Gestational age and dose influence on placental transfer of 63Ni in rats
Article Outline
- Abstract
- 1. Introduction
- 2. Materials and methods
- 3. Results
- 4. Discussion
- Conflict of interest statement
- Acknowledgements
- References
- Copyright
Abstract
The effects of gestational age and dose of nickel exposure on regulating and influencing placental transfer were investigated. Pregnant rats on gestational day (GD) 12, 15 or 20 were injected intraperitoneally with saline, 64, 320 or 640
kBq/kg body weight of 63Ni. Twenty-four hours after administration, samples were harvested from each for measurement of radioactivity by liquid scintillation counting and for autoradiography. In placenta, amniotic fluid and fetal membrane, 63Ni concentrations increased with increasing doses and gestational age. In fetus, 63Ni concentrations reached a maximum on GD 15 and then declined on GD 20 although they maintained a dose-dependency for each GD group. In fetal blood on GD 20, 63Ni concentration increased dose-dependently and was higher than in maternal blood. The autoradiographs demonstrated that 63Ni radioactivity was located within placental basal lamina, fetal bones and most organs. These findings suggest that the nickel uptake, retention and transport in placenta increase dose- and gestation age-dependently, and nickel transfer through placental barrier is primarily from mother into the fetus, but hardly from fetus to mother.
Keywords: Placenta, Fetus, Nickel, Transfer, Gestational age, Dose
1. Introduction
While carcinogenic potential of nickel is a focus of interests [1], [2], [3], its embryonic and fetal toxicity attract even more attention [1], [4], [5], [6], [7], [8], because females of all ages are more frequently exposed to nickel than men are as a result of daily use of metal articles that release nickel ions in modern industrial society [9]. A cross sectional study of female nickel hydrometallurgy workers in a Russian refinery plant reported increased rates of congenital malformations and spontaneous abortions [10]. The evidence indicates that higher exposure to nickel in females causes a higher risk in reproductive toxicology. Although it was recognized that dermatitis and allergy affect large parts of the female general population resulting from daily use of metal articles releasing nickel [9], the mechanism of toxicity to the reproductive system remains poorly understood.
The evidences relating nickel to embryotoxicity and fetal toxicity are mainly derived from animal studies. After intraperitoneal or intramuscular injection of nickel during pregnancy in mice and rats, reductions in number of live pups, body weights of fetuses and offspring, or malformations were observed [11], [12]. Intraperitoneal injections of nickel chloride in chick or mice embryos in the first day of gestation resulted in a higher frequency of both early and late resorptions, and a higher frequency of stillborn and abnormal fetuses [13]. Reproductive effects such as embryotoxicity and teratogenicity have been found following oral exposure of nickel chloride in pregnant rats during days 7–14 of organogenesis [14]. It is assumed that the effects of nickel on maternal and placental circulation do not play a role; instead, the direct embryo-damaging effect of nickel crossing the placenta (direct cytotoxic effect) may be held responsible for the fetal toxicity and teratogenicity of nickel [14], [15].
It is well known that placenta has a dual transport function in that it facilitates the passage of some bio-substances to the fetus while acting as a barrier to other materials. Besides nutrient substances crossing the placenta barrier, some harmful metals that can damage the embryo, including nickel, can also transverse the placenta [16]. It is unclear whether the nickel transportation in placenta is influenced by gestational age and dosage while placental morphological and permeable characteristics change markedly during development. The present studies were designed to provide information regarding placental uptake, retention and transfer of 63Ni following administration of various doses at different gestational ages.
2. Materials and methods
2.1. Animals
Pathogen-free female virgin Wistar rats, 90–120 days old, weight 190–220g (SPF, Certification SCX G2005-0007; Animal Center for Medical Science of Lanzhou University, China) were used in this study. Breeding was performed by placing three female rats into the cage of a male rat from 16:00h until 8:00h. This procedure was repeated on successive nights until copulation was confirmed by the presence of sperm in a vaginal smear (day 0 of gestation, GD 0). The pregnant rats were housed individually in polycarbonate cages, fed rat chow pellets (standard laboratory diet from Beijing Keaoxieli Feed. Co. Ltd, Beijing, China) and tap water ad libitum in an environment of controlled temperature (22±1°C), relative humidity (RH, 50±10%) and a 12-h-dark cycle (light on 07:00h–19:00h). All animal protocols were in accordance with the European Communities Council Directive of November 24, 1986 (86/609/EEC) and approved by Institutional Animal Care and Use Committees of Gansu Province Medical Animal Center and Lanzhou University Animal Committees Guideline.
2.2. Isotope and experimental protocol
The radioactive 63NiCl2 solution with a specific activity of 8.5GBq/L 63Ni (Radiopurity>99%) was purchased from China Isotope Corporation (Beijing, China) and diluted with physiological saline solution to obtain the concentrations of 6.4, 32 and 64kBq/mL for various doses in same volume. An administration of 63Ni dose was expressed as radioactivity in 10mL per kilogram body weight.
Pregnant rats were randomly divided into control group, 64, 320 and 640kBq/kg of 63Ni dose groups. Each group was injected intraperitoneally with either saline as control or 64, 320, 640kBq/kg body weight of 63Ni, respectively at 10:00h on GD 12, 15 or 20 (Table 1). The rats survived for 24h after each injection, their blood was withdrawn by femoral artery puncture in heparinized dry beakers under deep anesthesia with chloral hydrate (350mg/kg body weight), their abdomens were subsequently opened by a midline incision, amniotic fluid was withdrawn by amniotic cavity puncture, uterus with embryos/fetuses were tied off and cut above the ovary and vagina, and both kidneys were removed. Placentas and fetuses were extracted from uterus, blotted and weighed for estimation of their radioactivity. Five fetuses from different litters generated by pregnant rats on GD 20 were beheaded for 0.2mL blood. Unfortunately, fetus from pregnant rat on DG 12 or 15 was still too small to have enough blood for estimation. Samples were prepared for 63Ni radioactive estimation by liquid scintillation counting (LSC) or for 63Ni distribution in maternal organs and fetuses by autoradiography as detailed below.
Table 1. Experimental protocol.
| Group | Rat numbers of administration | 63Ni radioactive estimation in samples | ||||
|---|---|---|---|---|---|---|
| DG 12 | GD 15 | GD 20 | Liquid scintillation counting | Autoradiography | ||
| GD 12 & GD 15 | GD 20 | |||||
| Saline | 3 | 3 | 3 | Af, F, Fm, Mb, Mk, P | Af, F, Fb, Fk, Fm, Mb, Mk, P | |
| 64kBq/kg | 5 | 5 | 5 | Af, F, Fm, Mb, Mk, P | Af, F, Fb, Fk, Fm, Mb, Mk, P | F, Mk, P |
| 320kBq/kg | 5 | 5 | 5 | Af, F, Fm, Mb, Mk, P | Af, F, Fb, Fk, Fm, Mb, Mk, P | F, Mk, P |
| 640kBq/kg | 5 | 5 | 5 | Af, F, Fm, Mb, Mk, P | Af, F, Fb, Fk, Fm, Mb, Mk, P | F, Mk, P |
2.3. Liquid scintillation counting
Sample preparation of maternal kidney, maternal blood, placenta, amniotic fluid, fetus, fetal membrane and fetal blood, and counting procedures began with the acid digestion of small quantities of tissues at a low temperature. 0.2mL of blood or amniotic fluid was digested directly in the scintillation counting vials using 0.1mL of 70% perchloric acid and 0.2mL of 30% hydrogen peroxide. Samples from maternal organs and fetus were wet acid digested. For every 50mg of tissue wet weight, 0.1ml of 70% perchloric acid and 0.2ml of hydrogen peroxide were added. The vials were tightly capped and heated in a water bath at 80°C until the solution cleared, indicating that oxidation was complete. The test volume of each solid sample was taken by calculated with the formula [50mg×total volume of digestion (mL)/wet weight (mg)] for counting. Then 2mL scintillation liquid (Beckman Counter Inc, USA) was added when the solution was cooled. The scintillation vials were allowed to remain at 25°C for at least 24h in darkroom before scintillation counting. Radioactivity in blood, amniotic fluid and each sample from maternal organ and fetus were measured with a LS6500 Multi-purposes liquid scintillation spectrometer (Beckman Counter Inc, USA). The data obtained from LSC of each 63Ni-exposed sample were corrected by deducting the background radioactivity detected in control group.
2.4. Autoradiography
The samples including maternal kidneys, placentas and fetuses were immediately stored at −80°C until they were sliced. Sections of 20μm thickness were cut in a cryostat microtome at −20°C. Some sections were mounted on glass slides, air-dried at room-temperature, and exposed in direct apposition against glass plates coated with nuclear emulsion (ILFORD K5D, Ilford Photo Harman Technology Ltd, Cheshire, UK), which were prepared by dipping the clear glass plates into a jar containing K5D emulsion melted in a water bath at 40°C and dried in 5°C oven in darkroom. These sections were exposed for 4 weeks at 4°C in the dark. The others were exposed against the Kodak XBT-1 films (Carestream Health, Inc, Rochester, US) for 4 months at −80°C. The autoradiographic glass plates and films were developed by D-72 developer (Kodak) for 4min, fixed by F-24 fixer (Kodak) for 8min at 18°C and rinsed by running water in the darkroom. Corresponding tissue sections were also fixed in ethanol, stained with hematoxylin and eosin (HE).
2.5. Statistical analysis
The significance of the results in relation to dose or GD was determined by one-way ANOVA followed by Student's t test ad hoc using SPSS 16.0 for Windows, and the criterion for significance was p<0.05. The data were represented by the mean±SEM.
3. Results
3.1. 63Ni in placenta and fetus
The average weight of placentas on GD 12, 15 and 20 in rats injected with various doses of 63Ni for 24h were 0.132, 0.344 (2.6-fold increase over GD 12, p<0.001) and 0.664g (1.9-fold increase over GD 15, p<0.001) respectively and did not differ significantly from their respective controls. The dose- and gestational age-dependent increases of 63Ni Bq/g in placentas 24h after administration of 64, 320 and 640kBq/kg body weight of 63Ni on GD 12, 15 and 20 are summarized in Fig. 1A. For example, the 63Ni concentrations in placentas on GD 12 in rats injected with doses of 64, 320 and 640kBq/kg body weight were 4.3, 13.9 (p<0.01, compared with 64kBq/kg; Fig. 1A) and 35.77Bq/g (p<0.001, compared respectively with 64 and 320kBq/kg; Fig. 1A), respectively. Twenty-four hours after injection of 320kBq/kg body weight of 63Ni into rats on GD 12, 15 and 20 resulted in placental concentrations of 13.9, 29.69 (p<0.01, compared with GD 12) and 98.43Bq/g (P<0.001, compared respectively with GD 12 and 15; Fig. 1A), respectively.
Fig. 1
Radioactive concentrations detected in placentas and fetuses on GD 12, 15 and 20 in rats injected respectively with various doses of 63Ni for 24
h. (A) The significant increases of 63Ni concentrations in placentas depended upon the dose and the gestational age. (B) The significant increases of 63Ni concentrations in fetuses 24h after three doses injections were shown in a dose-dependent manner on each GD tested. However, in all three dose groups, 63Ni concentrations in fetuses increased markedly from GD 12 to 15, but decreased moderately on GD 20. Bars indicate mean±SEM, *p<0.05, **p<0.01, ***p<0.001.
The mean weight of fetus on GD 12, 15 and 20 in rats injected with three doses of 63Ni were 0.095, 0.472 (4.9-fold increase over GD 12, p<0.001) and 5.667g (12.0-fold increase over GD 15, p<0.001) respectively and did not significantly differ from their respective controls. The fetal 63Ni concentrations exhibited a significant increase in a dose-dependent manner 24h after three doses administration on each GD tested (Fig. 1B). For example, twenty-four hours after the dose of 640kBq/kg body weight of 63Ni administration into rats on GD 12, 15 and 20, the fetal 63Ni concentrations were 7.0 to 9.0-fold higher than those receiving 64kBq/kg body weight of 63Ni. However, in all three dose groups, the 63Ni concentrations in fetuses increased markedly from GD 12 to 15, but decreased moderately on GD 20 (Fig. 1B). In other words, the highest 63Ni concentrations were detected in fetuses on GD 15.
The autoradiograph of placenta demonstrated that the radioactivity of 63Ni was only concentrated within basal lamina 24h after three doses of 63Ni injection (Fig. 2). The autoradiographs of fetal sagittal sections produced with glass plates coated with nuclear emulsion and the roentgen films for different times are depicted in Fig. 3, Fig. 4. These photographs showed the radioactivity in fetuses on GD 20 in rats injected with three doses of 63Ni for 24h was located in bones including cranial bones, vertebrae, clavicle, scapula, costal cartilage, humerus and femur (Fig. 3, Fig. 4A, B, C and D), and in organs including eye, lung, heart, intestine, liver and kidney (Fig. 3). As expected, the dose of 640kBq/kg body weight of 63Ni induced more intensive radioactivity than doses of 320 and 64kBq/kg body weight did.
Fig. 2
The photograph (A) and autoradiograph (B, glass plate coated with nuclear emulsion, exposure time
=4 weeks) of a placenta on GD 20 in rat injected with the dose of 640kBq/kg body weight of 63Ni for 24h. The radioactivity is only concentrated within the basal lamina of placenta. Bar=2mm.
Fig. 3
Representative autoradiograph of fetal sagittal section (640
kBq/kg weight of 63Ni administration on GD 20 in rat for 24h) exposed to roentgen film for 4 months. It shows intensive radioactivity located in bones including frontal, parietal, occipital, sphenoidal bone and vertebrae, clavicle, scapula, costal cartilage, elbow-bone, radial bone, humerus and femur and the organs including heart, liver, kidney, eye, lung and intestine. Bar=5mm.
Fig. 4
Representative photographs and autoradiographs (glass plate coated with nuclear emulsion, exposure time
=4 weeks) of the 6th, 7th and 8th cervical vertebras (A), the 7th, 8th and 9th costal cartilages (B), tibia (C) and parietal bone (D) in fetuses on GD 20 in rats injected with the dose of 640kBq/kg body weight of 63Ni for 24h. Bar=500μm (A, B, C) and 200μm (D).
3.2. 63Ni in amniotic fluid and fetal membrane
The 63Ni concentration in amniotic fluid was also found to increase dose- and gestational age-dependently, and reached a maximum on GD 20 (Fig. 5A). For example, the 63Ni concentrations in amniotic fluids 24h after the dose of 640kBq/kg administration on GD 12, 15 and 20 in rats were 7.90, 18.13 (p<0.01, compared with GD 12) and 66.30Bq/mL (p<0.001, compared respectively with GD 12 and 15; Fig. 5A), respectively.
Fig. 5
Radioactive concentrations of 63Ni detected in amniotic fluid (A) and fetal membranes (B) on GD 12, 15 and 20 in rats injected intraperitoneally with different doses of 63Ni for 24
h. Bars indicate mean±SEM, *p<0.05, **p<0.01, ***p<0.001.
Among all tissues measured by LSC, fetal membrane had the highest 63Ni concentrations, which increased significantly in response to doses and gestational age (Fig. 5B). For example, the 63Ni concentrations in fetal membrane on GD 12, 15 and 20 in rats treated with the dose of 640kBq/kg body weight of 63Ni for 24h were 39.09, 92.30 (p<0.01, compared with GD 12) and 1534Bq/g (p<0.001, compared respectively with GD 12 and 15) respectively, and higher than those in placentas under the same conditions.
3.3. 63Ni in maternal and fetal blood
The 63Ni concentrations detected in maternal blood on GD 12, 15 and 20 in rats injected respectively with the dose of 64, 320 and 640kBq/kg body weight of 63Ni for 24h were not significant different (Fig. 6A). In contrast, 63Ni concentrations detected in fetal blood after 64, 320 and 640kBq/kg body weight of 63Ni respective administration on GD 20 for 24h increased dose-dependently and were 2.3-, 4.6- and 8.6-fold higher than those in maternal blood on GD 20 in rats injected with three doses, respectively (Fig. 6A).
Fig. 6
Radioactive concentrations of 63Ni in maternal blood (A) and kidney (B) on GD 12, 15 and 20, in fetal blood (A) and kidney (B) on GD 20 in rats injected intraperitoneally with different doses of 63Ni for 24
h. Bars indicate mean±SEM, *p<0.05, **p<0.01, ***p<0.001.
3.4. 63Ni in maternal and fetal kidney
The 63Ni concentrations detected in maternal kidneys on GD 12, 15 and 20 in rats injected respectively with the dose of 64, 320 and 640kBq/kg body weight of 63Ni for 24h exhibited a significant increase in relation to dose, but no significant difference in relation to gestational days (Fig. 6B). However, the 63Ni concentrations in fetal kidneys on GD 20 in rats injected with three doses were lower than those in maternal kidneys, although the fetal values increased in a dose-dependent manner also. The autoradiograph of maternal kidney on GD 20 in rats injected with the dose of 640kBq/kg body weight of 63Ni for 24h showed that the radioactivity located primarily in renal cortex, partially in renal medulla and blood vessels (Fig. 7).
Fig. 7
The photograph (A) and autoradiograph (B, glass plate coated with nuclear emulsion, exposure time
=4 weeks) of a maternal kidney on GD 20 in rat injected with the dose of 640kBq/kg body weight of 63Ni for 24h. The radioactivity locates primarily in renal cortex, partially in renal medulla and blood vessel. Bar=2mm.
4. Discussion
Our data have demonstrated that the 63Ni concentrations detected in placenta increased in a gestational age-dependent manner. In addition to the gestational age influence, dose effects of 63Ni were ascertained also. These results indicate that the placental uptake and retention of nickel increase consistently with increasing gestational age and dose of nickel-exposed rats, and suggest placental permeability characteristics of nickel persist during development. Olsen and Jonsen suggested that nickel could cross the placental barriers throughout gestation after 63NiCl2 intraperitoneal injection in an autoradiographic study in mice [17]. A haemodynamic study in pregnant rats following nickel chloride administration by gavage daily from GD 7 to 14 found that nickel concentrations in fetal blood depended on the dose given to the pregnant animal [14]. The placental permeability of nickel following human placenta incubation with varying nickel concentration for 3, 6, 12 or 24h increased markedly in the concentration- and time-dependent manner [18]. The placenta was shown to have a high affinity for nickel [19], and therefore placental barrier does not protect the fetus from nickel exposure [20]. It is well known that placenta plays a key role in the nickel transfer from maternal blood to fetuses. Although the placenta is hypothesized to provide a barrier protection against nickel toxicity [21], the evidence of much more 63Ni retained in placenta at the end of gestational age than at earlier age in the present study suggests that placental uptake and retention of nickel increase consistently during pregnancy. A possible explanation for these phenomena is that an increase in nickel load initiates biosynthesis of a nickel-binding protein [22]. The elevation of placental uptake and retentions of nickel may be due to an increase of nickel-binding protein, which regulates the nickel transfer [23], [24].
63Ni was relatively abundant in the basal lamina of placenta demonstrated by autoradiograph in our studies. The basal lamina contains syncytiotrophoblast of fetal origin which invade the maternal tissues. The syncytiotrophoblast are believed to be a barrier to feto-maternal transfer of serum proteins. The occurrence of 63Ni in the basal lamina may reflect localized accumulation of a 63Ni-albumin complex, since albumin is the principal transport protein for serum 63Ni [11]. The nickel-albumin shows an initial rapid binding to human trophoblastic cells reaching a quasi-steady state after 30min [25], and the components bound to nickel of the soluble fraction of placenta were associated with unknown low molecular weight components [26]. Goyer reported the syncytiotrophoblast was the site of metallothionein synthesis, a protein that binds cadmium and may also enhance transport of the essential trace metals [27]. Nickel accumulation predominantly in the syncytiotrophoblast may depress cytochrome oxidase activity in the placenta from women living in heavily polluted region [20]. The evidence of the abundant 63Ni within the placental basal lamina suggests where the nickel-binding protein and -transport protein which regulate the uptake, retention and transfer of nickel may reside.
The highest level of 63Ni was detected in fetal membrane in the present study. The increase of concentration was significantly dependent upon doses and gestational ages. Fetal membrane consists of the yolk sac, the amniotic membrane, the chorionic sac and the allantoic vesicle. The affluent 63Ni in fetal membrane supports the view that the yolk sac accumulates high radioactivity of 63Ni and may be involved in placental transport or accumulation of metals [28], [29].
In the present study, the 63Ni concentrations in fetus reached a maximum on GD 15 and then declined on GD 20 in rats injected respectively with three doses for 24h, although 63Ni concentrations in fetus increased in a dose-dependent manner for each GD tested. A previous study reported that fetal retention of 63Ni in mice reached at maximum values on GD 16 [17]. The reduction of 63Ni concentrations in fetus during the last period of pregnancy is presumably caused by an increase of body weight [12], as the mean weight of fetus from GD 15 to 20 increased markedly (12-fold increase). It may also be caused by increased nickel excretion into amniotic fluid through kidney which is better developed and able to function with increasing nickel excretory capacity [17], [30]. Consistent with this hypothesis, we have found that 63Ni concentrations in amniotic fluid increased in relation to gestational age and peaked on GD 20. Thus, it is unlikely that a decrease in placenta transfer rate at late gestational age is responsible for the reduction in fetal nickel levels at GD 20.
The fetal autoradiograph in the present study demonstrated that radioactivity of 63Ni is deposited almost in all organs and tissues. One of the nickel-sensitive organs is the fetal cartilage even at low dose (64kBq/kg body weight). Sunderman and his colleagues have found that the highest level of radioactivity was located in fetal urinary bladder after intramuscular injection of 50μCi/kg body weight of 63Ni [11]. The result does not agree with our observation due to the higher doses used and perhaps route of administration [31] in their studies. The relatively high level of 63Ni in fetal liver and kidney found in our study may be one of the causes for fetal toxicity of nickel, which corroborates the view that the direct embryo-damaging effect of nickel crossing the placenta (direct cytotoxic effect) may be held responsible for the embryotoxicity and teratogenicity of nickel [14].
It is quite intriguing that the 63Ni concentrations detected in fetal blood after 64, 320 and 640kBq/kg body weight of 63Ni respective administration on GD 20 for 24h were 2.3-, 4.6- and 8.6-fold higher than those in maternal blood on GD 20 in rats treated with three doses. However, the 63Ni concentrations in maternal blood 24h after three doses administrations on GD 12, 15 and 20 were not significantly different. Klopov revealed that nickel concentrations in umbilical cord blood (UCD) were higher than in maternal blood in women residing in Russian arctic [32]. Higher nickel concentrations in UCD are associated with elevated alpha-fetoprotein (AFP), which presents in fetal blood during fetal development, while maternal serum AFP levels mostly remained unchanged [33]. In our other study, the 63Ni concentrations in maternal blood on GD 20 in rats injected intraperitoneally with the dose of 640kBq/kg body weight peaked at half-hour and decreased gradually within 24h. In contrast, 63Ni concentrations in fetal blood peaked at 3h after same dose injection and declined a little within 24h (unpublished data). In addition, the fetal bone marrow retaining much radioactivity of 63Ni also provides important clues regarding the sources for the high concentration of 63Ni in fetal blood. During the later period of pregnancy, the fetus could swallow much more amniotic fluid containing rich 63Ni, which can be absorbed by the intestine. The fact that nickel concentrations in fetal blood are higher than in maternal blood suggests that nickel transfer is primarily unidirectional across the placenta, i.e., nickel could cross only the feto-maternal barrier and enter fetus, but not vice versa. Apparently, our results do not support the route postulated by Mas and his colleagues: maternal blood–placenta–fetus–amniotic membranes–endometrium–maternal venous blood [21].
In conclusion, our finding that placental 63Ni concentration increases dose- and gestational age-dependently suggests that placental nickel uptake, retention and transfer are upregulated in response to increasing doses and gestational ages. The underlying mechanism is currently unknown. The fact that abundant radioactivity of 63Ni was observed within the placental basal lamina where the nickel-binding protein and -transport protein predominantly reside suggests that upregulation of these proteins may be responsible for the enhanced placental uptake, retention and transfer. Nickel-binding protein and -transport protein have been reported to regulate nickel uptake, retention and transfer [23], [24], [26]. The observation that fetal 63Ni concentrations reached a maximum on GD 15 and then declined on GD 20, suggests that at later gestational age the fetus may be able to get rid of extra nickel through kidney which is better developed. Alternatively, the placenta may somehow divert extra nickel into amniotic fluid, which is in turn taken up by fetal membrane where extraordinarily high levels of 63Ni were found. Finally, we have found that 63Ni concentrations in fetal blood on GD 20 increase in a dose-dependent manner and are higher than those in maternal blood. The lack of an equilibrium between fetal and maternal blood nickel concentrations suggests that nickel is actively transferred across the placental barrier into the fetus, but hardly from fetus to mother. Taken together, our results indicate that the placenta mostly acts as a facilitator of nickel transfer from mother to fetus, but not much as a regulator in the dose range tested in this study.
Conflict of interest statement
The authors declare that there is no conflict of interest.
Acknowledgements
This study was supported by grant J0630962 from National Natural Science Foundation of China. The authors are grateful to Dr. S. Pu (Molecular Structure and Function Program, Hospital for Sick Children, Toronto, ON, Canada) for correction of English.
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PII: S0143-4004(10)00041-X
doi:10.1016/j.placenta.2010.01.015
© 2010 Elsevier Ltd. All rights reserved.
