.Aiello,“e
impact of bisphenol A and triclosan on immune parameters
in the U.S. population, NHANES –,” Environmental
Health Perspectives,vol.,no.,pp.–,.
[] J. H. Kim, L. S. Rozek, A. S. Soliman et al., “Bisphenol A-
associated epigenomic changes in prepubescent girls: a cross-
sectional study in Gharbiah, Egypt,” Environmental Health,vol.
, p. , .
[] J. Unterscheider, M. McMenamin, and F. Cullinane, “Rising
rates of caesarean deliveries at full cervical dilatation: a con-
cerning trend,” European Journal of Obstetrics Gynecology and
Reproductive Biology,vol.,no.,pp.–,.
[] J. Neu and J. Rushing, “Cesarean Versus Vaginal Delivery: long-
term infant outcomes and the Hygiene Hypothesis,” Clinics in
Perinatology,vol.,no.,pp.–,.
[] R. R. Dietert, “Natural childbirth and breastfeeding as preven-
tive measures of immune-microbiome dysbiosis and misregu-
lated inammation,” Journal of Ancient Diseases & Preventive
Remedies,vol.,p.,.
[] C.E.ChoandM.Norman,“Cesareansectionanddevelopment
of the immune system in the ospring,” American Journal of
Obstetrics and Gynecology,vol.,pp.–,.
[] M. B. Azad, T. Konya, H. Maughan et al., “Gut microbiota
of healthy Canadian infants: proles by mode of delivery and
infant diet at months,” Canadian Medical Association Journal,
vol. , pp. –, .
[] M. L. Houben, P. G. J. Nikkels, G. M. van Bleek et al., “e asso-
ciation between intrauterine inammation and spontaneous
vaginal delivery at term: A Cross-Sectional Study,” PLoS ONE,
vol. , no. , article e, .
[] V.C.Romero,E.C.Somers,V.Stolbergetal.,“Developmental
programming for allergy: a secondary analysis of the Mothers,
Omega-, and Mental Health Study,” American Journal of
Obstetrics & Gynecology, vol. , pp. .e–.e, .
[] C.-M. Shen, S.-C. Lin, D.-M. Niu, and Y. R. Kou, “Labour
increases the surface expression of two toll-like receptors in
the cord blood monocytes of healthy term newborns,” Acta
Paediatrica, International Journal of Paediatrics, vol. , no. ,
pp. –, .
[] B. Kr´
olak-Olejnik and I. Olejnik, “Late-preterm cesarean deliv-
ery and chemokines concentration in the umbilical cord blood
of neonates,” Journal of Maternal-Fetal and Neonatal Medicine,
vol. , pp. –, .
[] A. Malamitsi-Puchner, E. Protonotariou, T. Boutsikou, E.
Makrakis, A. Sarandakou, and G. Creatsas, “e inuence of
Advances in Medicine
the mode of delivery on circulating cytokine concentrations in
the perinatal period,” Early Human Development,vol.,no.,
pp. –, .
[] C.Roduit,S.Scholtens,J.C.DeJongsteetal.,“Asthmaatyears
ofageinchildrenbornbycaesareansection,”orax,vol.,no.
, pp. –, .
[] M. B. Azad and A. L. Kozyrskyj, “Perinatal programming of
asthma: the role of gut microbiota,” Clinical and Developmental
Immunology,vol.,ArticleID,pages,.
[] T. R. Abrahamsson, H. E. Jakobsson, A. F. Andersson, B.
Bj¨
orkst´
en, L. Engstrand, and M. C. Jenmalm, “Low diversity of
the gut microbiota in infants with atopic eczema,” Journal of
Allergy and Clinical Immunology, vol. , no. , pp. –,
.
[] E. Decker, M. Hornef, and S. Stockinger, “Cesarean delivery
is associated with celiac disease but not inammatory bowel
disease in children,” Gut Microbes,vol.,no.,pp.–,.
[] J. Phillips, N. Gill, K. Sikdar, S. Penney, and L. A. Newhook,
“History of cesarean section associated with childhood onset
of TDM in Newfoundland and Labrador, Canada,” Journal of
Environmental and Public Health,vol.,ArticleID,
pages,.
[] E. Bonifacio, K. Warncke, C. Winkler, M. Wallner, and A.-G.
Ziegler, “Cesarean section and interferon-induced helicase gene
polymorphisms combine to increase childhood type diabetes
risk,” Diabetes,vol.,no.,pp.–,.
[] S. avagnanam, J. Fleming, A. Bromley, M. D. Shields, and
C. R. Cardwell, “A meta-analysis of the association between
Caesarean section and childhood asthma,” Clinical and Experi-
mental Allergy,vol.,no.,pp.–,.
[] M. C. Magnus, S. E. H˚
aberg, H. Stigum et al., “Delivery by
Cesarean section and early childhood respiratory symptoms
and disorders: the Norwegian mother and child cohort study,”
American Journal of Epidemiology,vol.,no.,pp.–,
.
[] E.R.Bertone-Johnson,B.W.Whitcomb,S.A.Missmer,E.W.
Karlson, and J. W. Rich-Edwards, “Inammation and early-life
abuse in women,” American Journal of Preventive Medicine,vol.
, pp. –, .
[] N. Slopen, K. C. Koenen, and L. D. Kubzansky, “Childhood
adversity and immune and inammatory biomarkers associated
with cardiovascular risk in youth: a systematic review,” Brain,
Behavior, and Immunity,vol.,no.,pp.–,.
[] A. J. J. M. Vingerhoets, J. Assies, K. Goodkin, G. L. Van Heck,
and M. H. Bekker, “Prenatal diethylstilbestrol exposure and
self-reported immune-related diseases,” European Journal of
Obstetrics Gynecology and Reproductive Biology,vol.,no.,
pp. –, .
[] W. C. Strohsnitter, K. L. Noller, R. Troisi et al., “Autoimmune
disease incidence among women prenatally exposed to diethyl-
stilbestrol,” Journal of Rheumatology,vol.,no.,pp.–
, .
[] E. C. Tonk, D. M. de Groot, A. P. Wolterbeek et al., “Devel-
opmental immunotoxicity of ethanol in an extended one-
generation reproductive toxicity study,” Archives of Toxicolog y,
vol.,no.,pp.–,.
[] X.Zhang,N.Lan,P.Bachetal.,“Prenatalalcoholexposurealters
the course and severity of adjuvant-induced arthritis in female
rats,” Brain, Behavior, and Immunity, vol. , no. , pp. –,
.
[] X.-D.Ping,F.L.Harris,L.A.S.Brown,andT.W.Gauthier,“In
vivo dysfunction of the term alveolar macrophage aer in utero
ethanol exposure,” Alcoholism, vol. , no. , pp. –, .
[] J. McGill, D. K. Meyerholz, M. Edsen-Moore et al., “Fetal expo-
sure to ethanol has long-term eects on the severity of inuenza
virus infections,” JournalofImmunology,vol.,no.,
pp. –, .
[]S.J.Kelly,N.Day,andA.P.Streissguth,“Eectsofprenatal
alcohol exposure on social behavior in humans and other
species,” Neurotoxicology and Teratolog y,vol.,no.,pp.–
, .
[] N. L. Day, A. Helsel, K. Sonon, and L. Goldschmidt, “e
association between prenatal alcohol exposure and behavior at
years of age,” Alcoholism: Clinical and Experimental Research,
vol. , pp. –, .
[]C.G.Carson,L.B.Halkjaer,S.M.Jensen,andH.Bisgaard,
“Alcohol intake in pregnancy increases the child’s risk of atopic
dermatitis. e COPSAC prospective birth cohort study of a
high risk population,” PLoS One,vol.,articlee,.
[] W.Yuan,H.T.Sørensen,O.Basso,andJ.Olsen,“Prenatalmater-
nal alcohol consumption and hospitalization with asthma in
childhood: A Population-Based Follow-up Study,” Alcoholism,
vol.,no.,pp.–,.
[] S. O. Shaheen, C. Rutterford, L. Zuccolo et al., “Prenatal alcohol
exposure and childhood atopic disease: a Mendelian random-
ization approach,” Journal of Allergy and Clinical Immunology,
.
[] M. McDonnell Naughton, C. McGarvey, M. O. Regan, and T.
Matthews, “Maternal smoking and alcohol consumption during
pregnancy as risk factors for sudden infant death,” Iri sh Medical
Journal,vol.,no.,pp.–,.
[] A. P. Pineda-Zavaleta, G. Garc´
ıa-Vargas, V. H. Borja-Aburto et
al., “Nitric oxide and superoxide anion production in mono-
cytes from children exposed to arsenic and lead in region
Lagunera, Mexico,” Toxicology and Applied Pharmacology,vol.
, no. , pp. –, .
[] W.Karmaus,K.R.Brooks,T.Nebe,J.Witten,N.Obi-Osius,and
H. Kruse, “Immune function biomarkers in children exposed to
lead and organochlorine compounds: A Cross-Sectional Study,”
Environmental Health,vol.,no.,article,.
[] S. Li, Z. Zhengyan, L. I. Rong, and C. Hanyun, “Decrease of
CD+ T-lymphocytes in children exposed to environmental
lead,” Biological Trace Element Research,vol.,no.–,pp.–
, .
[] P.M.Lutz,E.A.Kelty,T.D.Brown,T.J.Wilson,G.Brock,and
R. E. Neal, “Environmental cigarette smoke exposure modulates
IgE levels of Pb-exposed children,” To x i c ology,vol.,no.–,
pp.–,.
[] C. A. Leifer and R. R. Dietert, “Early life environment and
developmental immunotoxicity in inammatory dysfunction
and disease,” Toxicological and Environmental Chemistry,vol.
,no.,pp.–,.
[] M. K. Selgrade, R. B. Blain, K. M. Fedak, and M. A. Cawley,
“Potential risk of asthma associated with in utero exposure to
xenobiotics,” Birth Defects Research C,vol.,pp.–,.
[] S. L. Prescott, “Eects of early cigarette smoke exposure on
early immune development and respiratory disease,” Paediatric
Respiratory Reviews,vol.,no.,pp.–,.
[] P.S.Noakes,J.Hale,R.omas,C.Lane,S.G.Devadason,and
S. L. Prescott, “Maternal smoking is associated with impaired
neonatal toll-like-receptor-mediated immune responses,” Euro-
pean Respiratory Journal,vol.,no.,pp.–,.
Advances in Medicine
[] K. M. Wilson, S. C. Wesgate, J. Pier et al., “Secondhand
smoke exposure and serum cytokine levels in healthy children,”
Cytokine,vol.,pp.–,.
[] G.Tebow,D.L.Sherrill,I.C.Lohmanetal.,“Eectsofparental
smoking on interferon 𝛾production in children,” Pediatrics,vol.
, no. , pp. e–e, .
[] P. Kum-Nji, L. Meloy, and H. G. Herrod, “Environmental
tobacco smoke exposure: prevalence and mechanisms of cau-
sation of infections in children,” Pediatrics,vol.,no.,pp.
–, .
[]G.Baynam,S.-K.Khoo,J.Roweetal.,“Parentalsmoking
impairs vaccine responses in children with atopic genotypes,”
Journal of Allergy and Clinical Immunology,vol.,no.,pp.
–, .
[] C.S.Wilhelm-Benartzi,B.C.Christensen,D.C.Koestleretal.,
“Association ofs econdhandsmoke exposures with DNA methy-
lation in bladder carcinomas,” Cancer Causes and Control,vol.
, no. , pp. –, .
[] A.B.T.Andersen,D.K.Farkas,F.Mehnert,V.Ehrenstein,and
R. Erichsen, “Use of prescriptionparacetamol during pregnancy
and risk of asthma in children: a population-based Danish
cohort study,” Clinical Epidemiology,vol.,no.,pp.–,
.
[] F. J. Gonzalez-Barcala, S. Pertega, T. P. Castro et al., “Exposure to
paracetamol and asthma symptoms,” European Journal of Public
Health,vol.,pp.–,.
[]A.J.HendersonandS.O.Shaheen,“Acetaminophenand
asthma,” Paediatric Respiratory Reviews,vol.,pp.–,.
[] A. R. Scialli, R. Ang, J. Breitmeyer, and M. A. Royal, “Childhood
asthma and use during pregnancy of acetaminophen: a critical
review,” Reproductive Toxicology,vol.,no.,pp.–,
.
[] M. Muc, C. Padez, and A. M. Pinto, “Exposure to paracetamol
and antibiotics in early life and elevated risk of asthma in
childhood,” Advances in Experimental Medicine and Biology,
vol.,pp.–,.
[]K.iele,T.Kessler,P.Arck,A.Erhardt,andG.Tiegs,
“Acetaminophen and pregnancy: short- and long-term conse-
quences for mother and child,” Journal of Reproductive Immu-
nology,vol.,pp.–,.
[] J. T. McBride, “e association of acetaminophen and asthma
prevalence and severity,” Pediatrics,vol.,no.,pp.–,
.
[] S. H. Kang, Y. H. Jung, H. Y. Kim et al., “Eect of paracetamol
use on the modication of the development of asthma by
reactive oxygen species genes,” Annuals of Allergy, Asthma &
Immunology, vol. , pp. –, .
[] S. O. Shaheen, R. B. Newson, S. M. Ring, M. J. Rose-Zerilli,
J. W. Holloway, and A. J. Henderson, “Prenatal and infant
acetaminophen exposure, antioxidant gene polymorphisms,
and childhood asthma,” Journal of Allergy and Clinical Immu-
nology,vol.,no.,pp.–,.
[] A. F. Hern´
andez, T. Parr´
on,A.M.Tsatsakis,M.Requena,R.
Alarc´
on, and O. L´
opez-Guarnido, “Toxic eects of pesticide
mixtures at a molecular level: their relevance to human health,”
Tox i c o l o g y ,vol.,pp.–,.
[] L. S. Kjeldsen, M. Ghisari, and E. C. Bonefeld-Jørgensen, “Cur-
rently used pesticides and their mixtures aect the function
of sex hormone receptors and aromatase enzyme activity,”
Toxicology and Applied Pharmacology,vol.,no.,pp.–
, .
[] N. Bonvallot, M. Tremblay-Franco, C. Chevrier et al.,
“Metabolomics tools for describing complex pesticide exposure
in pregnant women in brittany (france),” PLoS One,vol.,
article e, .
[] S. Boucher, M. N. Simard, G. Muckle et al., “Exposure to an
organochlorine pesticide (chlordecone) and development of -
month-old infants,” Neurotoxicology,vol.,pp.–,.
[] V. Rauh, S. Arunajadai, M. Horton et al., “Seven-year neurode-
velopmental scores and prenatal exposure to chlorpyrifos, a
common agricultural pesticide,” EnvironmentalHealthPerspec-
tives,vol.,no.,pp.–,.
[]S.M.Engel,J.Wetmur,J.Chenetal.,“Prenatalexposureto
organophosphates, paraoxonase , and cognitive development
in childhood,” Environmental Health Perspectives,vol.,no.,
pp. –, .
[]M.F.Bouchard,J.Chevrier,K.G.Harleyetal.,“Prenatal
exposure to organophosphate pesticides and IQ in -year-old
children,” EnvironmentalHealthPerspectives,vol.,no.,pp.
–, .
[] H.Zhou,C.Huang,J.Tong,andX.-G.Xia,“Earlyexposure
to paraquat sensitizes dopaminergic neurons to subsequent
silencing of PINK gene expression in mice,” Inte rnational
JournalofBiologicalSciences,vol.,no.,pp.–,.
[] T. Taetzsch and M. L. Block, “Pesticides, microglial NOX,
and Parkinson’s disease,” Journal of Biochemical and Molecular
Tox i c o l o g y ,vol.,pp.–,.
[] J. A. Hoppin, D. M. Umbach, S. J. London et al., “Pesticides
and atopic and nonatopic asthma among farm women in the
agricultural health study,” American Journal of Respiratory and
Critical Care Medicine,vol.,no.,pp.–,.
[] E.Corsini,M.Sokooti,C.L.Galli,A.Moretto,andC.Colosiom,
“Pesticide induced immunotoxicity in humans: a comprehen-
sive review of the existing evidence,” Tox icolo g y,vol.,pp.
–, .
[] S. B. Stølevik, U. C. Nygaard, E. Namork et al., “Prenatal
exposure to polychlorinated biphenyls and dioxins from the
maternal diet may be associated with immunosuppressive
eects that persist into early childhood,” Food and Chemical
Tox i c o l o g y ,vol.,pp.–,.
[] C. Heilmann, P. Grandjean, P. Weihe, F. Nielsen, and E. Budtz-
Jørgensen, “Reduced antibody responses to vaccinations in
children exposed to polychlorinated biphenyls,” PLoS Medicine,
vol. , no. , article e, .
[] C. Heilmann, E. Budtz-Jørgensen, F. Nielsen, B. Heinzow, P.
Weihe, and P. Grandjean, “Serum concentrations of antibodies
against vaccine toxoids in children exposed perinatally to
immunotoxicants,” Environmental Health Perspectives,vol.,
no.,pp.–,.
[] P.Grandjean,L.K.Poulsen,C.Heilmann,U.Steuerwald,andP.
Weihe, “Allergy and sensitization during childhood associated
with prenatal and lactational exposure to marine pollutants,”
Environmental Health Perspectives, vol. , no. , pp. –
, .
[] P. Grandjean, E. W. Andersen, E. Budtz-Jørgensen et al.,
“Serum vaccine antibody concentrations in children exposed
to peruorinated compounds,” Journal of the American Medical
Association,vol.,no.,pp.–,.
[] P. Grandjean and E. Budtz-Jørgensen, “Immunotoxicity of
peruorinated alkylates: calculation of benchmark doses based
on serum concentrations in children,” Environmental Health,
vol. , p. , .
Advances in Medicine
[] M. Vinceti, K. J. Rothman, C. M. Crespi et al., “Leukemia risk in
children exposed to benzene and PM from vehicular trac:
a case-control study in an Italian population,” European Journal
of Epidemiology,vol.,pp.–,.
[] W.Palinski,T.Yamashita,S.Freigang,andC.Napoli,“Devel-
opmental programming: maternal hypercholesterolemia and
immunity inuence susceptibility to atherosclerosis,” Nutrition
Reviews,vol.,no.,pp.S–S,.
[] D.Hinz,M.Bauer,S.R
¨
oder et al., “Cord blood Tregs with stable
FOXP expression are inuenced by prenatal environment and
associated with atopic dermatitis at the age of one year,” Allergy,
vol.,no.,pp.–,.
[]W.K.Kim,J.W.Kwon,J.H.Seoetal.,“Interactionbetween
IL genotype and environmental factors in the risk for allergic
rhinitis in Korean children,” JournalofAllergyandClinical
Immunology, vol. , pp. –, .
[] B. Gesundheit, J. P. Rosenzweig, D. Naor et al., “Immunological
and autoimmune considerations of Autism Spectrum Disor-
ders,” Journal Autoimmunity,vol.,pp.–,.
[] R. Parboosing, Y. Ba, L. Shen, C. A. Schaefer, and A. S. Brown,
“Gestational inuenza and bipolar disorder in adult ospring,”
Journal of the American Medical Association Psychatry,vol.,
no.,pp.–,.
[] G. M. Hosang, S. L. Johnson, J. Kiecolt-Glaser et al., “Gender
specic association of child abuse and adult cardiovascular
disease in a sample of patients with basal cell carcinoma,” Child
Abus e & Neg lect,vol.,pp.–,.
[] K. M˚
arild, O. Stephansson, S. Montgomery, J. A. Murray, and
J. F. Ludvigsson, “Pregnancy outcome and risk of celiac disease
in ospring: a nationwide case-control study,” Gastroenterology,
vol. , no. , pp. –, .
[] S.E.Roberts,C.J.Wotton,J.G.Williams,M.Grith,andM.J.
Goldacre, “Perinatal and early life risk factors for inammatory
bowel disease,” World Journal of Gastroenterology,vol.,no.,
pp. –, .
[] R.KodguleandS.Salvi,“Exposuretobiomasssmokeasacause
for airway disease in women and children,” Current Opinion in
Allergy and Clinical Immunology,vol.,no.,pp.–,.
[]S.Lu,H.Peng,L.Wangetal.,“Elevatedspecicperipheral
cytokines found in major depressive disorder patients with
childhood trauma exposure: a cytokine antibody array analysis,”
Comprehensive Psychiatry,vol.,no.,pp.–,.
[] M.Kvasko,A.Bijon,F.Clavel-Chapelon,S.Mesrine,andM.C.
Boutron-Ruault, “Childhood and adolescent exposures and the
risk of endometriosis,” Epidemiology,vol.,pp.–,.
[] M. La Merrill, P. M. Cirillo, M. B. Terry, N. Y. Krigbaum, J.
D. Flom, and B. A. Cohn, “Prenatal exposure to the pesticide
DDT and hypertension diagnosed in women before age :
A Longitudinal Birth Cohort Study,” Environmental Health
Perspective, vol. , pp. –, .
[]J.A.ompsonandT.R.H.Regnault,“Inuterooriginsof
adult insulin resistance and vascular dysfunction,” Seminars in
Reproductive Medicine,vol.,no.,pp.–,.
[]M.W.Koch,L.M.Metz,S.M.Agrawal,andV.W.Yong,
“Environmental factors and their regulation of immunity in
multiple sclerosis,” Journal of Neurological Sciences,vol.,pp.
–, .
[]M.Maes,F.N.M.Twisk,M.Kubera,andK.Ringel,“Evi-
dence for inammation and activation of cell-mediated immu-
nity in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
(ME/CFS): increased interleukin-, tumor necrosis factor-𝛼,
PMN-elastase, lysozyme and neopterin,” Journal of Aective
Disorders,vol.,no.,pp.–,.
[] S. Kempke, P. Luyten, S. Claes et al., “e prevalence and impact
of early childhood trauma in Chronic Fatigue Syndrome,”
Journal of Psychiatric Research,vol.,pp.–,.
[] A. Szak´
acs, N. Darin, and T. Hallb¨
o¨
ok, “Increased childhood
incidence of narcolepsy in western Sweden aer HN inuenza
vaccination,” Neurology,vol.,pp.–,.
[] L. Wijnans, C. Lecomte, and C. de Vries, “e incidence of
narcolepsy in Europe: before, during, and aer the inuenza
A(HN)pdm pandemic and vaccination campaigns,” Va c-
cine,vol.,pp.–,.
[] H.Li,R.Ye,L.Pei,A.Ren,X.Zheng,andJ.Liu,“Caesarean
delivery, caesarean delivery on maternal request and childhood
overweight: a Chinese birth cohort study of – children,”
Pediatric Obesity,.
[] R. G. Jense, A. Koch, P. Homøe, and Bjerregaard, “Tobacco
smokeincreasestheriskofotitismediaamongGreenlandic
Inuit children while exposure to organochlorines remain
insignicant,” Environment International,vol.,pp.–,
.
[] Z. Cs´
ak´
anyi,A.Czinner,J.Spangler,T.Rogers,andG.Katona,
“Relationship of environmental tobacco smoke to otitis media
(OM) in children,” International Journal of Pediatric Otorhino-
laryngology,vol.,pp.–,.
[] O. C. Erdivanli, Z. O. Coskun, K. C. Kazikdas, and M. Demirci,
“Prevalence of otitis media with eusion among Primary School
Children in Eastern Black Sea, in Turkey and the eect of
smoking in the development of otitis media with eusion,”
Indian Journal of Otolaryngology and Head and Neck Surgery,
vol.,no.,pp.–,.
[] Y.H.Yuan,J.D.Sun,M.M.Wu,J.F.Hu,S.Y.Peng,andN.
H. Chen, “Rotenone could activate microglia through NF𝜅B
associated pathway,” Neurochemical Research,vol.,pp.–
, .
[] G. Pereira, F. Haggar, A. W. Shand, C. Bower, A. Cook, and N.
Nassar, “Association between pre-eclampsia and locally derived
trac-related air pollution: A Retrospective Cohort Study,”
Journal of Epidemiology and Community Health,vol.,pp.–
, .
[] M. G. Ozden, N. S. Tekin, M. A. G¨
urer et al., “Environmental
risk factors in pediatric psoriasis: A Multicenter Case-Control
Study,” Pediatric Dermatology,vol.,pp.–,.
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