Abnormal Development - Heavy Metals

Embryology - 2 Dec 2023        Expand to Translate
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Introduction

The industrialization of the modern world has led to the proliferation in our environment of many heavy metals compounds. Some metals, such as zinc and iron are required in trace amounts for many biological functions. Other metals such as lead and mercury have had significant toxic effects on development.

There are historic examples of large scale disasters, for example the mercury poisoning of waterways in Japan (More? Mercury) Mercury poisoning (by methyl mercury) or Minamata disease had substantial neurological effects similar to Hunter Russell syndrome.

In addition to their direct toxic effects, the potential reduction in fetal growth and long-term effects should also be considered. Much of the basic research relies on studies in various animal models of development and we should also consider the ongoing development of new industrial products in the environment with unknown or untested effects upon development.

The specific effects of some metals are detailed in Safety and Data Sheets (SDSs), previously Material Safety and Data Sheets or MSDSs, available from an chemical index page that relate to developmental abnormalities. These sheets are now generally required to be supplied along with the chemical purchased from a supplier and give a standardised description of the chemical, its physical properties, handling and health effects/toxicity. There are also several internet sites that have searchable databases of SDS information. Note that handling chemical safety has previously varied from country to country. Recently the WHO has developed an internationally agreed-upon system Globally Harmonized System of Classification and Labeling of Chemicals (GHS) that will eventually standardise this information (see also Abnormal Development - Chemicals).

Some Recent Findings

Lead campaign poster 2013

Heavy metals in maternal and cord blood in Beijing and their efficiency of placental transfer "This study aimed to determine the effect of exposure to heavy metals in pregnant women in Beijing, China. We also evaluated the association of these heavy metals with birth weight and length of newborns. We measured the levels of 10 heavy metals, including lead (Pb), titanium (Ti), manganese (Mn), nickel (Ni), cadmium (Cd), chromium (Cr), antimony (Sb), stannum (Sn), vanadium (V), and arsenic (As), in 156 maternal and cord blood pairs. An inductively coupled plasma mass spectrometry method was used for measurement. Pb, As, Ti, Mn, and Sb showed high detection rates (>50%) in both maternal and cord blood. Fourteen (9%) mothers had blood Pb levels greater than the United States Center for Disease Control allowable threshold limit for children (50 μg/L). In prenatal exposure to these heavy metals, there was no significant association between any heavy metal and birth weight/length. Moreover, we estimated the placental transfer efficiency of each heavy metal, and the median placental transfer efficiency ranged from 49.6% (Ni) to 194% (Mn) (except for Cd and Sn). The level and detection rate of Cd in maternal blood were much higher than that in cord blood, which suggested that Cd had difficulty in passing the placental barrier." placenta The association between whole blood concentrations of heavy metals in pregnant women and premature births: The Japan Environment and Children's Study (JECS) "Heavy metals are widely distributed in the environment. Recent reports have demonstrated the risk of preterm birth following heavy metal exposure. Preterm births are classified as early and late, depending on the duration of pregnancy, and are associated with increased risk of congenital illnesses such as heart failure, asthma, etc. ...Maternal blood Cd levels during pregnancy are positively associated with the risk of early preterm birth among Japanese women. Identification of the main source of maternal Cd exposure may contribute to the prevention of early preterm births and health maintenance of mothers and their infants in the future." Household environmental exposures during gestation and birth outcomes: A cross-sectional study in Shanghai, China. " Our findings demonstrate that home renovation and environmental tobacco smoke (smoking) during gestation may be risk factors for adverse birth outcomes. Associations of these factors with adverse birth outcomes appear to be stronger in boys and among mothers older than 34years during gestation. Home renovation and smoking exposure should be avoided during gestation, especially for pregnancies with male fetuses and older pregnant women." Environmental cadmium exposure is associated with elevated risk of chronic otitis media in adults "Chronic otitis media (COM) is caused by an infection of the middle ear, although it may also be associated with environmental pollutants. Recent reports found that cadmium exposure could be toxic to middle ear cell lines, but the role of cadmium in the development of COM in humans has not been examined to date. We hypothesised that environmental cadmium exposure was associated with an increased risk of COM in the general population. METHODS: We analysed cross-sectional data for 5331 adults of 20 years of age or above, obtained from the Korea National Health and Nutrition Examination Survey 2010-2012. We examined the association between blood cadmium levels and COM diagnosed by an otolaryngologist. RESULTS: The highest quartile group of cadmium blood concentration was associated with an OR of 3.33 (95% CI 1.78 to 7.53) for COM, after adjusting for potential confounding factors. Doubling blood cadmium concentration resulted in an OR of 1.58 (95% CI 1.19 to 2.08) for COM. These associations were robust on sensitivity analyses after excluding current smokers and former smokers and after excluding subjects with a potential history of occupational exposure to cadmium. CONCLUSIONS: The results of our study suggest that environmental cadmium exposure is associated with increased risk of COM, and further studies are warranted to understand the pathogenetic mechanism by which COM is caused by cadmium exposure."

More recent papers

This table allows an automated computer search of the external PubMed database using the listed "Search term" text link. This search now requires a manual link as the original PubMed extension has been disabled. The displayed list of references do not reflect any editorial selection of material based on content or relevance. References also appear on this list based upon the date of the actual page viewing. 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: Heavy Metal Teratology | Lead Teratology | chromium Teratology

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. Acute effects of lead on porcine neonatal Sertoli cells in vitro "Environmental pollution is one of the main factors responsible for reducing fertility in males. Lead is one of the major heavy metal contaminants that impairs several organs; it preferentially accumulates in male reproductive organs and alters sperm quality both in vivo and in vitro. ...Purified and functional porcine neonatal SCs were exposed to lead acetate at three different concentrations. Lead exposure decreased the mRNA expression and protein levels of inhibin B and anti-Mullerian hormone (AMH) compared to control, indicating loss of FSH-r integrity in terms of 17-β-oestradiol production under FSH stimulation. In addition, we observed an increase in the mRNA levels of Akt and mTOR, and the phosphorylation of p38 and Akt in SCs exposed to lead at all concentrations compared to unexposed control SCs. In conclusion, lead is toxic to SCs, even at low concentrations, and is expected to alter spermatogenesis." Spermatozoa Development Prenatal Exposure to Cadmium, Placental Permeability and Birth Outcomes in Coastal Populations of South Africa "The impact of prenatal exposure to cadmium (Cd) on birth outcomes is an area of concern. This study aimed to assess an impact of prenatal Cd exposure on birth outcomes in distinct coastal populations of South Africa. ...Significant inverse associations between prenatal Cd exposure and birth anthropometry were found in female neonates but not in male neonates, suggesting potential sex differences in the toxico-kinetics and toxico-dynamics of Cd." Maternal-infant biomarkers of prenatal exposure to arsenic and manganese "Because arsenic (As) and manganese (Mn) are able to pass the placenta, infants among exposed populations may be exposed to considerable levels in utero. The main objective of this paper is to evaluate infant toenails, hair, and cord blood as biomarkers of prenatal exposure to As and Mn and determine the relationship between maternal and infant As and Mn concentrations in these biomarkers. ...Toenails and cord blood appear to be valid biomarkers of maternal-fetal transfer of As and Mn, whereas hair may not be a suitable biomarker for in utero exposure to Mn." Lead Exposure during Early Human Development and DNA Methylation of Imprinted Gene Regulatory Elements in Adulthood "The objective of this study was to determine if maternal, postnatal and early childhood lead exposure alter the differentially methylated regions (DMRs) that control the monoallelic expression of imprinted genes involved in metabolism, growth and development. ...The magnitude of associations between cumulative lead exposure and CpG methylation remained unaltered from 30 to 78 months. CONCLUSIONS: Our findings provide evidence for early childhood lead exposure resulting in sex-dependent and gene-specific DNA methylation differences in the DMRs of PEG3, IGF2/H19 and PLAGL1/HYMAI in adulthood." Epigenetics Birth outcome measures and maternal exposure to heavy metals (lead, cadmium and mercury) in Saudi Arabian population "This cross-sectional study was conducted to assess the association between exposure to heavy metals (lead, cadmium and mercury) during pregnancy and birth outcomes in 1578 women aged 16-50 years who delivered in Al-Kharj hospital, Saudi Arabia, in 2005 and 2006. The levels of lead, cadmium and mercury were measured in umbilical cord blood, maternal blood and the placenta. ... Cadmium, despite its partial passage through the placenta had the most prominent effect on several measures of birth outcome."" International Lead Poisoning Awareness Week (20 - 26 October 2013) "Despite what is known about the health risks arising from lead paint, such paints are still widely available and used in many countries for decorating the interiors and exteriors of homes. It can also be found in paint in public buildings such as schools and hospitals, as well as on toys, toy jewellery, glazes, furniture, and playground equipment." Meeting Diplomatic Conference for the Minamata Convention on Mercury 2013 | Minamata Convention on Mercury Mercury levels in an urban pregnant population in Durham County, North Carolina "The adverse effects of prenatal mercury exposure, most commonly resulting from maternal fish consumption, have been detected at very low exposure levels. The omega-3 fatty acids found in fish, however, have been shown to support fetal brain and vision development. Using data from a prospective, cohort study of pregnant women from an inland area in the US South, we sought to understand the fish consumption habits and associated mercury levels across subpopulations. Over 30% of women had at least 1 μg/L of mercury in their blood, and about 2% had blood mercury levels above the level of concern during pregnancy (≥ 3.5 μg/L). Mercury levels were higher among Asian/Pacific Islander, older, higher educated, and married women." Nickel toxicity in embryos and larvae of the South American toad: effects on cell differentiation, morphogenesis, and oxygen consumption "Nickel, a widely distributed heavy metal in the biosphere, produces systemic, carcinogenic, and teratogenic effects. The objectives of the present study are to report the acute, short-term chronic, and chronic toxicity of Ni in Rhinella arenarum embryos as well as the stage-dependent susceptibility to this heavy metal, including oxygen consumption, teratogenesis, and adverse effects on cell differentiation processes. ...The main teratogenic effects were retarded growth and development, extremely severe axis incurvations, persistent yolk plug, asymmetry, microcephaly and mouth and gill agenesia, and limited neuromuscular activity. Ciliated cells were not functional." Arsenite induces oxidative injury in rat brain: synergistic effect of iron "Sodium arsenite (arsenite)-induced neurotoxicity and its interaction with ferrous citrate (iron) was investigated in rat brain. In vitro data showed that arsenite (1-10 micromol/L) concentration dependently increased lipid peroxidation and the potency of arsenite was less than that of iron. ...Taken together, our study demonstrates that arsenite was less potent than iron in inducing oxidative stress. Furthermore, concomitant arsenite and iron potentiated oxidative injury in the nigrostriatal dopaminergic system, indicating that interaction of metals plays a more clinically-relevant role in pathophysiology of central nervous system neurodegeneration."

Metal Toxicity

Heavy Metals Toxicity (Table: U.S. GEOLOGICAL SURVEY CIRCULAR 1133, 1995)

In another recent study using the sea urchin embryo, Japanese researchers have identified a hierarchy of toxic effects from different heavy metals.

"Interactive toxic effects between heavy metals were investigated using a sea urchin (Anthocidaris crassispina) bioassay. An effluent from an abandoned mine showed significant inhibitory effects on embryo development as well as producing specific malformations. The effects on the embryos were reproduced by synthetic polluted seawater consisting of eight metals (manganese, lead, cadmium, nickel, zinc, chromium, iron, and copper) at the concentrations detected in the mine effluent. This indicated that the heavy metals were responsible for the effects observed. Five heavy metals were ranked in decreasing order of toxicity as follows: Cu > Zn > Pb > Fe > Mn. Among these, zinc and manganese could cause malformation of the embryos. From bioassay results using 27 combinations of heavy metals, 16 combinations including zinc could produce specific malformations, such as radialized, exo-gastrulal, and spaceship Apollo-like gastrulal embryos. Zinc was one of the elements responsible for causing malformations and its effects were intensified by the presence of the other metals, such as manganese, lead, iron, and copper." Naomasa Kobayashia and Hideo Okamurab.

Metal in Water

A major dilemma is the biological difficulty of clearing heavy metals and the subsequent accumulation of these metals in the food chain mainly from the hydrologic environment.

Lead

Lead pipe

CDC - Screening young children for lead poisoning

Lead in the environment is postnatally toxic and prenatally teratogenic. Lead exposure can occur in industrial and mining and can also be derived from leaded petrol, old lead piping, historic paints, and other environmental sources).

For children aged less than 6 years of age the CDC (USA) has defined an elevated blood lead level (BLL) as >10 µg/dL, but also indicated that evidence exists for subtle effects at lower levels. (Links: CDC - Lead Poisoning Prevention Program | Blood Lead Levels in Young Children - United States and Selected States 1996-1999)

• Lead crosses the placental barrier readily.
• Fetal blood levels are directly proportional to maternal levels.
• Lead poisoning affects virtually every system in the body, and often occurs with no distinctive symptoms.
• Lead in our diet is mainly found in osseous (bone) structures.
• Lead can damage a child's central nervous system, kidneys, and reproductive system and, at higher levels, can cause coma, convulsions, and death.
• Even low levels of lead are harmful and are associated with decreased intelligence, impaired neurobehavioral development, decreased stature and growth, and impaired hearing acuity.
• CDC has established a national surveillance system for children with elevated blood lead levels.
• CDC helped to initiate federal activities to reduce lead in gasoline, which brought about declines in average blood lead levels in the U.S. population. Data from the most recent National Health and Nutrition Examination Survey (NHANES) show that the percentage of U.S. children with elevated blood lead levels has dropped from 88.2% in the late 1970s to 4.4% in the early 1990s. (NHANES Chart)

Related References

• Interrelations of lead levels in bone, venous blood, and umbilical cord blood with exogenous lead exposure through maternal plasma lead in peripartum women
• Effect of breast milk lead on infant blood lead levels at 1 month of age

Links: Normal Development - Milk | CDC - Childhood Lead Poisoning Publications | Global Alliance to Eliminate Lead Paint

Mercury

Mercury

Used traditionally in the felting of hats, hence "mad hatters", a more recent example of mercury's toxicity was shown in Japan.

Japan Minamata disease map

Japan had industrial mercury poisoning of waterways by methyl mercury causing Minamata disease, which had substantial neurological effects similar to Hunter Russell syndrome. For more information on mercury the chemical, see Mercury MSDS. There has also been a movie available "Medical Study of Minamata Disease".

Australia - Food Standards Australia New Zealand (FSANZ)

"FSANZ’s Chief Scientist, Dr Marion Healy, said ‘Our investigations show that the level of mercury in most fish caught and sold in Australia is low."

"The Australian Dietary Guidelines advise eating one or two fish meals per week for good health. The good news is that FSANZ has found it is safe for all population groups to eat 2-3 serves per week of most types of fish. There are only a few types of fish, which FSANZ recommends limiting in the diet – these are billfish (swordfish / broadbill and marlin ), shark/flake, orange roughy and catfish." FSANZ updates advice on mercury in fish (Australia only) 18 March 2004 see also 2 June 2011.

Links: Diplomatic Conference for the Minamata Convention on Mercury 2013 | Minamata Convention on MercuryAustralia - food standards | NSW Food Authority | USA - federal register proposal 2011

Chromium

Chromium

Hexavalent chromium (CrVI) is used in more than 50 industries and is an important heavy metal pollutant. A recent study (2005) in monkeys (Macaca radiata) has demonstrated an effect on testicular spermatogenesis, possibly by inducing free radical toxicity. If these effects also occur in humans, then spermatazoa development could also be affected, the study further suggested a supplementation of antioxidant vitamins may be beneficial to the affected subjects.

Links: Related References

Cadmium

Cadmium (Cd) is a heavy metal pollutant produced during the smelting of other metals. It has many industrial and domestic uses (some paints, plastics, fertilisers, metal plating) and is founds use in the environment cadmium is in nickel-cadmium (NiCad) rechargeable batteries used in many portable devices as well as being present in cigarette smoke.

An animal study has shown that cadmium can induce retinoic acid signaling by regulating retinoic acid metabolic gene expression, suggesting that cadmium-induced teratogenicity may be due to altering levels of retinoic acid by disrupting the expression of retinoic acid-metabolizing genes. Developmental Signals - Retinoid acid

A recent human study of coastal populations of South Africa has identified associations between prenatal Cd exposure and birth anthropometry in female neonates but not in male neonates, suggesting a potential sex difference in the toxico-kinetics and toxico-dynamics of Cd.

Links: Retinoic acid

Lithium

Lithium

Lithium (Li, atomic number 3) is a soft alkali metal found in the natural environment, in industrial products (lithium batteries, some glass and ceramic products) and also is used to treat people with bipolar disorder. Lithium used as a drug, in a salt form, acts on the central nervous system as an antimanic agent to treat episodes of mania (frenzied, abnormally excited mood) associated with bipolar disorders. Lithium has been associated with fetal cardiac teratogenicity possibly by affecting Wnt/beta-catenin signaling.

Links: Abnormal Development - Drugs | MedlinePlus - Lithium | MedlinePlus - Lithium Toxicity | OTIS - Lithium and Pregnancy PDF

Yttrium-90

Yttrium

A therapeutic radioactive form of yttrium used in microspheres for the internal treatment of various liver cancers. As such it would be unlikely to be found in a human development situation.

Indium

Indium

A rare, malleable and easily fusible post-transition metal that is chemically similar to gallium and thallium, and also shows properties intermediate between these two elements. Currently used industrially in liquid crystal displays and touchscreens, and historically in thin-films to form lubricated layers. Medically used in a radioactive form (indium-111) in nuclear medicine tests and as a radio-tracker. Indium is not known to be used by any biological organism. There are some animal teratogenic studies that have looked at the effect of indium salts (indium chloride).

Embryotoxic and teratogenic effects of indium chloride in rats and rabbits "Indium was found to cross the placenta and appeared in fetal blood in proportion to the metal concentration of the maternal blood. In the amniotic fluid, indium concentrations remained below the detection limit. ...In rats, the effects of indium chloride causing fetal retardation was found to be independent of exposure time. The teratogenic effects were the highest on d 11 and 12 of gestation, when indium chloride caused gross external malformations. Data suggest that the teratogenic effects of indium chloride can be attributed primarily to a direct cytotoxic action of indium resulting from placental transfer, but the effect is not a selective one, as it appears only in the presence of maternal toxic effects."

References

Articles

Weinberg ED. (2010). Can iron be teratogenic?. Biometals , 23, 181-4. PMID: 20024603 DOI.

Chen H, Ke Q, Kluz T, Yan Y & Costa M. (2006). Nickel ions increase histone H3 lysine 9 dimethylation and induce transgene silencing. Mol. Cell. Biol. , 26, 3728-37. PMID: 16648469 DOI.

Hindin R, Brugge D & Panikkar B. (2005). Teratogenicity of depleted uranium aerosols: a review from an epidemiological perspective. Environ Health , 4, 17. PMID: 16124873 DOI.

Gulbis B, Jauniaux E, Decuyper J, Thiry P, Jurkovic D & Campbell S. (1994). Distribution of iron and iron-binding proteins in first-trimester human pregnancies. Obstet Gynecol , 84, 289-93. PMID: 8041549

Search Pubmed

June 2010 "Heavy Metal Teratogen" All (744) Review (72) Free Full Text (86)

Search Pubmed: Heavy Metal Teratogen

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• Globally Harmonized System of Classification and Labeling of Chemicals (GHS) | Implementation | U.S. Department of Labor
• Center for Disease Control and Prevention Screening Young Children for Lead Poisoning: Guidance for State and Local Public Health Officials | CDC - Blood Lead Levels United States, 1999-2002 | CDC - Childhood Lead Poisoning Publications
• Global Alliance to Eliminate Lead Paint
• UK Information Sheet - Cadmium and you Working with cadmium - Are you at risk?

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Cite this page: Hill, M.A. (2023, December 2) Embryology Abnormal Development - Heavy Metals. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Abnormal_Development_-_Heavy_Metals

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© Dr Mark Hill 2023, UNSW Embryology ISBN: 978 0 7334 2609 4 - UNSW CRICOS Provider Code No. 00098G