Abnormal Development - Environmental

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Educational Use Only - Embryology is an educational resource for learning concepts in embryological development, no clinical information is provided and content should not be used for any other purpose.

Introduction

Human critical periods of development
Human critical periods of development

Materal effects should really be called environmental (in contrast to genetic) removing the association of mother with the deleterious agent. Accepting this caveat, there are several maternal effects from lifestyle, environment and nutrition that can be prevented or decreased by change which is not an option for genetic effects.


Infections, collectively grouped under the acronym TORCH for Toxoplasmosis, Other organisms (parvovirus, HIV, Epstein-Barr, herpes 6 and 8, varicella, syphilis, enterovirus) , Rubella, Cytomegalovirus and Hepatitis. See related pages on maternal hyperthermia, viral and bacterial infections.


Maternal diet the best characterised is the role of low folic acid and Neural Tube Defects (NTDs) see also abnormal neural development and Neural Tube Defects and the sample environmental effects listed below.


Maternal drugs effects either prescription drugs (therapeutic chemicals/agents, thalidomide limb development), non-prescription drugs (alcohol, smoking, herbal drugs), and illegal drugs (Cannabis/Marijuana, Methamphetamine/Amphetamine, Cocaine, Heroin, Lysergic Acid Diethylamide)


Environment (smoking, chemical, heavy metals) and maternal endocrine function (maternal diabetes, thyroid development) and maternal stress.

Different environmental effects can act individually or in combination on the same developing system. For example, neural development can be impacted upon by alcohol (fetal alcohol syndrome), viral infection (rubella) and/or inadequate dietry folate intake (neural tube defects). These effects may also not be seen as a direct effect on a system or systems but result in a reduced birth weight and the potential postnatal developmental effects.


Finally, when studying this topic remember the concept of "critical periods" of development that will affect the overall impact of the above listed factors. This can be extended to the potential differences between prenatal and postnatal effects, for example with infections and outcomes.


This current page provides only a general overview of the topic, use the links below to get detailed information about specific environmental effects.


Environmental Links: Introduction | low folic acid | iodine deficiency | Nutrition | Drugs | Australian Drug Categories | USA Drug Categories | thalidomide | herbal drugs | Illegal Drugs | smoking | Fetal Alcohol Syndrome | TORCH | viral infection | bacterial infection | fungal infection | zoonotic infection | toxoplasmosis | Malaria | maternal diabetes | maternal hypertension | maternal hyperthermia | Maternal Inflammation | Maternal Obesity | hypoxia | biological toxins | chemicals | heavy metals | air pollution | radiation | Prenatal Diagnosis | Neonatal Diagnosis | International Classification of Diseases | Fetal Origins Hypothesis


Bacterial Links: bacterial infection | syphilis | gonorrhea | tuberculosis | listeria | salmonella | TORCH | Environmental | Category:Bacteria
Viral Links: viral infection | TORCH | cytomegalovirus | hepatitis | HIV | parvovirus | polio | rubella virus | chickenpox | Lymphocytic Choriomeningitis Virus | Zika virus | human papillomavirus | rotavirus | West Nile virus | varicella virus | vaccination | zoonotic infection | environment
Historic Embryology - Viral 
1941 Rubella Cataracts | 1944 Rubella Defects
Abnormality Links: abnormal development | abnormal genetic | abnormal environmental | Unknown | teratogens | ectopic pregnancy | cardiovascular abnormalities | coelom abnormalities | endocrine abnormalities | gastrointestinal abnormalities | genital abnormalities | head abnormalities | integumentary abnormalities | musculoskeletal abnormalities | limb abnormalities | neural abnormalities | neural crest abnormalities | placenta abnormalities | renal abnormalities | respiratory abnormalities | hearing abnormalities | vision abnormalities | twinning | Developmental Origins of Health and Disease |  ICD-11
Historic Embryology  
1915 Congenital Cardiac Disease | 1917 Frequency of Anomalies in Human Embryos | 1920 Hydatiform Degeneration Tubal Pregnancy | 1921 Anencephalic Embryo | 1921 Rat and Man | 1966 Congenital Malformations

Some Recent Findings

Yinchuan, China
Yinchuan, Ningxia, China
French regions - Ain, Brittany and Loire-Atlantique
Brindisi, Italy
  • Gene-environment interactions: aligning birth defects research with complex etiology[1] "Developmental biologists rely on genetics-based approaches to understand the origins of congenital abnormalities. Recent advancements in genomics have made it easier than ever to investigate the relationship between genes and disease. However, nonsyndromic birth defects often exhibit non-Mendelian inheritance, incomplete penetrance or variable expressivity. The discordance between genotype and phenotype indicates that extrinsic factors frequently impact the severity of genetic disorders and vice versa. Overlooking gene-environment interactions in birth defect etiology limits our ability to identify and eliminate avoidable risks. We present mouse models of sonic hedgehog signaling and craniofacial malformations to illustrate both the importance of and current challenges in resolving gene-environment interactions in birth defects. We then prescribe approaches for overcoming these challenges, including use of genetically tractable and environmentally responsive in vitro systems. Combining emerging technologies with molecular genetics and traditional animal models promises to advance our understanding of birth defect etiology and improve the identification and protection of vulnerable populations."
  • The association between maternal exposure to ambient particulate matter of 2.5 μm or less during pregnancy and fetal congenital anomalies in Yinchuan, China: A population-based cohort study[2] "Few studies from western countries have linked prenatal exposure to ambient particulate matter <2.5 μm (PM2.5) with increased risk of congenital anomalies. However, the results are mixed. Particularly, evidence is limited for Chinese pregnant women. METHODS: In this retrospective cohort study, we matched the data of all pregnant women laboured in public hospitals during 2015-2016 in Yinchuan, a capital city of northwest China and the data of daily average PM2.5, nitrogen dioxide (NO2), sulphur dioxide (SO2) and ozone (O3) concentrations of the nearest monitor station. We calculated a time-dependent exposure over the entire pregnancy for each woman. We used a time varying Cox proportional hazards model to explore the association between PM2.5 exposure and the risk of congenital anomalies, after adjusting for individual confounders and other pollutants. RESULTS: A total of 39,386 singleton live births were included in the study, and 530 (1.35%) were with congenital anomalies. An increase of 10 μg/m3 in PM2.5 exposure over the entire pregnancy was significantly associated with increased risk of congenital anomalies, with hazard ratio (HR) of 1.35 [95% confidence interval (95%CI): 1.16, 1.58]. For subtype analyses, PM2.5 exposure exhibited a significant association with cardiac anomalies and other unclassifiable anomalies, with HRs of 1.60 (95%CI: 1.24, 2.08) and 1.42 (95%CI: 1.07, 1.89), respectively. The impacts of PM2.5 exposure on orofacial anomalies and musculoskeletal anomalies were not significant. CONCLUSION: Our results indicate high concentration of PM2.5 could increase the risk of congenital anomalies among Chinese, especially for cardiac anomalies. Self-protective measures involving reducing PM2.5 pollution exposure during pregnancy as well as environmental policies aiming to restrict PM2.5 emission could be helpful to reduce the burden of cognitional anomalies."
  • Does the antidiabetic drug metformin affect embryo development and the health of brown trout (Salmo trutta f. fario)?[3] "Due to the rising number of type 2 diabetes patients, the antidiabetic drug, metformin is currently among those pharmaceuticals with the highest consumption rates worldwide. Via sewage-treatment plants, metformin enters surface waters where it is frequently detected in low concentrations (µg/L). Since possible adverse effects of this substance in aquatic organisms have been insufficiently explored to date, the aim of this study was to investigate the impact of metformin on health and development in brown trout (Salmo trutta f. fario) and its microbiome. Overall, weight reduction and the increased glycogen content belong to the described pharmaceutical effects of the drug in humans, but this study showed that they also occur in brown trout larvae. The impact of a shift in the intestinal microbiome caused by metformin on the immune system and vitality of the host organism should be the subject of further research before assessing the environmental relevance of the pharmaceutical."
More recent papers  
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  • The displayed list of references do not reflect any editorial selection of material based on content or relevance.
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References listed on the rest of the content page and the associated discussion page (listed under the publication year sub-headings) do include some editorial selection based upon both relevance and availability.

More? References | Discussion Page | Journal Searches | 2019 References | 2020 References

Search term: Environmental Abnormal Development | teratogen

Older papers  
These papers originally appeared in the Some Recent Findings table, but as that list grew in length have now been shuffled down to this collapsible table.

See also the Discussion Page for other references listed by year and References on this current page.

  • Recurrent pregnancy loss: A summary of international evidence-based guidelines and practice[4] "Recurrent pregnancy loss (RPL) is defined as two or more pregnancy losses. It affects <5% of couples. There are many proposed causes; however, in a significant proportion of cases, the cause is unknown. The aim of this paper is to provide a summary of the aetiology, investigations and management of RPL, which is based on the three most recent international guidelines on RPL (European Society of Human Reproduction and Embryology, 2017; American Society for Reproductive Medicine, 2012; and the Royal College of Obstetricians and Gynaecologists, 2011). Management of RPL should occur in a specialised clinic. Appropriate investigations include karyotyping of parents and products of conception, two-dimensional/three-dimensional ultrasonography with sonohysterography, thyroid function tests, and antibodies and testing for acquired thrombophilias. Management options encompass some lifestyle modifications for smoking, alcohol, illicit drug use and caffeine consumption. Acquired thrombophilias should be treated with unfractionated heparin and low-dose aspirin."
  • Impact of sample collection participation on the validity of estimated measures of association in the National Birth Defects Prevention Study when assessing gene-environment interactions[5] "To better understand the impact that nonresponse for specimen collection has on the validity of estimates of association, we examined associations between self-reported maternal periconceptional smoking, folic acid use, or pregestational diabetes mellitus and six birth defects among families who did and did not submit buccal cell samples for DNA following a telephone interview as part of the National Birth Defects Prevention Study (NBDPS). Analyses included control families with live born infants who had no birth defects (N = 9,465), families of infants with anorectal atresia or stenosis (N = 873), limb reduction defects (N = 1,037), gastroschisis (N = 1,090), neural tube defects (N = 1,764), orofacial clefts (N = 3,836), or septal heart defects (N = 4,157). Estimated dates of delivery were between 1997 and 2009. ...These findings support the validity of observed associations in gene-environment interaction studies for the selected exposures and birth defects among NBDPS participants who submitted DNA samples.
  • Maternal genetic variation accounts in part for the associations of maternal size during pregnancy with offspring cardiometabolic risk in adulthood[6] "Maternal pre-pregnancy body-mass index (ppBMI) and gestational weight gain (GWG) are associated with cardiometabolic risk (CMR) traits in the offspring. The extent to which maternal genetic variation accounts for these associations is unknown. Maternal genetic risk scores (GRS) were created using a subset of SNPs most predictive of ppBMI, GWG, and each CMR trait, selected among 1384 single-nucleotide polymorphisms (SNPs) characterizing variation in 170 candidate genes potentially related to fetal development and/or metabolic risk."
  • Work and Pregnancy (UK)[7] "Most pregnant women are exposed to some physical activity at work. This Concise Guidance is aimed at doctors advising healthy women with uncomplicated singleton pregnancies about the risks arising from five common workplace exposures (prolonged working hours, shift work, lifting, standing and heavy physical workload). The adverse outcomes considered are: miscarriage, preterm delivery, small for gestational age, low birth weight, pre-eclampsia and gestational hypertension. Systematic review of the literature indicates that these exposures are unlikely to carry much of an increased risk for any of the outcomes, since small apparent effects might be explicable in terms of chance, bias, or confounding, while larger and better studies yield lower estimated risks compared with smaller and weaker studies. In general, patients can be reassured that such work is associated with little, if any, adverse effect on pregnancy."
  • Congenital anomalies among live births in a polluted area[8] "Congenital anomalies and their primary prevention are a crucial public health issue. This work aimed to estimate the prevalence of congenital anomalies in Brindisi, a city in southeastern Italy at high risk of environmental crisis. This research concerned newborns up to 28 days of age, born between 2001 and 2010 to mothers resident in Brindisi and discharged with a diagnosis of congenital anomaly. ...Our findings indicated an increased prevalence of Congenital Anomalies (especially congenital heart diseases) in the city of Brindisi. More research is needed in order to analyze the role of factors potentially involved in the causation of congenital anomalies."
  • Environmental factors in axial skeletal dysmorphogenesis[9] "Approximately 1 in 1000 live births is afflicted with an axial skeletal defect. Although many of the known human teratogens can produce axial skeletal defects, the etiology of over half of the observed defects is unknown."
  • The temporal dynamics of vertebrate limb development, teratogenesis and evolution.[10] "Recent genetic and functional analysis of vertebrate limb development begins to reveal how the functions of particular genes and regulatory hierarchies can drastically change over time. The temporal and spatial interplay of the two instructive signalling centres are part of a larger signalling system that orchestrates limb bud morphogenesis in a rather self-regulatory manner. It appears that mesenchymal cells are specified early and subsequently, the progenitors for the different skeletal elements are expanded and determined progressively during outgrowth. Mutations and teratogens that disrupt distal progression of limb development most often cause death of the early-specified progenitors rather than altering their fates."
  • Developmental toxicity of pharmaceuticals using human embryonic stem cells and metabolomics.[11] "Teratogens, substances that may cause fetal abnormalities during development, are responsible for a significant number of birth defects. Animal models used to predict teratogenicity often do not faithfully correlate to human response. Here, we seek to develop a more predictive developmental toxicity model based on an in vitro method that utilizes both human embryonic stem (hES) cells and metabolomics to discover biomarkers of developmental toxicity."

Critical Periods

The table below identifies approximate windows of time, a "critical period", that following exposure to teratogens can lead to developmental abnormalities (anomalies, congenital). In general, the effects for many system are more severe (major anomalies) in the embryonic period during organogenesis in the first trimester. Later teratogen exposure are less severe (minor anomalies) for many systems in the fetal period during continued growth and differentiation in the second and third trimester. Note that different systems have different critical periods within the developmental timeline and extend for different lengths of time.


Critical Periods of Human Development
Conceptus Embryonic development (weeks) Fetal period (weeks)
1
2
3
4
5
6
7
8
9
16
20-36
38
Early zygote.jpg Week2 001 icon.jpg Stage9 sem4c.jpg Stage13 sem1c.jpg Stage15 bf1c.jpg Stage17 bf1c.jpg Stage19 bf1c.jpg Stage23 bf1c.jpg
Neural
Stage2.jpg Heart
Upper limbs
Lower limbs
Ear
Eye
CSt3.jpg Palate
Teeth
Week2 001 icon.jpg External genitalia
Loss Major abnormalities Functional and Minor abnormalities
  Critical Period Links: critical period | abnormal development | Critical Periods table | Image - Critical Periods table | Genital | Opioids | Neural | Thalidomide | Environmental


Critical Periods - Some Specific Examples
Genital Opioids Neural Thalidomide
Human- genital development critical periods.jpg Opioids and neural development timeline.jpg Neural-development.jpg Thalidomide external effects timeline.jpg
genital abnormalities neural abnormalities neural abnormalities thalidomide
  Critical Period Links: critical period | abnormal development | Critical Periods table | Image - Critical Periods table | Genital | Opioids | Neural | Thalidomide | Environmental


Scheuerle AE & Aylsworth AS. (2016). Birth defects and neonatal morbidity caused by teratogen exposure after the embryonic period. Birth Defects Res. Part A Clin. Mol. Teratol. , 106, 935-939. PMID: 27511745 DOI.

Fetal Period

A 2016 study classified teratogenic effects during the fetal period.[12]

"Defects with documented first trimester pathogenesis (e.g., anencephaly, heterotaxy) were eliminated from consideration, as were chromosomal and single gene disorders (e.g., trisomy 21, achondroplasia). The remaining defects include the following: (1) those that are known to or could reasonably originate or manifest after the embryonic period (e.g., porencephaly, cataracts); (2) those for which pathogenesis is unclear or variable enough that exposure at any gestational age might be considered relevant (e.g., club foot, microcephaly); and (3) those that include some component of abnormal growth (e.g., hemihyperplasia). "Unspecified" defects (e.g., "abnormality of the leg") were included by default because there is insufficient information to assume first trimester embryogenesis. The final result is a list of major and minor anomalies in 11 organ system categories that may be caused by teratogen exposure during the fetal period."

DevTox

The potential of a pesticide or biocide to cause adverse effects in the developing embryo or fetus is an important consideration in any health risk assessment for humans and wildlife.

Report of the 8th Berlin Workshop on Developmental Toxicity held in May 2014.[13]

"The main aim of the workshop was the continuing harmonization of terminology and innovations for methodologies used in the assessment of embryo- and feto-toxic findings. The following main topics were discussed: harmonized categorization of external, skeletal, visceral and materno-fetal findings into malformations, variations and grey zone anomalies, aspects of developmental anomalies in humans and laboratory animals, and innovations for new methodologies in developmental toxicology. The application of Version 2 terminology in the DevTox database was considered as a useful improvement in the categorization of developmental anomalies."


Links: DevTox

Travel

There is an increasing number of women travelling during pregnancy that may carry some additional environmental risks. The following information is summarised from a recent BMJ article.[14]

  • second trimester of pregnancy is considered the safest in which to travel
  • air travel may carry risk of miscarriage, preterm birth, and thromboembolism
  • obstetric and neonatal care facilities at destinations is varied
  • obtain adequate insurance and check with their airline for restrictions on travel
  • communicable diseases acquired abroad may increase risks of perinatal morbidity

References

  1. Beames TG & Lipinski RJ. (2020). Gene-environment interactions: aligning birth defects research with complex etiology. Development , 147, . PMID: 32680836 DOI.
  2. Liu C, Li Q, Yan L, Wang H, Yu J, Tang J, Yao H, Li S, Zhang Y & Guo Y. (2019). The association between maternal exposure to ambient particulate matter of 2.5 μm or less during pregnancy and fetal congenital anomalies in Yinchuan, China: A population-based cohort study. Environ Int , 122, 316-321. PMID: 30455103 DOI.
  3. Jacob S, Dötsch A, Knoll S, Köhler HR, Rogall E, Stoll D, Tisler S, Huhn C, Schwartz T, Zwiener C & Triebskorn R. (2018). Does the antidiabetic drug metformin affect embryo development and the health of brown trout (Salmo trutta f. fario)?. Environ Sci Eur , 30, 48. PMID: 30595998 DOI.
  4. Hong Li Y & Marren A. (2018). Recurrent pregnancy loss: A summary of international evidence-based guidelines and practice. Aust J Gen Pract , 47, 432-436. PMID: 30114870
  5. Jenkins MM, Reefhuis J, Herring AH & Honein MA. (2017). Impact of sample collection participation on the validity of estimated measures of association in the National Birth Defects Prevention Study when assessing gene-environment interactions. Genet. Epidemiol. , 41, 834-843. PMID: 29071735 DOI.
  6. Wander PL, Hochner H, Sitlani CM, Enquobahrie DA, Lumley T, Lawrence GM, Burger A, Savitsky B, Manor O, Meiner V, Hesselson S, Kwok PY, Siscovick DS & Friedlander Y. (2014). Maternal genetic variation accounts in part for the associations of maternal size during pregnancy with offspring cardiometabolic risk in adulthood. PLoS ONE , 9, e91835. PMID: 24670385 DOI.
  7. Palmer KT, Bonzini M & Bonde JP. (2013). Pregnancy: occupational aspects of management: concise guidance. Clin Med (Lond) , 13, 75-9. PMID: 23472500
  8. Gianicolo EA, Bruni A, Rosati E, Sabina S, Guarino R, Padolecchia G, Leo C, Vigotti MA, Andreassi MG & Latini G. (2012). Congenital anomalies among live births in a polluted area. A ten-year retrospective study. BMC Pregnancy Childbirth , 12, 165. PMID: 23270371 DOI.
  9. Alexander PG & Tuan RS. (2010). Role of environmental factors in axial skeletal dysmorphogenesis. Birth Defects Res. C Embryo Today , 90, 118-32. PMID: 20544699 DOI.
  10. Zeller R. (2010). The temporal dynamics of vertebrate limb development, teratogenesis and evolution. Curr. Opin. Genet. Dev. , 20, 384-90. PMID: 20537528 DOI.
  11. West PR, Weir AM, Smith AM, Donley EL & Cezar GG. (2010). Predicting human developmental toxicity of pharmaceuticals using human embryonic stem cells and metabolomics. Toxicol. Appl. Pharmacol. , 247, 18-27. PMID: 20493898 DOI.
  12. Scheuerle AE & Aylsworth AS. (2016). Birth defects and neonatal morbidity caused by teratogen exposure after the embryonic period. Birth Defects Res. Part A Clin. Mol. Teratol. , 106, 935-939. PMID: 27511745 DOI.
  13. Solecki R, Rauch M, Gall A, Buschmann J, Clark R, Fuchs A, Kan H, Heinrich V, Kellner R, Knudsen TB, Li W, Makris SL, Ooshima Y, Paumgartten F, Piersma AH, Schönfelder G, Oelgeschläger M, Schaefer C, Shiota K, Ulbrich B, Ding X & Chahoud I. (2015). Continuing harmonization of terminology and innovations for methodologies in developmental toxicology: Report of the 8th Berlin Workshop on Developmental Toxicity, 14-16 May 2014. Reprod. Toxicol. , 57, 140-6. PMID: 26073002 DOI.
  14. Hezelgrave, NL, Whitty, CJM, Shennan, AH, and Chappell, LC. Advising on travel during pregnancy BMJ 2011; 342:d2506 doi: 10.1136/bmj.d2506 (Published 28 April 2011) BMJ

Journals

  • Environmental Health Perspectives (EHP) is a monthly journal of peer-reviewed research and news on the impact of the environment on human health. EHP | Pubmed EHP

Reviews

Leeper C & Lutzkanin A. (2018). Infections During Pregnancy. Prim. Care , 45, 567-586. PMID: 30115342 DOI.

Arora N, Sadovsky Y, Dermody TS & Coyne CB. (2017). Microbial Vertical Transmission during Human Pregnancy. Cell Host Microbe , 21, 561-567. PMID: 28494237 DOI.

Sadler TW. (2017). Establishing the Embryonic Axes: Prime Time for Teratogenic Insults. J Cardiovasc Dev Dis , 4, . PMID: 29367544 DOI.

Foster WG, Evans JA, Little J, Arbour L, Moore A, Sauve R, Andrés León J & Luo W. (2017). Human exposure to environmental contaminants and congenital anomalies: a critical review. Crit. Rev. Toxicol. , 47, 59-84. PMID: 27685638 DOI.

Brent RL. (2004). Environmental causes of human congenital malformations: the pediatrician's role in dealing with these complex clinical problems caused by a multiplicity of environmental and genetic factors. Pediatrics , 113, 957-68. PMID: 15060188

Articles

Search Pubmed

June 2010 "teratogens" All (25401) Review (3026) Free Full Text (3991) "TORCH Infections" All (183) Review (37) Free Full Text (18)

Search Pubmed: teratogens | TORCH Infections | maternal abnormalities

External Links

External Links Notice - The dynamic nature of the internet may mean that some of these listed links may no longer function. If the link no longer works search the web with the link text or name. Links to any external commercial sites are provided for information purposes only and should never be considered an endorsement. UNSW Embryology is provided as an educational resource with no clinical information or commercial affiliation.

  • Environmental Health Perspectives (EHP) is a monthly journal of peer-reviewed research and news on the impact of the environment on human health. EHP
  • REPROTOX - contains summaries on the effects of medications, chemicals, infections, and physical agents on pregnancy, reproduction, and development.
  • DevTox

Glossary Links

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Cite this page: Hill, M.A. (2024, March 19) Embryology Abnormal Development - Environmental. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Abnormal_Development_-_Environmental

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