* Laboratoire de Physiologie materno-foetale, and
Centre détude des interactions biologiques entre la santé et lenvironnement (CINBIOSE), Département des Sciences Biologiques, Université du Québec à Montréal, Montréal, Québec, Canada H3C 3P8
Received June 2, 2003; accepted August 14, 2003
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ABSTRACT |
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Key Words: human placenta; syncytiotrophoblast; calcium uptake; polychlorinated biphenyls; p,p'-dichlorodiphenyltrichloroethane; p,p'-dichlorodiphenyl-dichloroethane; Aroclor 1260.
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INTRODUCTION |
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The placental barrier is a selective filter and although it is very effective it still allows toxic compounds of low molecular weight, of lipophilic nature or un-ionized (Rogers and Robert, 1996; WHO, 1996
), such as OCs, to penetrate in humans (Fein et al., 1985
) and animals (Bäcklin et al., 1998
; Sharma et al., 2000
). The toxicity of OCs may compromise placental functions and contribute to developmental problems in offspring (Rogers and Robert, 1996
; WHO, 1996
). At low levels (Clophen A50 at 0.65 mg or 2,2'-dichlorobiphenyl at < 200 µM), OCs may cause placental vascular lesions, fetal growth retardation, or death (Bäcklin et al., 1998
; Kodavanti et al., 1996
). Maternal vascular lesions in the placental labyrinthine zones comprise loss and degeneration of endothelial cells, thrombi, and hemorrhages. Studies of mink placental exposure to PCBs have shown that they affect maternal vasculature and produce degenerative changes in the trophoblast and fetal vessels leading to fetal growth retardation or death (Bäcklin et al., 1998
). OCs during pregnancy are associated with inferior head circumference and birthweight in newborns (Eberlee et al., 1997
; Fein et al., 1984
). Exposure to OCs before birth is also linked with cases of developmental neurotoxicity and intellectual deficiencies such as learning and memory disabilities (Eberlee et al., 1997
; Wong et al., 1997b
). Generally, concentrations of OCs in maternal serum are used to predict the concentrations that will be found in umbilical cord serum (Fein et al., 1984
).
Fetal growth and development during pregnancy require adequate calcium (Ca2+) intake. Ca2+ is the most abundant cation in the organism (Stulc, 1997) and is vital to most cell functions (Henzi and MacDermott, 1992
). Ca2+ insures mineralization and rigidity in fetal bone metabolism (Pansu, 1974
) and in the third trimester, fetal Ca2+ demand is at its highest (Pitkin, 1985
). The general Ca2+ transport model via the syncytiotrophoblast follows three steps: Ca2+ enters by some Ca2+ channels (Clarson et al., 2003
; Lafond et al., 2001
; Moreau et al., 2002
, 2003
; Robidoux et al., 2000
); it is taken over by Ca2+ binding proteins (CaPB; Belkacemi et al., 2003
); and is released to fetal circulation by Ca2+-ATPase pump (Husain and Mughal, 1992
; Lafond et al., 1991
; Salle et al., 1987
; Stulc, 1997
).
However, OCs are well known for altering different types of Ca2+ mediator functions resulting in disturbance of intracellular calcium homeostasis. DDT inhibits the ability of calmodulin, a Ca2+ mediator, to transport Ca2+ ions essential for the intraneuronal release of neurotransmitters (Ecobichon, 1996). Treinen and Kulkarni (1986)
carried out an in vitro study on Ca2+-ATPase inhibition in human term placental cells by pp-DDT and its metabolite, p,p-dichlorodiphenyl-dichloroethane (DDE). PCBs disturb Ca2+ homeostasis by inhibiting Ca2+ entry in mitochondria and microsomes and they also induce sequestration and an increase of Ca2+ in these organelles (Kodavanti et al., 1993
; Mundy et al., 1999
; Sharma et al., 2000
). Furthermore, they inhibit Ca2+-ATPase (Kodavanti et al., 1993
; Wong and Pessah, 1996
) and increase Ca2+ entry in synaptosomes (Rosin and Martin, 1981
). PCBs congeners are known to disrupt intracellular Ca2+ second messenger signaling systems (Wong et al., 1997a
,b
) by activation and translocation of protein kinase C (PKC; Kodavanti et al., 1995
, 1996
), the enzymes involved in ATP synthesis and inositol phoshate (IP) hydrolysis (Kodavanti et al., 1996
; Mundy et al., 1999
; Sharma et al., 2000
).
Most studies on OCs effects on Ca2+ transport and homeostasis were carried out on brain cells. It is possible that the effects of OCs observed in neural cells might be the same on Ca2+ homeostasis in syncytiotrophoblast, the exchange units in the human placenta. Considering the importance of Ca2+ placental transport for the fetus, it is primordial to study the influence of OCs on that transport system using isolated trophoblast cells exposed to OC concentrations during pregnancy and on Ca2+ blood levels.
Although epidemiological evidence exists about relations between exposure to OCs and pregnancy outcomes, few human studies explore biochemical mechanisms involved in this relationship. The exposure doses used in animal studies are rather higher than in the human general population, and duration of exposure in utero, depending on gestation duration, is much different between animals and humans. Considering these facts it is difficult to extrapolate observed effects to human health without confirmation of animal studies data in human subjects really exposed to environment pollutants.
Our objective was to study the placental calcium transport in relation to low environmental doses of OCs in women from a general population. We studied Arochlor 1260 and one of its principal components, congener 153, because it was suggested that noncoplanar PCB congeners are more susceptible to interference with calcium metabolism (Kodavanti et al., 1993, 1994
). We also studied the effect of pp'DDT and its principal metabolite, pp'DDE, both organochlorine pesticides currently detected in maternal and cord blood in Canadian populations and susceptible to inhibit the Ca-ATPase in human placenta (Treinen and Kulkarni, 1986
; Van Oostdam et al., 1999
).
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MATERIALS AND METHODS |
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Population.
Recruitment took place over a two-year period at the Centre Local de Services Communautaires (CLSC) in the southwestern region of Quebec, Canada. Thirty women who consult physicians associated with this hospital early in pregnancy were recruited. The exclusion criteria were occupational exposure to toxic substances, medication that may affect hormonal levels, a history of cardiovascular and/or neurological disorders, and prepregnancy diabetes. Gestational diabetes, diagnosed according to the procedure in use at the hospital, twins, or other multifetal gestational outcomes were excluded post hoc.
Sampling procedures.
At term, maternal blood, umbilical cord blood, and placental samples were collected. For the analysis of DDT, DDE, and PCBs, heparinized "PCB-free" tubes were used to collect the maternal and umbilical venous blood samples. The plasma was separated by centrifugation and it was transferred into glass tubes.
All plasma samples were frozen upon collection at -20°C until analysis. Laboratory analyses of OCs were performed at the Centre de Toxicologie du Québec in Quebec City. For blood plasma, 2 mm were extracted, cleaned-up on Florisil columns, taken to a final volume of 100 µl and analyzed on the gas chromatograph (GC; 5890A from Hewlett Packard with ECD detector) with dual-capillary columns and dual Ni-63 electron-capture detectors. Peaks were identified by their relative retention times obtained on the two columns. Quantification was mainly done on the Ultra-1 column. The obtained detection limits were 0.02 µg/l for PCB congeners and chlorinated pesticides, 0.03 for p,p'-DDT, and 0.2 µg/l for Aroclor 1260.
For placenta, aliquots of tissues were weighted, homogenized with a mechanical homogenizer (Polytron), and extracted with a combination of organic solvents. A portion of the organic extract was isolated for lipid determination purposes. The remaining extract was processed by gel permeation chromatography (GPC). The extract was cleaned up by column chromatography on deactivated Florisil. PCBs and organochlorinated pesticides were eluted with a mixture of organic solvents. The residue was analyzed by GC (5890 from Hewlett Packard with ECD detector). The obtained detection limits were 0.3 µg/kg for PCB congeners and chlorinated pesticides, 0.6 µg/kg for p,p'-DDT, and 3 µg/kg for Aroclor 1260. It should be noted that Aroclor 1260, a commonly used PCB indicator, was calculated in the following manner: ([congener 138 + congener 153] x 5.2). Routine checks of accuracy and precision were done using reference materials from National Institute of Standards and Technology (NIST). Also, periodic evaluations were accomplished through participation in an external proficiency testing programs (Laboratoire de la Direction de la toxicologie humaine/INSPQ and Erlangen, Germany, for plasma and QUASIMEME, U.K., for tissues).
Ca2+ in serum was measured at Service de biochimie clinique from Hôpital St-François dAssise à Québec, by spectrophotometric quantification. Ca2+ was also measured in placenta. The samples of placental tissues were homogenized, lyophilized, burnt, and measured by spectrophotometric quantification at the Chemistry Department of Université du Québec à Montréal.
Human placental cytotrophoblast cells isolation.
Cytotrophoblast cells were prepared using the method of Kliman et al.(1986). The placentas were obtained from normal deliveries (n = 27) and caesarean sections (n = 3) and collected randomly from samples aforementioned and constituted the subpopulation used in the study of Ca2+ uptake by human syncytiotrophoblast. Briefly, amnion, chorion, and decidua were removed and villous tissue was cut into approximately 1-in. cubes and washed extensively with saline in order to remove blood. The tissue was then incubated three times in HBSS containing 1.51.6 mg/ml trypsin and 0.2 mg/ml DNase I at 37°C and 50 cycles/min for 30 min. After each incubation, the supernatant was removed and replaced by fresh digestion media. The supernatant was layered on calf serum and centrifuged at 1,215 x g for 15 min. Pellets were resuspended in DMEM, deposited on top of a discontinuous 5 to 70% Percoll gradient, and centrifuged at 507 x g for 20 min. Cytotrophoblast cells layers (4050% of Percoll) were removed and washed in DMEM. Cells were seeded at approximately 1.7 x 106 cells/well in 24-well plates, as currently used in our laboratories (Belkacemi et al., 2003
; Bernatchez et al., 2003
; Moreau et al., 2002
, 2003
). The medium was refreshed daily with DMEM containing 10% FBS. After four days of culture, cytotrophoblast cells were differentiated in syncytiotrophoblast, and subsequently used for Ca2+ uptake studies.
Calcium uptake studies.
Cells were washed twice with the Ca2+ uptake buffer (HBSS containing 1.26 mM CaCl2, 10 mM HEPES, and 0.1% BSA). The incubation at 370C was initiated by the addition of uptake buffer containing 45CaCl2 (24 µCi/well) for different intervals of time and stopped by rapid aspiration. The cells were washed three times with 1 ml of ice cold phosphate buffer sodium (PBS) containing 4 mM EGTA. Cells were solubilized in 0.1 M NaOH. The cell-associated radioactivity was measured by a ß-scintillation 1400 Wallac counter (Turku, Finland). The cellular protein content of each well was evaluated by spectrophotometric quantification using the BCA reagent with BSA as standard. The Ca2+ uptake is expressed as nmole of Ca2+ (from specific activity) per mg of cellular proteins.
Statistical analysis.
Students paired test was used to compare serum levels of Ca2+ between maternal and umbilical cord serum. For maternal/cord blood comparison of OC concentrations we used lipid corrected values which were compared by Wilcoxon matched pairs test. The correlation coefficients between OCs and Ca2+ in maternal and umbilical cord serum were obtained with a Spearmans test. The 75th percentile was chosen as threshold to separate two groups of exposure. Each Ca2+ uptake value at its specific kinetic time was also analysed under repeated measures using ANOVA test. Differences were considered significant when p values were <0.05.
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RESULTS |
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Data Distribution
Data obtained from samples measured on the 30 women studied are shown in Table 1 for distribution of Ca2+ concentrations and in Table 2
for OCs. Data distribution shows that Ca2+ concentrations in umbilical cord serum are significantly 1.2 times higher than Ca2+ maternal serum concentration (Table 1
). Table 2
shows that concentrations of OCs are significantly higher in maternal serum compared to concentrations found in the umbilical cord serum. The levels are 6.1, 6.0, 3.1, and 2.9 times lower in umbilical cord serum than in maternal serum at parturition respectively for Aroclor 1260, PCB 153, DDE, and DDT. However, the order of concentrations in placenta is DDE, PCB 153, DDT, and A1260. DDE seems to accumulate at higher levels than other contaminants in placental tissues. For example, it is 6.2 times more concentrated than PBC153.
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DISCUSSION |
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Nevertheless, OCs are still present in maternal serum. We demonstrated that there is a significant effect of pp'-DDE on Ca2+ uptake by human syncytiotrophoblast.
The mothers metabolism increases during pregnancy in order to provide adequate nutrients to support the development of maternal and fetal tissues. As early as the tenth week of pregnancy, this induces an "accelerated fasting" phase where lipids are mobilized from adipose tissues. This phase is amplified throughout pregnancy and reaches its peak towards the end. Lipids and fatty acids are found in maternal blood circulation and are transferred to the fetus with all essential elements; this is pursued after parturition through lactation (Papiernik et al., 1995). It is known that OCs are highly lipophilic substances and bioaccumulate in adipose tissues in animals and humans (Ando, 1982
; Ecobichon, 1996
). Thus, lipid metabolism is highly disrupted during pregnancy and may vary. Therefore, unlike most studies, we have chosen not to report concentrations of OCs in lipids since it would not be representative of the real concentrations to which the placenta is exposed throughout pregnancy.
The placental barrier is a selective filter and although it is very effective it still allows toxic compounds of low molecular weight lipophilic nature or unionized to go through. Because of their lipophilic nature, OCs are known to be transferred readily through the placenta in humans (Bäcklin et al., 1998; Fein et al., 1985
). In our study, it is probable that, at these low maternal levels of contamination (<2 µg/l serum), placental functions are not impaired thus allowing the placenta to play its role. In actual fact, the placenta seems to block most OCs since concentrations found in the umbilical cord are 6.1, 6.0, 3.1, and 2.9 times lower respectively for Aroclor 1260, PBC 153, DDE, and DDT compared to maternal serum. Also, during pregnancy, hypocalcemia can occur along with an increased concentration in parathyroid hormone (PTH) in maternal blood. This is mainly due to Ca2+ storage by the fetus, which will be necessary during pregnancy and after parturition. Ca2+ crosses placental tissues easily. Thus, Ca2+ is more concentrated in fetal than maternal plasma. However, it is important to take into account the increase of plasmatic maternal volume, hence a downward concentration that can evoke a Ca2+ deficiency. During the third trimester, the fetus must bind 2030 g of Ca2+ (200300 mg/day; Papiernik et al., 1995
). In our study, maternal and umbilical cords serum concentrations found here (mother: 2.25 mM, umbilical cord: 2.71 mM) are similar to normal values (mother: 2.1 mM, umbilical cord: 2.65 mM) (Husain and Mughal, 1992
).
The results of the present study indicate a decreasing but not a significant tendency in mother serum and placental Ca2+ concentrations with increasing concentrations of OCs. However, Ca2+ concentrations in cord and Ca2+ uptake by syncytiotrophoblast are not linked to concentrations of OCs. Only an increase in DDE in maternal serum is significantly linked to a decrease of Ca2+ concentrations in maternal serum and Ca2+ uptake by syncytiotrophoblast. It is important to note that the present study demonstrated that Ca2+ concentrations in maternal blood do not influence Ca2+ uptake by syncytiotrophoblast. Thus, concentration modulation in Ca2+ encountered by OCs at maternal blood level should not influence Ca2+ uptake by syncytiotrophoblast. It would therefore take direct damage to the placenta to influence Ca2+ uptake.
The transfer of Ca2+ from mother to fetus via the placenta is done via cellular diffusion and is principally regulated by Ca2+ channels (CaT1 and CaT2; Moreau et al., 2003), second-messengers (CaM, PKC, CaBP; Belkacemi et al., 2003
; Laramée et al., 2002
), Ca2+-ATPase pump and Na+/Ca2+ exchangers (Husain and Mughal, 1992
; Lafond et al., 1991
; Salle et al., 1987
; Stulc, 1997
). A disruption at one of those cellular levels could provoke a disruption in Ca2+ global homeostasis. Functionally, PBCs disrupt Ca2+ homeostasis at neural levels (Mundy et al., 1999
) by inhibiting Ca2+ entry in mitochondria and by inducing a sequestration and an increase of Ca2+ in them (Kodavanti et al., 1993
; Sharma et al., 2000
). At synaptosome levels, they inhibit the Ca2+-ATPase (Kodavanti et al., 1993
; Wong and Pessah, 1996
) and increase Ca2+ entry (Rosin and Martin, 1981
). It has therefore been demonstrated that at mature neuronal levels, in adult rat brain homogenized samples, mitochondria, and synaptosomes are disrupted by PBC congeners, which provoke a disruption in transduction systems (intracellular signaling) thus, Ca2+ intracellular transport (Wong et al., 1997a
,b
). They also enable the activation and the translocation of PKC (Kodavanti et al., 1995
, 1996
) and enzymes implicated in ATP synthesis and they hydrolyze inositol phosphate (IP) (Kodavanti et al., 1996
; Mundy et al., 1999
; Sharma et al., 2000
). PCB mixtures, such as A1254 may also alter Ca2+ intracellular homeostasis by decreasing acid
-aminobutyrique GABAA receptor response (Inglefield and Shafer, 2000
; Inglefield et al., 2001
). However, in this study, PCB 153 and PCB mixtures (Aroclor 1260) have not shown significant effect on Ca2+ uptake by syncytiotrophoblast. This may be due in part by the fact that PBCs do not seem to cross and to accumulate significantly in placental tissues. Other indirect mechanisms could be implicated in the modulation of placental Ca2+ homeostasis, since Lilienthal et al.(2000)
demonstrated a reduced level of 1,25-dihydroxyvitamin D3 in rat dams and offspring after exposure to a reconstituated PCB mixture.
On the other side, Treinen and Kulkarni (1986) demonstrated in vitro an inhibition of human placental Ca2+-ATPase by pp'-DDT and pp'-DDE. Moreover, Kodavanti et al.(1996)
mention that DDT, and possibly DDE, principally target four different action sites at neuronal membrane levels that may function simultaneously. It affects permeability to K+ ions, therefore decreasing K+ transport through the membrane. It interferes with Na+ active transport out the axone during repolarisation by maintaining Na+ channels opened which close very slowly thereafter. It inhibits neuronal ATPases, particularly Na+/K+-ATPase and Ca2+/Mg2+-ATPase which both play a vital role in neuronal repolarization. Moreover, DDT inhibits CaM, a Ca2+ mediator that transports Ca2+ ions essential for neurotransmitters release. By examining Treinen and Kulkarni (1986)
results on the effects of DDT and DDE on the placenta, it is possible to see that phenomenon observed at synaptosome levels in Ecobichon (1996)
and Kodavanti et al.(1996)
studies are applicable at syncytiotrophoblastic levels. It is therefore possible that DDT and DDE inhibit Ca2+ intracellular transfer from maternal to fetal syncytiotrophoblast side and also inhibit Ca2+ exit via Ca2+-ATPase. This could partly explain the increase Ca2+ uptake by the syncytiotrophoblast related to higher DDE concentrations (
0.70 µg/l) in maternal blood. However, DDT concentrations being far lower (mean = 0.038 µg/l) in maternal blood could demonstrate that DDT does not have significant effect on Ca2+ uptake.
In summary, notwithstanding the low levels of pp'-DDE concentrations of women in this study, a significant increase can be observed for Ca2+ uptake by human syncytiotrophoblast. However, Ca2+ umbilical cord levels are not significantly affected by low OC serum concentrations in women. Effects of Ca2+ uptake are possibly not sufficient to reduce maternal Ca2+ transfer to the fetus. It must be taken into account that the placenta was exposed to OCs during the nine-month period. The chronic effects of OCs on trophoblast cells and subsequently until cell differentiation, are possibly the genomic alterations on expression or number of Ca2+-ATPase and/or second messengers. Furthermore studies should be undertaken to characterize action mechanisms of OCs on Ca2+ uptake by human syncytiotrophoblast.
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ACKNOWLEDGMENTS |
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NOTES |
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