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The level of maternal methemoglobin during pregnancy in an air-polluted environment.


The objective of this prospective study was to determine if a correlation could be established between the ground-level concentrations of sulfur dioxide and methemoglobin methemoglobin /met·he·mo·glo·bin/ (met-he´mo-glo?bin) a hematogenous pigment formed from hemoglobin by oxidation of the iron atom from the ferrous to the ferric state.  concentrations in pregnant women when a coal-powered thermoelectric power plant was in operation ("dirty" period) and when it was closed ("clean" period). The location of the power plant, Plomin 1, in Labin, Croatia, was taken into consideration. Blood and urine samples of each pregnant woman in the study were tested three times in the clean period (n = 138) and three times in the dirty period (n = 122), with 1 month between each test. I observed a correlation between the increase in mean values of methemoglobin and the ground-level concentration of S[O.sub.2] on corresponding dates during the dirty period (r = 0.72, p < 0.01). In the clean period, the negative mean value of methemoglobin was significant (r = -0.60, p [less than or equal to] < 0.05), whereas in the dirty period, the positive mean value of methemoglobin was significant (r = 0.73, p [less than or equal to] < 0.01). The increase of maternal methemoglobin could be a useful biomarker to determine when the health of pregnant women is threatened by toxic substances in the environment. Key words." biomarker, environmental toxicants, maternal methemoglobinemia Methemoglobinemia Definition

When excessive hemoglobin in the blood is converted to another chemical that cannot deliver oxygen to tissues, called methemoglobin.
, precursor, pregnancy, toxic substances. Environ Health Perspect 111:1902-1905 (2003). doi:10.1289/ehp.6055 available via http://dx.doi.org/[Online 13 November 2003]

**********

In recent years, researchers have focused on explaining the role of oxygen, free radicals, and oxidative stress during embryogenesis Embryogenesis

The formation of an embryo from a fertilized ovum, or zygote. Development begins when the zygote, originating from the fusion of male and female gametes, enters a period of cellular proliferation, or cleavage.
 and placental stages, and development of pathologic pregnancy, especially preeclampsia preeclampsia /pre·eclamp·sia/ (pre?e-klamp´se-ah) a toxemia of late pregnancy, characterized by hypertension, proteinuria, and edema.

pre·e·clamp·si·a
n.
 and fetal intrauterine growth restriction intrauterine growth restriction
n.
See intrauterine growth retardation.


intrauterine growth retardation Fetal growth restriction Neonatology A generic term for any delay in achieving intrauterine developmental
 (IUGR IUGR intrauterine growth retardation (or restriction).

IUGR
abbr.
intrauterine growth retardation


IUGR Intrauterine growth retardation, see there
). Because I found no evidence that methemoglobin levels had been tested during human pregnancy in an air-polluted environment, I reevaluated research performed in this laboratory in the past. My objective was to identify a biomarker for methemoglobin to be used as a precursor and proof of the presence of oxidants before clinically manifested symptoms occur, even in early pregnancy. The statistical analysis was incomplete, thus requiring additional research, which ,was delayed because of the Croatian War for independence that lasted from 1991 to 1995.

Methemoglobinemia is a condition in which hemoglobin is oxidized oxidized

having been modified by the process of oxidation.


oxidized cellulose
see absorbable cellulose.
 to the ferric ferric (fĕr`ĭk), iron in the +3 valence state.


See ferrous.
 form and is unable to transport oxygen to tissues, therefore causing hypoxia hypoxia

Condition in which tissues are starved of oxygen. The extreme is anoxia (absence of oxygen). There are four types: hypoxemic, from low blood oxygen content (e.g., in altitude sickness); anemic, from low blood oxygen-carrying capacity (e.g.
. The physiologic level of methemoglobin is 1% in peripheral blood, and it may increase because of a variety of genetic, dietary, idiopathic, toxic, and other Factors. Methemoglobinemia primarily occurs when erythrocytes Erythrocytes
Red blood cells.

Mentioned in: Bartonellosis

erythrocytes (ē·rithˑ·rō·sīts),
n.pl red blood cells.
 are affected by xenobiotics and pharmaceutical compounds with toxicologic properties, such as volatile organic compounds, oxidants, nitrogen oxides, peroxynitrites, phenacetin phenacetin /phe·nac·e·tin/ (fe-nas´e-tin) an analgesic and antipyretic, whose major metabolite is acetaminophen, now little used because of its toxicity.

phenacetin

see acetophenetidin.
, and sulfonamides Sulfonamides Definition

Sulfonamides are medicines that prevent the growth of bacteria in the body.
Purpose

Sulfonamides are used to treat many kinds of infections caused by bacteria and certain other microorganisms.
.

Materials and Methods

To determine the toxic substances in the environment and the level of air pollution, I chose to study the population living near Plomin 1, a coal-powered thermoelectric power plant in Labin, Croatia. The plant, with a 110-m-tall chimney, is the single major air polluter within a 40-km radius of the target population. Every hour of operation, the plant emits about 8.5 tons (18,080 mg/[m.sup.3], or 6,900.8 ppm) of sulfur dioxide in addition to nitrogen oxides (N[O.sub.x]), carbon dioxide, carbon monoxide, total suspended particles, iron, titanium, vanadium vanadium (vənā`dēəm), metallic chemical element; symbol V; at. no. 23; at. wt. 50.9415; m.p. about 1,890°C;; b.p. 3,380°C;; sp. gr. about 6 at 20°C;; valence +2, +3, +4, or +5. Vanadium is a soft, ductile, silver-grey metal. , chromium, nickel, copper, zinc, selenium selenium (səlē`nēəm), nonmetallic chemical element; symbol Se; at. no. 34; at. wt. 78.96; m.p. 217°C;; b.p. about 685°C;; sp. gr. 4.81 at 20°C;; valence −2, +4, or +6. , lead, and other products of coal combustion. The coal from this area has a high sulfur content (9-11%) and a high level of radioactivity (the activity of [sup.238]U is 300 Bq/kg, which is 10-15 times higher than the average for other types of coal in the world). In the approximately 700,000 tons of crude waste from coal combustion surrounding the plant, the concentration of radionuclides was 5-10 times higher than that in the unburned coal (Saric 1996). Because the plant was closed from 19 February 1989 to 6 September 1989, I was able to carry out research during two separate periods: the "clean" period from April to July 1989 and the "dirty" period from December 1989 to March 1990. In the dirty period, the daily ground-level concentrations of S[O.sub.2] were monitored at three different locations.

Air quality data and samples. Daily minimum, maximum, and average air temperatures; quantity and type of precipitation; wind direction and strength; and relevant data on weather conditions were provided by the Labin meteorologic station. Air quality (S[O.sub.2], fumes fumes

odorous gases and other volatile materials; inhalation of irritating fumes causes coughing and, if sufficiently severe, irreversible pulmonary edema.
, and particulates) was analyzed by an acidimetric ac·i·dim·e·ter  
n.
A hydrometer used to determine the specific gravity of acid solutions.



a·cidi·met
 method based on the British standards recommended by the World Health Organization (WHO 1976). Briefly, air samples were collected in a weak solution of hydrogen peroxide; after particulates were removed by filtration, the quantity of the absorbed S[O.sub.2] in the [H.sub.2][O.sub.2] solution was determined by titration titration (tītrā`shən), gradual addition of an acidic solution to a basic solution or vice versa (see acids and bases); titrations are used to determine the concentration of acids or bases in solution. . The Regional Institute of Health Care (Pula Pula (p`lä), Ital. Pola, city (1991 pop. 62,378), W Croatia, on the Adriatic and at the southern tip of the Istrian peninsula. , Croatia) performed the air quality, measurements.

Subjects. Pregnant women were selected for the research target group from patients of the Primary Health Center, which is responsible for the health of about 25,500 residents, of which about 6,180 women of reproductive age bad a permanently assigned obstetrician obstetrician /ob·ste·tri·cian/ (ob?ste-trish´in) one who practices obstetrics.

ob·ste·tri·cian
n.
A physician who specializes in obstetrics.
 or gynecologist gynecologist /gy·ne·col·o·gist/ (-kol´ah-jist) a person skilled in gynecology.

gy·ne·col·o·gist
n.
A physician specializing in gynecology.
. Subjects were informed about the purpose of the research and gave written consent. Out of 273 women who were pregnant at the time of the study, 260 women were considered representative based on the criteria that they were pregnant and came to the center for regular monthly checkups during the clean and dirty periods. Patients received care from the Primary Health Center, the Obstetric-Gynecological Clinic in Rijeka, or the regional Obstetric-Gynecological Hospital in Pula.

Blood and urine samples from women in the study were tested three times in the clean period (n = 138) and three times in the dirty period (n = 122), with 1 month between each test. All 260 of the pregnant women in the study lived in Labin and the surrounding area.

The pregnant women were divided into six groups on the basis of the location of their places of residence within zones defined by concentric circles around the Plomin 1 plant. Most of the pregnant women lived in the zones 3.5-7.5 km (71.63%) and 7.5-12.5 km from the plant (21.63%). The town of Labin, with 12,000 inhabitants, is also in these zones.

The Obstetric-Gynecological Clinic and the Obstetric-Gynecological Hospital, where women from the area surrounding Plomin 1 were treated, provided data on reproductive loss for the clean and dirty periods.

Blood samples. According to the planned prospective study, 2 cm3 of each blood sample (heparinized) was tested. Hemoglobin and methemoglobin were measured by spectrophotometric method in the toxicology laboratory, at the Department of Occupational Medicine (Rijeka, Croatia). Briefly, the erythrocytes were lysed with Triton X-100 and spectrophotometry spectrophotometry

Branch of spectroscopy dealing with measurement of radiant energy transmitted or reflected by a body as a function of wavelength. The measurement is usually compared to that transmitted or reflected by a system that serves as a standard.
 was performed using the cyanohematin method. The maximal absorption of methemoglobin is 630-633 mm.

Samples (10 mL buffer, 0.1 mL blood from exposed or nonexposed pregnant women, or one drop of Triton X-100) were placed into test tubes, mixed well by turning the tubes five to eight times, and then left for 5 min. The mixture was then poured into another test tube, and the photometry photometry (fōtŏm`ətrē), branch of physics dealing with the measurement of the intensity of a source of light, such as an electric lamp, and with the intensity of light such a source may cast on a surface area.  was performed toward water at 633 mm (measurement A1). Afterward, one drop of neutral sodium cyanide was added to the mixture, which was stirred, left for 5 rain, and measured again at 633 mm (measurement A2).

Methemoglobin (g/L) = (A1 - A2) x F

F is determined by adding 0.1 mL potassium ferricyanide solution to 10.0 mL buffer and 0.1 mL normal blood. The mixture was then stirred and left for 2-3 min so that all of the hemoglobin could oxidize oxidize /ox·i·dize/ (ok´si-diz) to cause to combine with oxygen or to remove hydrogen.

ox·i·dize
v.
1. To combine with oxygen; change into an oxide.

2.
 into methemoglobin. The absorption was measured at 633 mm (measurement A3). A drop of neutral sodium cyanide was then added to the mixture, and after 5 min, the absorption was measured again at 633 mm (measurement A4). The difference (A3 - A4) corresponds to the absorption of total hemoglobin in the form of methemoglobin. I also used the cyanohematin method to determine the difference in absorption between hemoglobin and methemoglobin.

F = g/L hemoglobin / A3 - A4

Percentage methemoglobin in total hemoglobin = (g/L methemoglobin / g/L hemoglobin) x 100 The mean of two blood samples was used to determine F.

The standards used to relate absorbance absorbance /ab·sor·bance/ (-sor´bans)
1. in analytical chemistry, a measure of the light that a solution does not transmit compared to a pure solution. Symbol .

2.
 values to hemoglobin and methemoglobin concentrations were 120-160 g/L and 0.0-2.5 g/L, respectively.

Results

I found a statistically significant positive correlation between the mean concentration of methemoglobin and the daily ground-level concentration of S[O.sub.2] in the dirty period on the days that blood samples were taken (r = 0.72, p < 0.01) (Figure 1). Linear correlation (Figure 2) shows that, in the clean period, the downward trend of methemoglobin is statistically significant (r = -0.60, p " 0.05). In contrast, in the dirty period, the upward trend of methemoglobin is significant (r= 0.73, p" 0.01).

[FIGURES 1-2 OMITTED]

The monthly value of S[O.sub.2] during the dirty period ranged from 34.1 [micro]g/[m.sup.3]; (0.013 ppm) to 252.9 [micro]g/[m.sup.3] (0.10 ppm), varying with weather conditions. The ground-level concentration of S[O.sub.2] was proportionally higher on sunny and predominantly sunny days with no wind. To provide a weekly weather pattern, the following data were recorded: daily temperatures; wind from the southeast or northeast, which influences the ground-level concentrations of S[O.sub.2]; and meteorologic conditions (the ground-level concentration of S[O.sub.2] is lower on rainy and cloudy days).

The frequencies of miscarriages and stillbirths were significantly different between the clean and the dirty periods (p < 0.05). The stillbirths occurred only during the second half of pregnancy, and only mothers of stillborn stillborn /still·born/ (-born) born dead.

still·born
adj.
Dead at birth.


stillborn,
n an infant who is born dead.


stillborn

born dead.
 babies (and the mother of a baby who died on the second day) had methemoglobin values > 1.5 g/L (1% of hemoglobin) (Table 1). In one case of stillbirth Stillbirth Definition

A stillbirth is defined as the death of a fetus at any time after the twentieth week of pregnancy. Stillbirth is also referred to as intrauterine fetal death (IUFD).
 and the only case of spontaneous abortion after [greater than or equal to] 20 weeks of exposure to S[O.sub.2], methemoglobin was not detected in the mothers' blood. The adverse outcome of these cases can be explained by the influence of other intrinsic and extrinsic causes, but not by the influence of environmental toxicants (Table 1). Cases of increased methemoglobin values with confirmed symptoms of preeclampsia are in accordance with the assumption that environmental toxicants influence the course and outcome of pregnancy. I found no differences in methemoglobin levels or pregnancy loss by zones around the power plant. These data lead to the supposition that methemoglobinemia is related to the adverse outcomes and linked with IUGR, preeclampsia, complicated pregnancy, and a high percentage of perinatal mortality and morbidity.

In blood samples from pregnant women, the mean incidence of methemoglobin concentrations > 1.5 g/L fell from 22.7% to 13.4% in the clean period, whereas in the dirty period it increased from 10.8% to 32.8% (Figure 3).

[FIGURE 3 OMITTED]

The level of sulfates in urine samples significantly decreased during the clean period (p < 0.05), whereas it increased in the dirty period, bur not statistically significantly (p > 0.05).

Discussion

Methemoglobinemia during pregnancy is often unrecognized and underemphasized by obstetricians. Methemoglobinemia is a precursor to preeclampsia and eclampsia preeclampsia and eclampsia

Hypertensive conditions unique to pregnancy. Preeclampsia is marked by hypertension, protein in the urine, and hand and face edema, which develop late in pregnancy or soon after.
 and has the same symptoms: headache, breathing difficulties, dyspnea dyspnea /dysp·nea/ (disp-ne´ah) labored or difficult breathing.dyspne´ic

paroxysmal nocturnal dyspnea
, skin discoloration dis·col·or·a·tion  
n.
1.
a. The act of discoloring.

b. The condition of being discolored.

2. A discolored spot, smudge, or area; a stain.

Noun 1.
, cyanosis cyanosis (sī'ənō`sĭs), bluish coloration of the skin, mucous membranes, and nailbeds, resulting from a lack of oxygenated hemoglobin in the blood. , weakness, confusion, palpitations, chest pains, altered mental status, and delirium delirium

Condition of disorientation, confused thinking, and rapid alternation between mental states. The patient is restless, cannot concentrate, and undergoes emotional changes (e.g., anxiety, apathy, euphoria), sometimes with hallucinations.
 leading to coma.

As methemoglobin levels increase, patients demonstrate evidence of cellular hypoxia; death occurs when methemoglobinemia during pregnancy approaches 70%. Tabacova et al. (1997) confirmed that methemoglobinemia is connected with complications during pregnancy. In their study, Tabacova et al. (1997) measured methemoglobin as a biomarker of individual exposure; the most common complications were anemia (67%), threatened abortion/premature labor (33%), and signs of preeclampsia (23%). Methemoglobin was elevated significantly, compared with normal pregnancies. These results suggest that maternal exposure to environmental oxidants can increase the risk of pregnancy complications through stimulation of the formation of cell-damaging lipid peroxides and from a decrease in maternal antioxidant reserves (Gladen et al. 1999; Little and Gladen 1999; Tabacova ct al. 1997).

In the present study, the level of methemoglobin was monitored during pregnancy in an air-polluted area. The claim that the methemoglobin levels during pregnancy can indicate the adverse outcomes was based on the observation that, out of 10 cases of reproductive loss during the dirty period, three pregnant women had methemoglobin values > 1.5 g/L. Also, during the same period, a statistically significant linear increase of methemoglobin was established in the pregnant women tested.

When inhaled N[O.sub.x] enters the mother's blood circulation directly through the alveolar-capillary membrane, oxidant oxidant /ox·i·dant/ (ok´si-dant) the electron acceptor in an oxidation-reduction (redox) reaction.

ox·i·dant
n.
See oxidizer.
 electron loss changes hemoglobin to its pathologic reversible form--methemoglobin. Hemoglobin oxidation causes not only the rise in methemoglobin concentration but also the inhibition of enzyme and nonenzyme antioxidants, causing methemoglobinemia and adverse effects of hypoxemia hypoxemia /hy·pox·emia/ (hi?pok-sem´e-ah) deficient oxygenation of the blood.

hy·pox·e·mi·a
n.
Insufficient oxygenation of arterial blood.
 and hypoxia on particularly sensitive target organs.

Additional effects of methemoglobinemia include a) hypoxia and misbalanced production of reactive oxygen species reactive oxygen species,
n molecules and ions of oxygen that have an unpaired electron, thus rendering them extremely reactive. Many cellular structures are susceptible to attack by ROS contributing to cancer, heart disease, and cerebrovascular disease.
, normal by-products of cellular metabolism that can cause problems when present in excessive amounts; b) increased exogenous toxic oxidants; c) oxidative stress to cellular membranes; d) cellular damage to DNA DNA: see nucleic acid.
DNA
 or deoxyribonucleic acid

One of two types of nucleic acid (the other is RNA); a complex organic compound found in all living cells and many viruses. It is the chemical substance of genes.
, proteins, lipids, and carbohydrates; and e) tissue damage in target organs. These effects occur during early placentation, when "local" placental vascular endothelium endothelium /en·do·the·li·um/ (-the´le-um) pl. endothe´lia   the layer of epithelial cells that lines the cavities of the heart, the serous cavities, and the lumina of the blood and lymph vessels.  dysfunctions manifest clinically in nonsymptomatic fetal IUGR in the first half of pregnancy.

Therefore, the continuous monitoring of methemoglobin concentrations in the maternal bloodstream would be the first reliable early indicator of adverse effects of free radicals, oxidants, and oxidative stress.

Several articles have been published on the impact of toxic substances, metabolic oxygen free radicals, and oxidative stress on the placenta; other articles have described how placental circulation, nutrition, and oxygen concentration are vital to the fetus (Burton et al. 2001; Ferre 2001; Jaffe et al. 1997; Walsh et al. 2000). Increased fetal-maternal transfusion appears to result from the disintegration of the fetal--maternal barrier (Evain-Brion 2000; Morikawa et al. 1997; Pertl and Bianchi 1999; Wang and Walsh 1998).

It is well known that N[O.sub.x] species from coal combustion are hemoglobin oxidants; however, the mechanism of toxicity of inhaled S[O.sub.2] is nor fully understood. Low levels of S[O.sub.2], when inhaled, are immediately neutralized to form sulfite sulfite /sul·fite/ (sul´fit) any salt of sulfurous acid.

sul·fite
n.
A salt or ester of sulfurous acid.
 or bisulfite bi·sul·fite
n.
1. The univalent inorganic acid group HSO3.

2. A salt of sulfurous acid containing this group.
, which is metabolized and eventually excreted as sulfate sulfate, chemical compound containing the sulfate (SO4) radical. Sulfates are salts or esters of sulfuric acid, H2SO4, formed by replacing one or both of the hydrogens with a metal (e.g., sodium) or a radical (e.g., ammonium or ethyl). .

The effect of S[O.sub.2] on the antioxidant status and lipid peroxidation of red blood cells Red blood cells
Cells that carry hemoglobin (the molecule that transports oxygen) and help remove wastes from tissues throughout the body.

Mentioned in: Bone Marrow Transplantation

red blood cells 
 and their reactions to ingested, inhaled, and parenterally administered sulfite have been described (Etlik et al. 1997; Jenkins et al. 2000). Inhalation of S[O.sub.2] causes bronchoconstriction (Lazarus et al. 1997). An increase in plasma endothelin levels has been observed during severe preeclampsia; because endothelin is a strong vascular constrictor con·stric·tor
n.
One that constricts, especially a muscle that contracts or compresses a part or organ of the body.
, this suggests a correlation between plasma endothelin levels and the disease process (Dekker et al. 1991). However, the effect of placental transfer of toxicants during pregnancy and its impact on fetal hemoglobin--an immature form that is more readily oxidized than is adult hemoglobin--has not yet been fully clarified.

Conclusion

This prospective study of methemoglobin in pregnancy showed a positive correlation between the level of methemoglobin and exposure to S[O.sub.2], N[O.sub.x], and other coal combustion products Coal combustion products (CCPs) are categorized in four groups, each based on physical and chemical forms derived from coal combustion methods and emission controls:

*Fly ash
.

Plomin 1 is a coal-powered thermoelectric power plant 3.5 m above sea level, and the town of Labin is on a 200-300-m-high plateau 10 km to the southwest. The power plant is in an unsuitable location because northeast winds (40% of all winds) blow pollution directly from the plant to Labin. Instability of the atmosphere, temperature inversions, the chimney height, and fumes could explain the ground-level concentrations of toxic products of coal combustion in the research area.

The role of N[O.sub.x] as an oxidant is well known, but the role of S[O.sub.2] and its metabolites on human antioxidants is not clear and requires further epidemiologic and laboratory research. Methemoglobin, which is a result of exposure to toxic substances in the environment and which may lead to hypoxia and hypoxemia in pregnant women, has an important influence on maternal health and placental and fetal development.
Table 1. Reproductive loss in clean and dirty periods. (a)

                       Maternal
                     methemoglobin        Pregnancy
  Case no.               level             outcome

Clean period (4
    April-13
    July 1989)
  1                    Negative      Twins, (e) one mace-
                                       rated, one death
  2                    Negative      Spontaneous abortion
  3                    Negative      Spontaneous abortion
  4                    Negative      Premature birth (f)
Dirty period (7
    December 1989-
    15 March 1990)
  1                    Negative      Spontaneous abortion
  2                    Negative      Spontaneous abortion
  3                    Negative      Spontaneous abortion
  4                    > 1.5 g/L     Stillbirth
  5                    Negative      Spontaneous abortion
  6                    Negative      Spontaneous abortion
  7                    Negative      Missed abortion
  8                    > 1.5 g/L     Stillbirth
  9                    Negative      Stillbirth
  10                   > 1.5 g/L     Premature birth (g)

                                                              Weeks of
                                        Gesta-   Residence   S[0.sub.2]
                                        tional   location     exposure
  Case no.               Date (b)        week       (c)         (d)

Clean period (4
    April-13
    July 1989)
  1                  12 August 1989       11        SW            0

  2                  22 June 1989         15        WSW           0
  3                  25 May 1989          17        SW            1
  4                  28 June 1989         27        SW            8
Dirty period (7
    December 1989-
    15 March 1990)
  1                  22 December 1989     14        SW           14
  2                  31 December 1989      8        SW            8
  3                  30 January 1990      13        SW           13
  4                  1 February 1990      40        SW           22
  5                  7 February 1990      20        SW           20
  6                  11 February 1990     15         N           15
  7                  15 February 1990     13        SW           13
  8                  23 February 1990     39        SW           25
  9                  9 May 1990           41        SSW          35
  10                 28 May 1990          28        SW           28

Abbreviations: N, north; SW, southwest; WSW, west southwest.

(a) The "clean" period was from April to July 1989; the "dirty"
period was from December 1989 to March 1990. The plant was
closed 19 February--6 September 1989. (b) Date of stillbirth,
spontaneous abortion, or premature birth. (c) Location of pregnant
woman's residence, which is important to the population density
and unfavorable weather conditions (winds) in relation
to the source of air pollution and distance from the plant.
(d) Weeks each pregnant woman was exposed during the "dirty"
period. (e) The twins were aborted at the same time; the next day
the second twin briefly showed signs of life. (f) The child died 3
days later. (g) The child died 2 days later.


REFERENCES

Burton GJ, Hempstock J, Jauniaux E. 2001. Nutrition of the human fetus during the first trimester. Placenta 22(suppl):70-77.

Dekker GA, Kraayenbrink AA, Zeeman GG, Van Kamp GJ. 1991. Increased plasma levels of the novel vasoconstrictor vasoconstrictor /vaso·con·stric·tor/ (-kon-strik´ter)
1. causing constriction of blood vessels.

2. a nerve or agent that does this.


va·so·con·stric·tor
n.
 peptide endothelin in severe preeclampsia. Eur J Obstet Gynecol Reprod Biol 40:215-220.

Etlik O, Tomur A, Tuncer M, Ridvanagaol AY, Andac O. 1997. Protective effect of antioxidant vitamins on red blood cell red blood cell: see blood.  lipoperoxidation induced by S[O.sub.2] inhalation. J Basic Clin Physiol Pharmacol 8:31-13.

Evain-Brion D. 2000. The 2 differentiation pathways of the human trophoblast trophoblast /tro·pho·blast/ (tro´fo-blast) the peripheral cells of the blastocyst, which attach the blastocyst to the uterine wall and become the placenta and the membranes that nourish and protect the developing organism. . Gynecol Obstet Fertil 29:457-502.

Ferre F. 2001. Regulation of fetal placental circulation. Gynecol Obstet Fertil 29:512-517.

Gladen BC, Tabacova S, Baird DD, Little RE, Balabaeva L. 1999. Variability of lipid hydroperoxides in pregnant and non-pregnant women. Reprod Toxicol 13:41-44.

Jaffe R, Jauniaux E, Hustin J. 1997. Maternal circulation in the first-trimester human placenta--myth or reality? Am J Obst Gynecol 176:695-705.

Jenkins C, Wilson R, Roberts J, Miller H, McKilcop JH, Walker JJ. 2000 Antioxidants: their role in pregnancy and miscarriage. Antioxid Redox Signal 2:623-628.

Lazarus SC, Wong HH, Watts MJ, Boushey HH, Lavins BJ, Minkwitz MC. 1997. The leukotreine receptor antagonist zafirlukast zafirlukast /za·fir·lu·kast/ (zah-fir´loo-kast) a leukotriene receptor antagonist used as an antiasthmatic agent.

za·fir·lu·kast
n.
 inhibits sulfur dioxide-induced bronchoconstriction in patients with asthma. Am J Respir Crit Care Med 156:1725-1730.

Little RE, Gladen BC. 1999. Levels of lipid peroxides in uncomplicated pregnancy: a review of the literature. Reprod Toxicol 13:347-352.

Morikawa S, Kurauchi O, Tanaka M, Yoneda M, Uchida K, Itakura A, et al. 1997. Increased mitochondrial mitochondrial

pertaining to mitochondria.


mitochondrial RNAs
a unique set of tRNAs, mRNAs, rRNAs, transcribed from mitochondrial DNA by a mitochondrial-specific RNA polymerase, that account for about 4% of the total cell RNA that
 damage by lipid peroxidation in trophoblast cells of preeclamptic placentas. Biochem Mol Biol Int 41:767-775

Pertl B, Bianchi SW. 1999. First trimester prenatal diagnosis: fetal cells in the maternal circulation. Semin Perinatol 23:393-402.

Saric M. 1996. Environmental Exposure Assessment and Health Effect Studies in the Republic of Croatia (1985-1995). Zagreb, Croatia:Croatia Academy of Science and Arts.

Tabacova S, Balabaeva L, Little RE. 1997. Maternal exposure to exogenous nitrogen compounds and complications of pregnancy Complications of pregnancy are the symptoms and problems that are associated with pregnancy. There are both routine problems and serious, even potentially fatal problems. The routine problems are normal complications, and pose no significant danger to either the woman or the fetus. . Arch Environ Health 52:341-347.

Walsh SW, Vaughan JE, Wang Y, Roberts LJ. 2000 Placental isoprostane is significantly increased in preeclampsia. FASEB FASEB Federation of American Societies for Experimental Biology  J 14:1289-1296.

Wang Y, Walsh SW. 1998. Placental mitochondria as a source of oxidative stress in pre-eclampsia. Placenta 19:581-586.

WHO. 1976. Selected Methods of Measuring Air Pollutants. WHO offset publication no. 74. Geneva Geneva, canton and city, Switzerland
Geneva (jənē`və), Fr. Genève, canton (1990 pop. 373,019), 109 sq mi (282 sq km), SW Switzerland, surrounding the southwest tip of the Lake of Geneva.
:World Health Organization.

Lucijan Mohorovic

Obstetric and Gynecologic gynecologic /gy·ne·co·log·ic/ (gi?ne-) (jin?e-kah-loj´ik) pertaining to the female reproductive tract or to gynecology.  Primary Care, Labin, Croatia

Address correspondence to L. Mohorovic, Creska 2, 52221 Rabac, Croatia. Telephone: 385-52-885-026. Fax: 385-52-885-026. E-mail: lucijan.mohorovic@ pu.tel.hr

I thank Aleksandra Frkovic, M. Vukelic, Anton Frkovic, I. Svel, S. Bulesic, S. Mladinov, M. Ljubacev, and E. Tirelli.

This study was supported in part by PP Plomin Ltd.

The author declares a competing financial interest because the Croatian electricity company, PP Plomin Ltd., the management company for Plomin 2, provided funding for the study.

Received 14 October 2002; accepted 30 October 2003.
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Title Annotation:Research
Author:Mohorovic, Lucijan
Publication:Environmental Health Perspectives
Date:Dec 1, 2003
Words:3515
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