Int. J. Environ. Res. Public Health 2010, 7, 1-x manuscripts; doi:10.3390/ijerph70x000x
OPEN ACCESS
International Journal of
Environmental
Research and
Public Health
ISSN 1660-4601
www.mdpi.com/journal/ijerph
Case Report
Four Polygamous Families
with Congenital Birth Defects from Fallujah, Iraq
Samira Alaani 1,
Mozhgan Savabieasfahani 2, Mohammad Tafash 1,3
and Paola Manduca 4,*
1 Fallujah General
Hospital , Althubbadh district ,Fallujah, 00964.Iraq; E-Mails: [email protected] (S.A.);
[email protected] (M.S.); [email protected]
(M.T.)
2 P.O. Box 7038; Ann Arbor, Michigan 48107 U.S.A
3 Medical College, Al-Anbar University, Fallujah,
00964.Iraq
4 Laboratory of Genetics, DIBIO, University of
Genoa, Genoa, 16132, Italy
* Author to
whom correspondence should be addressed; E-Mail: [email protected];
Tel.:
+39 10 2470145/+39 10 3538240/ +39 3472540531.
Received: 27 October 2010; in
revised form: 3 December 2010 / Accepted: 21 December 2010 /
Published:
Abstract: Since 2003, congenital malformations have increased to account
for 15% of all births in Fallujah, Iraq. Congenital heart defects have the
highest incidence, followed by neural tube defects. Similar birth defects were
reported in other populations exposed to war contaminants. While the causes of
increased prevalence of birth defects are under investigation, we opted to
release this communication to contribute to exploration of these issues. By
using a questionnaire, containing residential history and activities that may
have led to exposure to war contaminants, retrospective reproductive history of
four polygamous Fallujah families were documented. Our findings point to sporadic, untargeted events, with different
phenotypes in each family and increased recurrence. The prevalence of familial birth defects
after 2003 highlights the relevance of epigenetic mechanisms and offers
insights to focus research, with the aim of reducing further damage to people’s
health.
Keywords: Iraq;
birth defects; war contaminants; epigenetics
1.
Introduction
In Fallujah (Iraq), birth defects, with
prevalence of congenital heart defects (CHD) and neural tube defects (NTD),
have reached in 2010 unprecedented numbers, above the World average [1]. Lack
of a comprehensive birth registry has made it difficult to make an accurate
comparison with the pre war period and to understand modalities and dimension
of this unusual occurrence in Fallujah. We thus introduced a protocol allowing
for reconstruction of the reproductive history of families with birth defects
in Fallujah that allows to see the pattern of their presentation in time. We
present here the analysis of four cases of fathers
with two lineages of progeny, chosen among more than 50 cases under study. Birth
defects presented here are classified according to the primary defect as NTD
(neural tube defects), CHD (cardiac birth defects), SK (skeletal defects), even
when they have additional phenotypes, or O (others). Modalities of presentation
within each family suggest that epigenetic factors may be at the origin of the
mechanisms responsible for these defects. The timing of the birth defect
occurrences suggests that they may be related to war-associated long-term
exposure
to contamination.
The epigenetic origin of many birth
defects is extensively supported by the existing literature [2]. Neural tube
defects are rarely due to traceable genomic changes. The high rate of recurrence of anencephaly in siblings (6.3%) is
understood as due to environmental factors and maternal effects. Studies of NTD
in mice indicate that anencephaly may be due to multifactorial combinations of
hypomorphs and low-penetrance heterozygotes. It is not known how many genes may
contribute to anencephaly in humans.
Congenital heart defects have various
phenotypes and can be compounded by different cardiac-unrelated features.
Approximately 30% of CHD and tetralogy of
Fallot (TOF) have been shown to be associated with wide genomic
rearrangements. Only in a very small fraction of the cases investigated have
cohort studies detected mutations in single genes which are putatively involved
(e.g., Holt-Oram syndrome). Environmental factors are implied in the induction
of most CHD phenotypes, through epigenetic mechanisms.
In mice,
cleft lip is caused by epistatic interactions in the context of genetic
maternal effects. Cleft lip and palate inheritance patterns suggest that the
causes are combinations of genetic and nongenetic factors. Also in mice,
synpolydactyly is linked to Hoxd13 mutations and its manifestation is dependent
upon environmental factors.
Tumorigenesis is a multistep process
involving mutations and epigenetic changes [2]. Repeated cases of infant
leukemia in families are due to genetic predisposition and epigenetic changes
that can occur in-utero by epigenetic modifiers. Transplacental
effector-molecules and epigenetic trans-generational mechanisms are implied in
the manifestation of infant leukemia.
Thus, although in teratogenesis and
infant leukemia can occur through genomic rearrangements or concurrence of
multiple single mutational events, they are most often described and understood
to be due to pleiotropic epigenetic changes which affect more than one
function, or to a combination of these three mechanisms.
Many known war contaminants have the
potential to interfere with normal embryonic and fetal development. The
devastating reproductive health effects of dioxins (the major contaminant of
Agent Orange) on the Vietnamese people is well known. Data is also accumulating on increased rates of reproductive
diseases in veterans of U.S. and U.K. wars during the last 20 years. As
environmental effectors, metals are potential good candidates to cause birth
defects. Metals are also integral to modern “augmented” and “targeted” weapons
[3]. Metals, which are toxicants at relatively low concentrations, are highly
persistent in the environment and in the body of exposed individuals, where
they accumulate. Metals can disrupt events associated with embryo/fetal
development and can act synergistically with other metals and/or with other
environmental toxicants to induce phenotypic changes at the level of the cell,
and to disrupt tissue homeostasis [4]. Many metals are weak mutagens but strong
carcinogens, which implies that metals act more commonly at the epigenetic
level leading to changes that are inherited by the progeny of cells.
The
analysis of four cases of fathers with two lineages of progeny is presented
here. In each case, we discuss what can be deduced from the family's
reproductive history, from the phenotypes of their offspring and from the
modality of birth defects' chronological occurrence. We discuss the
compatibility of occurrence of birth defects with the actions of potential
effectors, with the demographic of the families, and with the exposure of the
parents to war-related events. We have put our evaluation into the context of
mechanisms of actions for teratogens. The timing of presentation of birth
defects in these families shows that they mostly occurred after 2003.
2. Experimental Section
We developed an ad hoc questionnaire to collect the retrospective reproductive
history of families that had come to Fallujah General Hospital for childbirth
and treatment. Questions about history of residence, demographic
characteristics and lifestyle habits of the parents, and activities that may
have led to their exposure to war-contaminants, were included.
3. Results and Discussion
Data
from four polygamous families are presented. Mothers were admitted to Fallujah
General Hospital between April 2008 and May 2010 for childbirth. Figure 1
summarizes their reproductive histories and illustrates their offspring's birth
defects. Parents’ siblings and their progeny (total n = 40) do not present
birth defects or cancer. Figure 1 shows that birth defects occur sporadically
with different phenotypes in a family and without obvious suggestion of known
genetic contributions from the father or the mother. These represent a few
families reported from a greater number of families with birth defects in
Fallujah. In May 2010, over 15% of all deliveries (547)
in Fallujah General Hospital presented
birth defects. During the same period, spontaneous abortions were 14% of
assisted pregnancies, premature deliveries (<30 weeks of gestation) were
11%, and there was one stillbirth. These numbers are not significantly
different in each of the months of 2010 (manuscript in preparation). Our
historical reconstruction of the reproductive lives of these families shows
that incidences of birth defects began in 2003 with one exception, namely the
infant leukemia case. A composite of genetic and epigenetic factors is
understood to cause infant leukemia. The same family also presented a sporadic
case of unrelated birth defect, TOF. Table 1 summarizes demographic
characteristics and lifestyle habits of the parents of the malformed children
born in Fallujah General Hospital (Iraq), between April 2008 and May 2010.
Figure 1. Top
panel- Family
reproductive history is graphically represented. Bottom
panel-Photographic record
of birth defects: (A) Male child
diagnosed with very short webbed neck, rocker bottom feet, malformed thighs,
and legs flexed at hips, knees and ankles, retracted penile skin-born full
term, August 7, 2010—Family 107—daughter progeny. (B) Female child diagnosed
with cleft palate, poly and sindactily of both feet and right hand and
congenital heart defect-born at 42 weeks, October 1, 2009—Family 107. (C)
Induced abortion (at 22 weeks) of a male fetus with anencephaly, May 31, 2010.
(D) Female child, with ventricular
septal defect (VDS), born at full term, April 28, 2010—Family 139. Patient
consent for publication of the data was obtained from all concerned.
Table 1. Demographic
characteristics, lifestyle habits, history of residence and activities that may
have led to exposure to war-contaminants of the parents of malformed children
born in Fallujah General Hospital (Iraq), between April 2008 and May 2010.
|
Birth defect |
Age |
Race |
Education |
Occupation |
Smoking /Alcohol |
House/ OR |
White |
Rescue/ |
Acute |
Residence 2003/2010 |
|
vicinity |
Phosphorus |
Rubble |
poisoning |
|||||||||
bombed |
burns |
clearing |
sympthoms |
|||||||||
Family107 |
|
|
|
|
|
|
|
|
|
|
|
|
Father |
|
44 |
White |
High School diploma |
Day laborer |
No |
No |
No/No |
No |
No |
No |
Baghdad/2006 Fallujah Alshuhadaa |
First wife |
O |
44 |
White |
Elementary School |
House wife |
No |
No |
No/No |
No |
No |
No |
Baghdad/2006 Fallujah Alshuhadaa |
Second wife |
CHD |
27 |
White |
Junior High School |
House wife |
No |
No |
No/No |
No |
No |
No |
Baghdad/2006 Fallujah Alshuhadaa |
first female child |
SK |
21 |
White |
|
House wife |
No |
No |
No/No |
No |
No |
No |
Baghdad/2006 Fallujah Alshuhadaa |
Family123 |
|
|
|
|
|
|
|
|
|
|
|
|
Father |
|
46 |
White |
Police Academy graduate |
Police officer |
No |
No |
|
|
|
|
Fallujah- Daffar |
First wife |
|
40 |
White |
Elementary School |
House wife |
No |
No |
No/Yes2004 |
No |
No |
No |
Fallujah- Daffar |
Second wife |
NT-NT-NT |
31 |
White |
Elementary School |
House wife |
No |
No |
No/Yes2004 |
No |
No |
No |
Fallujah- Daffar |
Family139 |
|
|
|
|
|
|
|
|
|
|
|
|
Father |
|
39 |
White |
High School diploma |
Day laborer |
Yes |
No |
No/No |
No |
Yes |
No |
Fallujah City |
First wife |
CHD |
35 |
White |
Elementary School |
House wife |
No |
No |
No/No |
No |
Yes |
No |
Fallujah City |
Second wife |
|
31 |
White |
High School diploma |
House wife |
No |
No |
No/No |
No |
Yes |
No |
Fallujah City |
Family 1 |
|
|
|
|
|
|
|
|
|
|
|
|
Father |
CHD |
36 |
White |
Military Academy graduate |
Military officer |
No |
No |
Yes/Yes 2004 |
No |
Yes |
Yes |
Fallujah-Aljumhooreya/ 2009 Garmah |
First wife |
|
35 |
White |
Elementary School |
House wife |
No |
No |
Yes/Yes 2004 |
No |
No |
No |
Fallujah-Aljumhooreya/ 2009 Garmah |
Second wife |
|
31 |
White |
Teachers College graduate |
Elementary school teacher |
No |
No |
Yes/Yes 2004 |
No |
No |
No |
Fallujah-Aljumhooreya/ 2009 Garmah |
Table I. Demographics and life style habits of four Fallujah families (NT=Neural
tube defect; CHD=Congenital heart
defect; SK=Skeletal defect; O= Other defect. |
The data shows that each was stably resident, in
different areas of the town up to 2009–2010, none of the parents were directly wounded or trapped
under rubble and that, among them, only
the male parent
in Family 1 reported acute symptoms immediately after bombings. There is no obvious relationship to immediately adjacent
bombing/burning of their houses or to the activity of cleaning/recovery of
injured-dead people or to personal acute symptoms with them having a child with
birth defect in the following years. This suggests that the birth defect in
these families might not be due directly to acute exposure, but could be
associated to their long term exposure and body accumulation of toxicants which
are persistent in the environment.
More efficaciously than chromosomal mutations or than
multiple single gene mutations, epigenetic changes (alone or associated with
other genetic changes) can account for the patterns and diversity of
malformation which we see in families 107, 139 and 1. Epigenetic effectors can
produce simultaneously different damages and multiple phenotypes, which vary
depending on the specific agent(s), and on the timing and level of exposure
during embryonic life. This possibility, per se, would fit the data. The novel
presentation of sporadic and diverse birth defects, which can be caused
uniquely or in composite fashion by epigenetic events, also suggest that agents
capable of initiating these changes are still present in the environment and
continue to induce novel effects.
Teratogens in the postwar environment
include metals and metal alloys which persist in the environment and in the
body, and are potential risks to health (genotoxic, fetotoxic and epigenetic
mechanisms of action). Metals are involved in regulating genome stability, in X
chromosome inactivation, in gene imprinting, and in reprogramming gene
expression. They act as metalloestrogens, inhibit DNA repair, alter DNA
methylation, change transcriptome and microRNAs production, histone acetylation
and methylation; all of which can lead to birth defects, whether translated
into mutations or not [4]. As a consequence of internal radiation, some metals
can induce sporadic gene mutations or oxidative DNA damage. In the case of
depleted uranium (DU) it is unclear whether its radiation-derived mutational
effects or its chemical toxic effects are more relevant. DU can induce
epigenetic changes that are associated with leukemia via hypomethylation of the
DNA. Exposure to teratogens of either father or mothers are potentially
effective to induce birth defects at the epigenetic as well as the genetic level.
In the cases we report here, the pattern of presentation does not exclude the
contribution of either parent: the epigenetic changes are likely to behave as
stochastic and not striclty deterministic events, and lack of effects in one of
the two families branch with the same father cannot exclude his contribution to
the occurrence of birth defects in the other family branch. Nonetheless,
pregnant mothers' exposure to metal contaminants is potentially more relevant
to the development of malformations in the case of Family 107, where both wives
had deformed babies, but with different phenotypes, and where the daughter of
one of the mothers, who herself delivered a child with atrophic and ectopic
kidney, had a child with multiple skeletal and dermal abnormalities. There are
no known candidate mutations governing both kidney and skeletal/dermal
development, and it is likely that independent exposure to effectors in the
environment during both pregnancies induced diverse epigenetic effects in the
developing offspring. Prenatal exposure best explain, but also paternal
exposure could account for, the cases in those families where only the progeny
of one spouse presented birth defects which recurred in diverse phenotypes.
Cases in point are the still births and ventricular septal defect (VDS) in Family
139 and multiple cases of child leukemia and TOF in Family 1.
Continuing
exposure to environmental effectors could also explain the unusually high
frequency of recurrence of anencephaly and infant leukemia in a genetically-prone
context (Family 123 and Family 1). These phenotypes are indeed known to
derive from concomitant genetic predisposition (possibly informing the maternal
effect) and from epigenetic effects due to the external environment.
Frequent miscarriages in several women
during the last years are also indicative of a general negative (teratogenic)
load from the environment. Epidemiological evidence on birth defects which are
caused by war contaminants is common in the literature. Hindin et al. offered a review of
epidemiological studies on the teratogenicity of DU and concludes that human
epidemiological evidence is consistent with increased risk of birth defects in
the offspring of persons exposed to this war contaminant [5]. Studies in
another war contaminant, Agent Orange, also find parental exposure to be
associated with an increased risk of birth defects in the offspring [6].
The family history questionnaire which we developed
filled serious gaps in a long history of inadequacies of the health system in
Iraq. It has allowed us to begin interpretation of the facts. The strong
indication of our data, that epigenetic mechanisms are at the root of the
recurrence of birth defects in Fallujah, offers the hope to develop therapeutic
interventions for severely affected families. Our
findings can lead to a deeper understanding of the effects of war contaminants
(including metalloestrogens), can help elucidate causes and mechanisms that
have culminated in such high rates of birth defects in Fallujah, and can open the
way to intervention, both regarding immediate counseling and in terms of therapeutic
intervention.
4. Conclusions
We conclude that the high prevalence of birth defects
in Fallujah is impairing the population’s health and its capacity to care for
the surviving children. These defects could be due to environmental
contaminants which are known components of modern weaponry. Investigations of
metal contaminants, and elucidation of the types and body burden of metals,
combined with simultaneous registry of the population’s reproductive history,
will allow the identification of families at high risk and will facilitate
therapeutic measures to remediate the damages.
Acknowledgements
Thanks are
due to S. Allawi for her suggestions and problem solving, and to E. Burgio for
critical reading of the manuscript. We further thank Blaine Coleman for
technical support and language editing of this work. We also recognize “Kuala
Lumpur Foundation to Criminalize War” for funding.
References
1.
Romitti, P.A. Utility of family history reports of major birth defects
as a public health strategy. Pediatrics
2007, 120, S71-S77.
2.
Surani, M.A. Reprogramming of genome function through epigenetic
inheritance. Nature 2001, 414, 122-128.
3.
Skaik, S.; Abu-Shaban, N.; Barbieri, M.; Barbieri, M.; Giani, U.;
Manduca, P. Metals detected by ICP/MS in wound tissue of war injuries without
fragments in Gaza. BMC Int. Health Hum.
Rights 2010, 10, 17.
4.
Beyersmann, D.; Hartwig, A. Carcinogenic metal compounds: recent insight
into molecular and cellular mechanisms. Arch.
Toxicol. 2008, 82, 493-512.
5.
Hindin, R.; Brugge, D.; Panikkar,
B. Teratogenicity of depleted uranium aerosols: A review from an
epidemiological perspective. Environ. Health 2005, 4, 17.
6.
Ngo, A.; Taylor, R.; Roberts, C.;
Nguyen, T. Association between Agent Orange and birth defects: systematic
review and meta-analysis. Int. J.
Epidemiol. 2006, 35, 1220-1230.
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