Toxicological impact of heavy metals on the placenta: A literature review

Mantakas Xenofon1, Sofoudis Chrisostomos2, Koumousidis Antonios2, Sinha Prabha2

1Laboratory of Forensic Science, University hospital of Heraklion, Crete, Greece

2Department of Obstetrics and Gynecology, Conquest hospital, East Sussex Healthcare NHS Trust, United Kingdom                                                                              

Correspondence: Koumousidis Antonios, Conquest Hospital, 46 Oast House Close St Leonards on sea, East Sussex, TN377UY, United Kingdom

E - mail: This email address is being protected from spambots. You need JavaScript enabled to view it.




The purpose of this study is the review of the literature regarding the placental damage after exposure to heavy metals. The role of the feto-placental unit is particularly important during pregnancy and replaces the function of the not fully formed organs of the fetus, like the lungs, kidneys, the gastrointestinal and the endocrine system. Moreover, it protects the fetus from infections, toxins, pharmaceutical agents, drugs as well as chemical substances. The examination of the placenta provides relevant information for the endometrium as well as it contributes significantly in the investigations of the perinatal deaths, the intrauterine growth retardation, the malformations, the infections and the maternal diseases effects on the fetal development. The size of the clinical problem associates with the development of the placenta function so intensely, that the histological aspect of the human placenta should be taken a lot into consideration. A thorough examination is often underestimated, although it can yield invaluable role regarding the fetal development. Most people during their lifetime are exposed to a large number of chemical substances which may be hazardous to the reproduction system. Many chemicals have been identified in laboratory studies to create reproductive problems, but also problems in the function of placenta, the fetal development and even cause perinatal death.

Key words: placenta, heavy metals, toxicity, complications



The placenta examination provides important information on the state of the endometrium and the investigations of the perinatal death, the intrauterine growth restriction, the malformations, the maternal infectious diseases and their effects on fetal development1.

The magnitude of the clinical problems associated with the development of placental function requires proper action to be taken towards the histological investigation of the human placenta in several occasions. A thorough examination, though often underestimated, can yield invaluable role regarding fetal development2. The histopathologic examination of the placenta postnatally, in cases of maternal or fetal complications, abortion or neonatal death, may provide an explanation regarding the aforementioned complications as well as relevant information on the management of future pregnancies3.

The placenta has two main functions, exchange of nutrients and protection of the embryo4. It may adapt continuously to maximize maternal and fetal nutrient offer and export, without compromising the integrity of the circulatory system of participants, meaning the mother and the fetus. Furthermore, the placenta performs a protective role against innumerous inflammatory conditions5. A normal placenta is 22cm in diameter and from 2.0 to 2.5cm thick, and, generally, it weighs about 470gr6. However, these values may vary. The maternal surface of the placenta is dark brown and shows lobules or cotyledons, which are complete. The fetal surface of the placenta is usually gray and transparent. The placental membranes are characterized by a metallic smell. Additionally, the umbilical cord belongs in the feto - placental unit and connects the fetus to the placenta. In full - term pregnancies, the umbilical cord is about 55 - 60cm with a diameter 2.0 - 2.5cm7. The placenta contains a viscous substance, the so-called Wharton’s jelly crossed by the umbilical vein and the two umbilical arteries8.

Generally, the placenta is sufficiently impermeable to chemical or pharmaceutical substances with a molecular weight of 1,000Da or more9,10. Most pharmaceutical agents have a molecular weight of 500Da or less. Therefore, the molecular size rarely represents a risk factor for pharmaceutical agents in correlation with the placenta and the fetus/neonate. The permeability of the placenta to chemicals reflects the characteristics of the agent, the thickness of the surface, and the concentration of lipid-protein membranes11. The intrinsic characteristics of the chemical substance, like the degree of ionization, the solubility of the lipids, the protein binding and the molecular weight also affect the substance’s transport through the placenta12. Of note, gases, vitamins, amino acids, sugars, ions, viruses, and fat soluble chemicals have easier access to the fetus13,14. Unionized lipo - soluble substances readily penetrate from ionized water soluble materials. Furthermore, the passage of the fetal membranes is not dependent on the number of placental layers formed as the fetus matures15. Although more than 80 known metals are crucial for the human physiological processes, other metals are known for their toxicity to the human body. Many metals are considered essential for normal cellular activity, while prolonged exposure to them can cause toxic reactions. The metals are also used in medicine as in diagnostic and therapeutic procedures16. The major heavy metals are: antimony, aluminium, silver, arsenic, vanadium, barium, bismuth, tungsten, gallium, zirconium, thallium, indium, iridium, cadmium, tin, lanthanum, platinum, manganese, lead, nickel, niobium, palladium, rhodium, ruthenium, scandium, strontium, tantalum, mercury, yttrium, copper, hafnium, gold, chrome. Most metals appear in the natural environment at relatively low levels. However, with regards to human exposure and toxicological significance, human activities are increasing the levels of metals in several regions.


Common toxic mechanisms and side effects

Enzyme inhibition/activation. An important point of the toxic actions of metals is the enzyme interaction, resulting in either enzyme inhibition or activation. Two mechanisms are particularly important: Inhibition may occur as a result of interaction between the metal and the sulfhydryl groups (sulfhydryl, SH) on the enzyme, or the metal may displace an essential cofactor of the enzyme17.

Intracellular organelles. Toxic metals can disrupt the structure and function of a significant number of organelles. For example, enzymes associated with the endoplasmic reticulum may be suspended, the metals can accumulate in the lysosomes, the respiratory enzymes in mitochondria can be suspended and the metallic inclusion can be formed in the core18.

Carcinogenesis. A number of metals have been shown to be carcinogenic in humans or animals. Arsenic, certain chromium compounds, and nickel metals are known carcinogens in humans. Beryllium, cadmium and cisplatin are probably toxic carcinogens. The carcinogenic action, in certain instances, is believed to result from the interaction of metal ions with DNA19.

Kidney. As kidney is the main excretory organ of the body, it is also a main target organ for metal toxicity. Cadmium and mercury, in particular, are key toxic substances that affect the kidneys20.

Nervous system. The nervous system is also affected by particular toxic metals, which are derived from organic metal compounds. For example, methylmercury, due to lipid solubility, enters the nervous system by crossing the bloodstream. In contrast, inorganic mercury compounds, which are more water soluble, are less likely to enter the nervous system, particularly affecting the kidneys. Similarly, organic lead compounds are especially neurotoxic substances21.

Endocrine and reproductive system. Since the male and the female reproductive organs are characterized by complexity in terms of hormones, any toxic substance, altering some of the hormonal processes, can have an impact on the reproductive system. Moreover, metals may act directly on the reproductive organs. Cadmium, for example, is known to cause damage to the testicles after acute exposure and binds to testicular degeneration, inhibition of spermatogenesis and Leydig cell atrophy22.

Respiratory system. Occupational exposure to metals in metallic powder form makes respiratory system a potential target. Acute exposure may cause irritation and inflammation of the respiratory tract, while chronic exposure can result in fibrosis (aluminium) or carcinogenesis (arsenic, chrome, nickel)23.

Heavy metals are considered one of the most important groups of environmental pollutants, which may well in small quantities be essential nutrients protecting health, but in greater quantities they can become toxic and dangerous. Heavy metals such as arsenic, mercury, copper, lead and cadmium have adverse effects in pregnancy. An overview of the current knowledge of the toxic effect of metals during pregnancy is very important. Arsenic, for example, can be harmful in pregnancy. Exposure to this substance can come from food, brought from agricultural areas where fertilizers containing arsenic have been used. It can also come from water wells near mines or manufacturing plants. Arsenic affects pregnant women who are at an increased risk for gestational diabetes. Chronic arsenic exposure through drinking water can increase fetal morbidity and mortality. There are reported higher proportions of infants with mental retardation and developmental disabilities due to maternal exposure. Exposure to lead during pregnancy can cause miscarriage or premature birth with low birth - weight, and is often associated with brain developmental defects and mental retardation24. Infants and fetuses exposed to lead, can develop behavioral and learning disabilities. Regarding the exposure to copper, estrogens promote its conservation and enhance its toxic effects on fertility rates25. Mercury is transferred from the mother to the fetus via the placenta and to the infant through the breastfeeding. In the United States, it is estimated that one in ten fetuses are born annually with increased risk of neurological disorders due to mercury exposure during pregnancy. The mercury toxicity can damage the fetal developing nervous system causing learning difficulties and can affect the reproductive system, involving in problems such as infertility, miscarriage and premature birth. Mercury reduces zinc levels, which can cross the placental barrier and the blood-brain barrier. It is also associated with reduced libido and premenstrual syndrome. Mercury is also transmitted through breast milk and is affecting the learning ability of the newborn26. Association of cadmium exposure in pregnancy with low birth - weight and premature birth is also often reported27. Various heavy metals such as lead, mercury and cadmium are known to alter the delicate balance of mother - fetus, potentially causing long - term damage in newborns. The thickness of placental layers is one of the major determining factors which affect the ability and interactive substance transport from the mother to the fetus28. Lead is known to be easily crossing the placental barrier by passive diffusion. This certifies a positive correlation. Similarly, a positive correlation was observed in the majority of studies on its levels in placental and cord blood. According to toxicodynamics, lead can alter the associated with calcium cellular processes in syncytiotrophoblasts and appears to be associated with reduced oxidation activity on cytochrome29. The role of the placenta as a mercury barrier is not completely clear: the cellular uptake of this heavy metal appears to be related to its chemical structure. It has been observed that the mercury and methylmercury fumes can cross the placenta, using passive transfer and amino acid transporters. On the contrary, inorganic mercury often accumulates in the placenta, limiting the amount that reaches the fetus30. The mercury - induced toxicity to the placenta has an impact on the hormone secretion deregulation, the amino acid transport, the oxygen consumption and the membrane fluidity.



Heavy metals have a negative impact on the placenta formation and further pregnancy development. Multiple biochemical procedures interact and exert toxic effects on the fetus formation. Multidisciplinary cooperation is necessary in order to ensure a healthy gestation.



Conflict of interest

All authors declare no conflict of interest.




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