Effects of Lead Exposure before Pregnancy and Dietary Calcium during Pregnancy on Fetal Development and Lead Accumulation.Millions of women of child-bearing age have substantial bone lead stores due to lead exposure as children. Dietary calcium ingested in·gest tr.v. in·gest·ed, in·gest·ing, in·gests 1. To take into the body by the mouth for digestion or absorption. See Synonyms at eat. 2. simultaneously with lead exposure can reduce lead absorption and accumulation. However, the effects of dietary calcium on previously accumulated maternal lead stores and transfer to the fetus fetus, term used to describe the unborn offspring in the uterus of vertebrate animals after the embryonic stage (see embryo). In humans, the fetal stage begins seven to eight weeks after fertilization of the egg, when the embryo assumes the basic shape of the newborn have not been investigated. We studied the effects of lead exposure of female rats at an early age on fetal development during a subsequent pregnancy. We gave 5-week-old female Sprague-Dawley rats lead as the acetate in their drinking water drinking water supply of water available to animals for drinking supplied via nipples, in troughs, dams, ponds and larger natural water sources; an insufficient supply leads to dehydration; it can be the source of infection, e.g. leptospirosis, salmonellosis, or of poisoning, e.g. for 5 weeks; controls received equimolar e·qui·mo·lar adj. Chemistry Having an equal number of moles. sodium acetate Sodium acetate, (also rarely, sodium ethanoate) is the sodium salt of acetic acid. It is an inexpensive chemical produced in industrial quantities for a wide range of uses. . This was followed by a 1-month period without lead exposure before mating. We randomly assigned pregnant rats (n = 39) to diets with a deficient (0.1%) or normal (0.5%) calcium content during pregnancy. A total of 345 pups were delivered alive. Lead-exposed dams and their pups had significantly higher blood lead concentrations than controls, but the concentrations were in the range of those found in many pregnant women. Pups born to dams fed the calcium-deficient diet during pregnancy had higher blood and organ lead concentrations than pups born to dams fed the 0.5% calcium diet. Pups born to lead-exposed dams had significantly (p [is less than] 0.0001) lower mean birth weights and birth lengths than controls. There were significant inverse univariate associations between dam or pup organ lead concentrations and birth weight or length. The 0.5% calcium diet did not increase in utero in utero (in u´ter-o) [L.] within the uterus. in u·ter·o adj. In the uterus. in utero adv. growth. Stepwise regression In statistics, stepwise regression includes regression models in which the choice of predictive variables is carried out by an automatic procedure.[1][2][3] analysis demonstrated that greater litter size and female sex were significantly associated with reduced pup birth weight and length. However, lead exposure that ended well before pregnancy was significantly (p [is less than] 0.0001) associated with reduced birth weight and length, even after litter size, pup sex, and dam weight gain during pregnancy were included in the regression analysis In statistics, a mathematical method of modeling the relationships among three or more variables. It is used to predict the value of one variable given the values of the others. For example, a model might estimate sales based on age and gender. . The data demonstrate that an increase in dietary calcium during pregnancy can reduce fetal lead accumulation but cannot prevent lead-induced decreases in birth weight and length. The results provide evidence that dietary nutrients can influence the transfer of toxins to the fetus during pregnancy. If these results are applicable to women, an increase in diet calcium during pregnancy could reduce the transfer of lead from prepregnancy maternal exposures to the fetus. Key words: birth weight, calcium, fetus, lead, pregnancy. Environ Health Perspect 108:527-531 (2000). [Online 18 April 2000] http://ehpnet1.niehs.nih.gov/docs/2000/108p527-531han/abstract.html Adequate birth weight is a key marker of a successful pregnancy and has a major influence on neonatal mortality Noun 1. neonatal mortality - the death rate during the first 28 days of life neonatal mortality rate death rate, deathrate, fatality rate, mortality rate, mortality - the ratio of deaths in an area to the population of that area; expressed per 1000 per year . Both maternal nutritional factors and exposure to environmental toxicants can greatly influence fetal growth and development. However, very few studies have addressed interactions among dietary components, environmental toxicants, and fetal development. There is considerable evidence that a diet low in calcium can enhance gastrointestinal lead absorption and toxicity in humans and experimental animals (1-5). Diets that have adequate amounts of calcium will reduce lead absorption and may provide additional protection against lead toxicity by inhibiting the adverse effects of lead on calcium-mediated cellular functions (6,7). In a previous investigation (8), we demonstrated that lead exposure of rats during pregnancy can retard fetal growth and development, especially if the maternal diet during pregnancy is low in calcium. However, in humans, most lead exposure in women occurs during childhood, with relatively little additional exposure during pregnancy. Nevertheless, lead exposure as a child and at other ages before pregnancy will result in retention of considerable amounts of lead in the skeleton (5,9,10). Recent evidence demonstrates that maternal skeletal lead stores are mobilized during pregnancy and, in part, are transferred through the bloodstream to the fetus (11,12). One recent study in Mexican women demonstrated an inverse association between maternal bone lead stores and birth weight (13); in this study, maternal nutritional status nutritional status, n the assessment of the state of nourishment of a patient or subject. , assessed by calf circumference, was positively associated with birth weight. However, there was no evaluation of the maternal diet. The present study is based on the hypothesis that an adequate intake adequate intake (AI), n the consumption and absorption of sufficient food, vitamins, and essential minerals necessary to maintain health. See also dietary reference intakes; estimated average requirement; recommended dietary allowances; and upper intake of calcium during pregnancy will prevent or reduce the adverse effects of maternal lead stores on fetal development and lead accumulation in utero. Our primary objective was to determine the influence of deficient and normal calcium intakes in pregnant rats on the effects on the fetus of lead stores from previous maternal lead exposures. Major outcome variables were birth weight, birth length, and fetal blood and organ lead concentrations. A second objective was to assess relationships among the major outcome and other variables to provide insight into mechanisms by which lead and calcium can interact to influence pregnancy and fetal development. Materials and Methods Animal care and treatment. Weanling weanling /wean·ling/ (wen´ling) 1. recently weaned. 2. a recently weaned infant. weanling see weaner. female Sprague-Dawley (SD) rats (Taconic Farms, Kingston, NY; n = 76) were allowed to acclimate to the research animal facility environment for 1 week. This facility is fully accredited accredited recognition by an appropriate authority that the performance of a particular institution has satisfied a prestated set of criteria. accredited herds cattle herds which have achieved a low level of reactors to, e.g. by the Association for Assessment and Accrediting for Laboratory Animal Care. The rats were housed in individual plastic cages in a temperature- and humidity-controlled environment with light/dark cycles of 12 hr each. Beginning at 5 weeks of age, half of the rats were exposed to lead as the acetate in the drinking water (250 mg/L); controls were simultaneously given equimolar sodium acetate in the drinking water. A 5-week period of lead exposure was followed by a 4-week period without lead exposure. During these periods before mating, the rats consumed diets containing 0.5% calcium. At this time, the rats were 14 weeks of age. The female rats were then mated with 14-week-old male SD rats, with 1 male and 3 females caged together. Of the 76 female rats, 39 (51.3%) were impregnated im·preg·nate tr.v. im·preg·nat·ed, im·preg·nat·ing, im·preg·nates 1. To make pregnant; inseminate. 2. To fertilize (an ovum, for example). 3. . Lead-exposed and nonexposed pregnant rats were then randomly assigned to either normal (0.5%) or low (0.1%) calcium diets during pregnancy. Nonpregnant animals were also randomly assigned to one of the calcium diets. We used a stratified stratified /strat·i·fied/ (strat´i-fid) formed or arranged in layers. strat·i·fied adj. Arranged in the form of layers or strata. design based on the blood lead concentration at the time of random assignment. This ensured comparable initial blood lead concentrations in the two lead-exposed treatment groups that were fed either 0.1% or 0.5% calcium. During pregnancy, dam body weights were measured twice each week. In addition, blood samples (150 [micro]L) were drawn from a tail vein once each week. We allowed pregnant rats to carry their litters to term. The 39 pregnant rats delivered a total of 345 live pups; 13 pups were stillborn stillborn /still·born/ (-born) born dead. still·born adj. Dead at birth. stillborn, n an infant who is born dead. stillborn born dead. . Within 3-18 hr of birth, we weighed all pups and measured their lengths (distance from nose to origin of tail) using a micrometer micrometer (mīkrŏm`ətər, mī`krōmē'tər). 1 Instrument used for measuring extremely small distances. . We randomly chose two male and two female pups from each litter using a table of random numbers. The pups were anesthetized a·nes·the·tize also a·naes·the·tize tr.v. a·nes·the·tized, a·nes·the·tiz·ing, a·nes·the·tiz·es To induce anesthesia in. a·nes with methoxyflurane (Metafane; Pittman-Moore, Inc., Mundelin, IL) and euthanized within 18 hr of birth; blood and several organs (brain, kidney, liver) were harvested from each pup. Within 18 hr of delivery, we collected blood from the dams by cardiac puncture puncture /punc·ture/ (-cher) the act of piercing or penetrating with a pointed object or instrument; a wound so made. cisternal puncture ; after euthanizing the dams by decapitation Decapitation See also Headlessness. Antoinette, Marie (1755–1793) queen of France beheaded by revolutionists. [Fr. Hist.: NCE, 1697] Argos lulled to sleep and beheaded by Hermes. [Gk. Myth. under heavy pentobarbital pentobarbital /pen·to·bar·bi·tal/ (pen?to-bahr´bi-tal) a short- to intermediate-acting barbiturate; the sodium salt is used as a hypnotic and sedative, usually presurgery, and as an anticonvulsant. anesthesia, we harvested the following tissues: kidney, liver, brain, femur femur (fē`mər): see leg. , and spinal column spinal column, bony column forming the main structural support of the skeleton of humans and other vertebrates, also known as the vertebral column or backbone. It consists of segments known as vertebrae linked by intervertebral disks and held together by ligaments. bone. The modified calcium diets used were prepared by Research Diets Inc. (New Brunswick New Brunswick, province, Canada New Brunswick, province (2001 pop. 729,498), 28,345 sq mi (73,433 sq km), including 519 sq mi (1,345 sq km) of water surface, E Canada. , NJ) and have been previously described (1,8). The above procedures were approved by the Institutional Animal Care and Use Committee Institutional Animal Care and Use Committees are of central importance to the application of laws to animal research in the United States. Most research involving laboratory animals is funded by the United States National Institutes of Health or other federal agencies. of the New Jersey Medical School. Laboratory analyses. We used electrothermal e·lec·tro·ther·mal adj. 1. Of, relating to, or involving both electricity and heat. 2. Of or relating to the production of heat by electricity. atomic absorption 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. to determine whole blood lead concentrations (14). We used a quality control sample (Bio-Rad whole blood control level 3; Bio-Rad, Anaheim, CA) to monitor the accuracy of these analyses. Concentrations determined for this sample were within 8% of the certified value. We ashed the organs with a 3:1 mixture of double-distilled nitric nitric /ni·tric/ (ni´trik) pertaining to or containing nitrogen in one of its higher valences. nitric oxide and perchloric acids perchloric acid /per·chlor·ic ac·id/ (per-klor´ik) a colorless volatile liquid, HClO4, which can cause powerful explosions in the presence of organic matter or anything reducible. per·chlo·ric acid n. (GFS See Google File System. GFS - Grandfather, Father, Son Chemicals, Columbus, OH); the residue was quantitatively transferred to a 10- or 25-mL volumetric flask A volumetric flask (vol flask for short) is a type of laboratory flask (piece of laboratory glassware) used to contain or measure a very precise and accurate amount of a liquid. It is shaped like a Florence flask with a flatter bottom so as to not tip over. and diluted with distilled, deionized water Deionized water (DI water or de-ionized water; also spelled deionised water, see spelling differences) is water that lacks ions, such as cations from sodium, calcium, iron, copper and anions such as chloride and bromide. . Further dilutions were necessary for some organs. We determined lead concentrations of the ashed samples by electrothermal atomic absorption spectrophotometry. Calculations of concentrations were based on wet tissue weight. We used National Institute of Standards and Technology National Institute of Standards and Technology, governmental agency within the U.S. Dept. of Commerce with the mission of "working with industry to develop and apply technology, measurements, and standards" in the national interest. bovine liver (NIST (National Institute of Standards & Technology, Washington, DC, www.nist.gov) The standards-defining agency of the U.S. government, formerly the National Bureau of Standards. It is one of three agencies that fall under the Technology Administration (www.technology. 1577b; Gaithersburg, MD) as a quality control sample. Assays of this sample in our laboratory gave results within 5% of certified values. Statistics. We performed data reduction and analysis using dBASE III+ (Ashton-Tate, Torrance, CA) and the Statistical Analysis System (SAS Institute SAS Institute Inc., headquartered in Cary, North Carolina, USA, has been a major producer of software since it was founded in 1976 by Anthony Barr, James Goodnight, John Sall and Jane Helwig. , Cary, NC). We used analysis of variance (ANOVA anova see analysis of variance. ANOVA Analysis of variance, see there ; SAS (1) (SAS Institute Inc., Cary, NC, www.sas.com) A software company that specializes in data warehousing and decision support software based on the SAS System. Founded in 1976, SAS is one of the world's largest privately held software companies. See SAS System. General Linear Models, SAS Institute) to evaluate the effects of treatment on blood and organ lead concentrations, birth weights, birth lengths, and other variables. If ANOVA indicated statistically significant (p [is less than] 0.05) differences among groups for a specific variable, we then made pair-wise comparisons using Duncan's multiple range test at [Alpha] = 0.05. Kidney lead concentrations are known to vary considerably among individual animals, even for rats in the same treatment group (1,8,14). Therefore, kidney lead concentrations were log transformed before evaluation by ANOVA. We assessed univariate associations between variables by calculating Pearson correlation coefficients Correlation Coefficient A measure that determines the degree to which two variable's movements are associated. The correlation coefficient is calculated as: . In addition, we performed stepwise stepwise incremental; additional information is added at each step. stepwise multiple regression used when a large number of possible explanatory variables are available and there is difficulty interpreting the partial regression multiple regression Multiple regression The estimated relationship between a dependent variable and more than one explanatory variable. analyses to assess the possibility that other factors besides lead exposure or dietary calcium might influence the effect of these variables on birth weight or birth length. In these analyses, birth weight or birth length was the dependent variable, and the independent variables were lead exposure status, dietary calcium intake during pregnancy, litter size, pup sex, dam weight gain during pregnancy, and dam body weight before pregnancy and after delivery. Results Lead dosing and dam growth. The mean ([+ or -] SE) daily intakes of drinking water during the 5-week period of lead exposure were 22.4 [+ or -] 0.9 mL/day for control rats and 20.9 [+ or -] 0.6 mL/day for rats given lead in the drinking water. These values do not differ significantly (t-test, p [is greater than] 0.05). Figure 1 shows growth curves for rats before mating and after random assignment to 0.1% or 0.5% calcium diets during pregnancy. Mated females that did not become pregnant are also included in Figure 1. Growth of lead-exposed and nonexposed rats was comparable before and after mating, and was not influenced by the dietary calcium content subsequent to mating. Pregnant rats developed substantially higher body weights than the nonpregnant rats (~ 100 g greater), but their body weights did not differ significantly among the four treatment groups (ANOVA, p [is greater than] 0.05). [Figure 1 ILLUSTRATION OMITTED] Fetal development. Figures 2 and 3 show birth weights and lengths of the 345 pups (163 males and 182 females) that were delivered alive by the 39 pregnant dams. Female pups had lower body weights and lengths than male pups; therefore, males and females in the various treatment groups are compared separately. Lead exposure reduced birth weight and length for both the males and the females. The dietary calcium intake of the dams during pregnancy generally did not influence fetal growth. However, the higher diet calcium intake increased birth weight for the male pups not exposed to lead. In addition, we observed reduced birth length in the male and female pups whose lead-exposed mothers were fed the 0.5% calcium diet. [Figures 2-3 ILLUSTRATION OMITTED] Blood and organ lead concentrations. Figure 4 shows blood lead concentrations of the dams before pregnancy and for days 9, 16, and 21 of gestation GESTATION, med. jur. The time during which a female, who has conceived, carries the embryo or foetus in her uterus. By the common consent of mankind, the term of gestation is considered to be ten lunar months, or forty weeks, equal to nine calendar months and a week. . Blood lead concentrations were much higher in dams previously exposed to lead than in those not given lead in the drinking water. Blood lead concentrations of the lead-exposed dams declined during pregnancy, as expected, because lead exposure was terminated 1 month before pregnancy. For both the lead-exposed and unexposed dams, blood lead concentrations on days 9, 16, and 21 of gestation were lower in rats fed the 0.5% calcium diet during pregnancy than in those receiving the 0.1% calcium diet. However, the differences were only significant for day 21 of gestation for the lead-exposed rats. [Figure 4 ILLUSTRATION OMITTED] Organ lead concentrations of the dams are shown in Table 1; lead-exposed dams had significantly higher lead concentrations than unexposed dams in each of the five organs assessed. Lead-exposed dams fed the normal calcium diet during pregnancy had lower lead concentrations in brain, femur, kidney, liver, and spinal column bone than those fed the low calcium diet. Of these, the brain and kidney lead concentrations were significantly lower (p [is less than] 0.05).
Table 1. Organ lead concentrations of dams.
Not lead-exposed
Low calcium Normal calcium
diet diet
Brain 0.22 [+ or -] 0.10 C 0.16 [+ or -] 0.06 C
Femur 6.98 [+ or -] 1.86 B 3.93 [+ or -] 1.29 B
Kidney 2.74 [+ or -] 0.59 C 1.34 [+ or -] 0.40 D
Liver 0.14 [+ or -] 0.05 B 0.48 [+ or -] 0.33 B
Spinal column bone 6.59 [+ or -] 1.63 B 3.15 [+ or -] 0.94 B
Lead-exposed
Low calcium Normal calcium
diet diet
Brain 2.37 [+ or -] 0.25 A 1.70 [+ or -] 0.14 B
Femur 884 [+ or -] 104 A 757 [+ or -] 62 A
Kidney 138 [+ or -] 37 A 58 [+ or -] 12 B
Liver 4.00 [+ or -] 0.74 A 2.94 [+ or -] 0.41 A
Spinal column bone 763 [+ or -] 95 A 696 [+ or -] 70 A
Data shown are mean [+ or -] SE (nmol/g); n = 8-12. Kidney concentrations were log transformed before ANOVA analysis. Values in the same row that are not marked with the same letter are significantly different (p < 0.05; ANOVA with Duncan's test). The blood and organ lead concentrations for the rat pups are shown in Table 2. Pups born to lead-exposed dams had significantly higher lead concentrations than pups born to unexposed dams for blood, kidney, liver, and carcass carcass, carcase 1. the body of an animal killed for meat. The head, the legs below the knees and hocks, the tail, the skin and most of the viscera are removed. The kidneys are left in and in most instances the body is split down the middle through the sternum and the vertebral , but not for brain. Pups delivered by dams fed the normal calcium diet had lower lead concentrations than those delivered by dams fed the low calcium diet. Of these, the blood, liver, and carcass concentrations were significantly lower.
Table 2. Blood and organ lead concentrations of pups.
Not lead-exposed
Low calcium Normal calcium
diet diet
Blood 0.137 [+ or -] 0.030 C 0.032 [+ or -] 0.003 C
Brain 0.05 [+ or -] 0.02 A 0.05 [+ or -] 0.02 A
Kidney 0.77 [+ or -] 0.52 B 0.21 [+ or -] 0.09 B
Liver 0.40 [+ or -] 0.15 C 0.38 [+ or -] 0.07 C
Carcass 0.14 [+ or -] 0.07 C 0.05 [+ or -] 0.03 C
Lead-exposed
Low calcium Normal calcium
diet diet
Blood 1.160 [+ or -] 0.053 A 0.771 [+ or -] 0.056 B
Brain 0.11 [+ or -] 0.02 A 0.07 [+ or -] 0.03 A
Kidney 1.93 [+ or -] 0.39 A 1.16 [+ or -] 0.25 A
Liver 2.16 [+ or -] 0.19 A 1.27 [+ or -] 0.12 B
Carcass 1.39 [+ or -] 0.31 A 0.53 [+ or -] 0.08 B
Data shown are mean [+ or -] SE; n = 6-13. Units are [micro]mol/L for blood and nmol/g for organs and carcass. Kidney concentrations were log transformed before ANOVA analysis. To convert blood lead concentrations to [micro]g/dL, multiply [micro]mol/L by 20.7. Values in the same row that are not marked by the same letter are significantly different (p < 0.05; ANOVA with Duncan's test). Relationships between birth weights, birth lengths, and other variables. Univariate associations between birth weight, birth length, and other measured variables are presented in Table 3. Birth weight and length were significantly and negatively associated with litter size, dam brain lead, dam kidney lead, dam femur lead, and dam spinal column lead. Birth weight was also significantly associated with pup kidney lead. There was also a significant positive association between birth weight and birth length. Birth length but not weight was significantly associated with weight gain during pregnancy and prepregnancy dam weight. Table 3. Univariate associations between birth weight, or birth length, and other variables.
Birth weight Birth length
r(a) p r(a) p
Pup birth length 0.73 0.0001 -- --
Litter size -0.43 0.0001 -0.43 0.0001
Lead exposure -0.31 0.0001 -0.24 0.0001
Dietary calcium -0.01 NS -0.08 NS
Pup sex(b) 0.28 0.0001 0.35 0.0001
Pregnancy weight -0.02 NS -0.11 0.049
gain
Dam weight -0.02 NS 0.11 0.040
before pregnancy
Dam brain lead -0.26 0.0001 -0.23 0.0001
Dam liver lead 0.01 NS -0.01 NS
Dam kidney lead -0.26 0.0001 -0.17 0.0015
Dam femur lead -0.24 0.0001 -0.21 0.0001
Dam spinal column -0.20 0.0002 -0.21 0.0001
bone lead
Pup kidney lead(c) -0.40 0.0001 -0.18 NS
NS, not significant (p > 0.05). (a) Pearson correlation coefficient. (b) Female = 0 and male = 1. (c) n = 89; for all other variables, n = 335-345. Table 4 presents regression models of birth weight and length on other measured variables. In these models, birth weight or length is the dependent variable, and litter size, pup sex, pregnancy weight gain, dam weight before pregnancy and after delivery, lead exposure status, and dietary calcium status during pregnancy are the independent variables. Lead exposure remained a significant (p = 0.0001) predictor of birth weight and length even after inclusion of the other variables in the model. Together, litter size, lead exposure, pup sex, and dam weight gain during pregnancy explained 32.5% of the variability in birth weight and 33.5% of the variability in birth length. Table 4. Multiple regression models of birth weight and birth length on other measured variables.
Birth weight
Partial Parameter
[R.sup.2] estimate p
Intercept 7.284
Litter size 0.185 -0.126 0.0001
Lead exposure 0.074 -0.002 0.0001
Pup sex 0.056 0.355 0.0001
Darn weight gain 0.010 0.006 0.03
during pregnancy
Dietary calcium -- -- NS
Dam weight
before delivery -- -- NS
Dam weight
after delivery -- -- NS
Birth length
Partial Parameter
[R.sup.2] estimate p
Intercept 53.771
Litter size 0.178 -0.535 0.0001
Lead exposure 0.037 -1.151 0.0001
Pup sex 0.099 1.344 0.0001
Darn weight gain 0.021 -0.032 0.001
during pregnancy
Dietary calcium -- -- NS
Dam weight
before delivery 0.012 0.072 0.016
Dam weight
after delivery 0.024 -0.059 0.0004
NS, not significant. [R.sup.2] = 0.325 for the birth weight model, and [R.sup.2] = 0.371 for the birth length model. Data are from stepwise multiple regression analyses with entry and exclusion criteria exclusion criteria AIDS Donor exclusion criteria, see there of [Alpha] = 0.05. n = 344. Dam and pup weights were measured in grams and pup length was measured in millimeters. For birth length, [R.sup.2] = 0.335 if dam weights before and after delivery are not included in the model. Discussion The present study demonstrates that lead exposure which ends well before pregnancy can nevertheless cause decreases in birth weight and length in the rat. This observation is relevant to human pregnancy because most women are likely to have limited exposure to lead during pregnancy, but may have considerable body lead burdens from a history of lead exposure, including exposure during childhood. This may be especially true for older women and those who are nulliparous, factors that are associated with greater bone lead stores (15). Bone lead is considered the dominant source of blood lead if environmental exposures are low, especially during pregnancy and lactation lactation Production of milk by female mammals after giving birth. The milk is discharged by the mammary glands in the breasts. Hormones triggered by delivery of the placenta and by nursing stimulate milk production. , conditions that tend to mobilize skeletal lead stores (12). In the present study, an increase in dietary calcium during pregnancy reduced fetal lead accumulation, but did not prevent the adverse effects of lead on birth weight and length. Paradoxically, the diet with higher calcium reduced birth length (but not birth weight) in male pups with in utero lead exposure. This effect is likely due to effects on birth length of other variables (litter size, pup sex, pregnancy weight gain, and organ lead concentrations) because the impact of diet calcium does not remain after consideration of these variables (Tables 3 and 4). The decrease in blood lead concentrations during pregnancy is probably due to the gradual increase in time since the end of lead exposure, despite the expected mobilization of skeletal lead during pregnancy. Dams fed the low-calcium diet had higher blood lead concentrations at the end of the third trimester Noun 1. third trimester - time period extending from the 28th week of gestation until delivery trimester - a period of three months; especially one of the three three-month periods into which human pregnancy is divided than dams fed the normal calcium diet; this suggests suppression of bone lead mobilization by the normal calcium diet. Studies in humans have not consistently demonstrated an inverse relationship A inverse or negative relationship is a mathematical relationship in which one variable decreases as another increases. For example, there is an inverse relationship between education and unemployment — that is, as education increases, the rate of unemployment between lead exposure and birth weight (16-21). This may in part be related to the numerous factors that can influence birth weight and to a limited ability to accurately assess maternal lead exposure and other relevant factors. An advantage of studying the effects of lead and dietary calcium on fetal development in experimental animals is the ability to regulate lead exposure and dietary calcium intake; this permits a more precise assessment of effects on other variables. The present study demonstrates that the lead exposure before pregnancy was a significant predictor of reduced birth weight and length, even after adjustment for other factors such as pup sex, litter size, and maternal weight gain during pregnancy. The blood lead concentrations of the dams in the present study are higher than those currently found in most pregnant women in the United States United States, officially United States of America, republic (2005 est. pop. 295,734,000), 3,539,227 sq mi (9,166,598 sq km), North America. The United States is the world's third largest country in population and the fourth largest country in area. , but they are in the same range (10-70 [micro]g/dL) as concentrations that may be found in women from more heavily polluted pol·lute tr.v. pol·lut·ed, pol·lut·ing, pol·lutes 1. To make unfit for or harmful to living things, especially by the addition of waste matter. See Synonyms at contaminate. 2. regions of the world (17,19,20). In contrast to the present study, other studies in experimental animals used maternal lead exposure during pregnancy instead of exposure only before pregnancy. These studies typically found reduced birth weights as a result of lead exposure during pregnancy (8,22,23). The present study extends these findings to lead exposure that occurs well before pregnancy. In 1994, Andrew et al. (17) reviewed studies on the relationships between prenatal prenatal /pre·na·tal/ (-na´tal) preceding birth. pre·na·tal adj. Preceding birth. Also called antenatal. prenatal preceding birth. lead exposure, gestational age ges·ta·tion·al age n. See estimated gestational age. Gestational age The estimated age of a fetus expressed in weeks, calculated from the first day of the last normal menstrual period. , and birth weight. They concluded that lead exposure appears to increase the risk of preterm preterm /pre·term/ (-term´) before completion of the full term; said of pregnancy or of an infant. pre·term adj. delivery and reduce birth weight, but the results of individual studies were quite disparate. Some of the variability in results of the studies reviewed appeared to be due to differences in study design or control for confounders. More recent human studies also had mixed results. West et al. (18) found an inverse relationship between gestational age and maternal blood lead concentrations, but the latter did not differ significantly for birth weights [is greater than] 2,500 g versus [is less than] 2,500 g. Studies in Kosovo (19,20) did not find associations between blood lead concentrations and birth weight or gestational age, despite relatively high maternal blood lead concentrations attributible to environmental exposure from a lead smelter. In a Canadian study of over 9,000 women living in either a smelter community or a control community (21), fetal development was not influenced by lead exposure. The variability of results from previous studies on the relationships between maternal blood lead concentrations and human fetal development may be due in part to the inadequacy of blood lead concentrations as a marker for lead toxicity. Gonzalez-Cossio et al. (13) used [sup.109]Cd X-ray fluorescence X-ray fluorescence (XRF) is the emission of characteristic "secondary" (or fluorescent) X-rays from a material that has been excited by bombarding with high-energy X-rays or gamma rays. to measure blood lead concentrations at delivery and at 1 month postpartum postpartum /post·par·tum/ (post-pahr´tum) occurring after childbirth, with reference to the mother. post·par·tum adj. Of or occurring in the period shortly after childbirth. , as well as tibia tibia: see leg. and patella patella (pətĕl`ə): see kneecap. lead concentrations at 2 months postpartum. Anthropometric an·thro·pom·e·try n. The study of human body measurement for use in anthropological classification and comparison. an and sociodemographic data known to influence birth weight were also collected. After adjustment for other determinants of birth weight, Gonzalez-Cossio et al. (13) found that tibia lead was the only lead biomarker biomarker /bio·mark·er/ (bi´o-mahr?ker) 1. a biological molecule used as a marker for a substance or process of interest. 2. tumor marker. bi·o·mark·er n. 1. associated with birth weight. Other significant predictors of birth weight included maternal nutritional status, gestational age, and cigarette smoking during pregnancy, factors that have been consistently associated with birth weight. The observation in the present study of an association between birth weight and length and dam organ (but not blood) lead concentrations, including dam femur lead, suggests that concentrations of lead in organs other than blood may be better biomarkers of lead toxicity to the fetus, and is thus consistent with the study of Gonzalez-Cossio et al. (13). The diet calcium concentrations used in the present study are considered moderately deficient (0.1% Ca) or adequate (0.5%) for the rat. Despite the 5-fold higher concentration in the calcium-adequate diet, there was no effect of dietary calcium on fetal birth weight. There is evidence that a wide range of dietary calcium intakes can support normal fetal growth and development during pregnancy in experimental animals or in humans because the maternal skeleton can serve as a source of this key nutrient (23-26). Because the skeleton is also the major repository for lead, mobilization of skeletal lead and calcium occurs simultaneously when dietary calcium intake during pregnancy is inadequate. This is probably the reason for the higher fetal blood, organ, and carcass lead concentrations in pups born to dams fed the low calcium diet. A recent study (16) used high-precision measurements of lead isotopes in maternal blood and urine and in environmental samples to confirm the increases in lead mobilization from the maternal skeleton that occur during human pregnancy. Because skeletal mobilization of calcium and lead occurs primarily in the third trimester, the ability of increased diet calcium to alter fetal lead accumulation but not fetal growth suggests that the adverse effects of lead on fetal growth may occur primarily in the first and/or second trimesters Noun 1. second trimester - time period extending from the 13th to the 27th week of gestation trimester - a period of three months; especially one of the three three-month periods into which human pregnancy is divided . In the United States, African-American women have a greater risk of delivering low birth weight neonates than white women (27,28). Although there are likely numerous variables that may contribute to this higher risk, a largely unexplored factor could be the higher skeletal lead stores of some African-American women due to childhood lead exposures while living in inner cities. In a recent study, Ballew et al. (29) evaluated relationships between blood lead concentrations and anthropometric measurements anthropometric measurements (anˈ·thrō·p in over 4,000 children 1-7 years of age. Significant negative associations between blood lead concentrations and height or head circumference were found. Their regression models predicted a reduction in height of 1.57 cm for each 10 [micro]g/dL (0.48 [micro]mol/L) increase in the blood lead concentration. In this study (29), calcium intake from supplements was a significant predictor of increased height and head circumference. In contrast, we found in the present study that increased maternal diet calcium did not increase birth weight and length. The mechanisms by which calcium-lead interactions influence growth in utero may differ from those that are operative after birth. Events in utero can influence health for many years after birth; the term "fetal programming" has been used to describe this process. For example, several studies found associations between low birth weight and the development of hypertension as an adult (30-32). Other studies found associations between hypertension and bone or blood lead concentrations in adults (33-35). Skeletal lead, whether accumulated in utero or after birth, is in equilibrium with blood lead. It is possible that in utero lead exposure could cause both reduced birth weight, as suggested by the present study, and hypertension many years later. If this possibility is supported by additional studies, then the association between low birth weight and hypertension as an adult could be due in part to in utero lead exposure. In summary, the results of this study demonstrate that lead exposure which ends well before pregnancy can reduce birth weight and birth length and that an increase in dietary calcium intake during pregnancy can reduce fetal lead accumulation in pregnant rats with a history of previous lead exposure. The results provide evidence that the composition of the diet can influence the transfer of an environmental toxicant toxicant /tox·i·cant/ (tok´si-kant) 1. poisonous. 2. poison. tox·i·cant n. 1. A poison or poisonous agent. 2. An intoxicant. adj. to the fetus during pregnancy. REFERENCES AND NOTES (1.) Bogden JD, Gertner SB, Christakos S, Kemp FW, Yang Z, Katz SR, Chu C. Dietary calcium modifies concentrations of lead and other metals and renal calbindin in rats. J Nutr 122:1351-1360 (1992). (2.) Mahaffey KR, Gartside PS, Glueck CJ. Blood lead levels and dietary calcium intake in 1-11 year old children: the Second National Health and Nutrition Examination Survey, 1976-1980. Pediatrics 78:257-262 (1986). (3.) Ziegler EE, Edwards BB, Jensen RL, Mahaffey KR, Fomon SJ. Absorption and retention of lead by infants. Pediatr Res 12:29-34 (1978). (4.) Mahaffey KR, Goyer R, Haseman JK. Dose response to lead ingestion ingestion /in·ges·tion/ (-chun) the taking of food, drugs, etc., into the body by mouth. in·ges·tion n. 1. The act of taking food and drink into the body by the mouth. 2. in rats fed low dietary calcium. J Lab Clin Med 82:92-100 (1973). (5.) Bogden JD, Oleske JM, Louria DB. Lead poisoning--one approach to a problem that won't go away. Environ Health Perspect 105:1284-1287 (1997). (6.) Miller GD, Massaro TF, Massaro EJ. Interactions between lead and essential elements: a review. Neurotoxicology 11:99-120(1990). (7.) Kerper LE, Hinkle PM. Cellular uptake of lead is activated by depletion of intracellular calcium stores. J Biol Chem 272:8346-8352 (1997). (8.) Bogden JD, Kemp FW, Han S, Murphy M, Fraiman M, Czerniach D, Flynn CJ, Banua M, Scimone A, Castrovilly L. Dietary calcium and lead interact to modify maternal blood pressure, erythropoiesis erythropoiesis /eryth·ro·poi·e·sis/ (-poi-e´sis) the formation of erythrocytes.erythropoiet´ic e·ryth·ro·poi·e·sis n. The formation or production of red blood cells. , and fetal and neonatal growth in rats during pregnancy and lactation. J Nutr 125:990-1002 (1995). (9.) Kosnett MJ, Becker CE, Osterloh JD, Kelly TJ, Pasta DJ. Factors influencing bone lead concentration in a suburban community assessed by noninvasive K X-ray fluorescence. JAMA JAMA abbr. Journal of the American Medical Association 271:197-203 (1994). (10.) O'Flaherty EJ. Physiologically based models of bone-seeking elements. V. Lead absorption and disposition in childhood. Toxicol Appl Pharmacol 131:297-308 (1995). (11.) Gulson BL, Jameson CW, Mahaffey KR, Mizoh KJ, Korsch MJ, Vimani G. Pregnancy increases mobilization of lead from the maternal skeleton. J Lab Clin Med 130:51-62 (1997). (12.) Gulson BL, Mahaffey KR, Jameson CW, Patison N, Law AJ, Mizon KJ, Korsch MJ, Pederson D. Impact of diet on lead in blood and urine in female adults and relevance of mobilization of lead from bone stores. Environ Health Perspect 107:257-263 (1999). (13.) Gonzalez-Cossio T, Peterson KE, Sanin LH, Fishbein E, Palazuelos E, Aro A, Hernandez-Avila M, Hu H. Decrease in birth weight in relation to maternal bone-lead burden. Pediatrics 100:856-862 (1997). (14.) Han S, Qiao X, Kemp FW, Bogden JD. Lead exposure at an early age substantially increases lead retention in the rat. Environ Health Perspect 105:412-417 (1997). (15.) Silbergeld EK, Schwartz J, Mahaffey K. Lead and osteoporosis: mobilization of lead from bone in postmenopausal post·men·o·paus·al adj. Of or occurring in the time following menopause. postmenopausal Change of life Gynecology adjective Referring to the time in ♀ when menstrual periods stop for ≥ 1 yr women. Environ Res 47:79-94 (1988). (16.) 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Int J Epidemiol 20:722-728 (1991). (20.) Factor-Litvak P, Wasserman G, Kline JK, Graziano J. The Yugoslavia prospective study of environmental lead exposure. Environ Health Perspect 107:9-15 (1999). (21.) Phillon JJ, Schmitt N, Rauve J, Gelpke M. Effect of lead on fetal growth in a Canadian smelter city. Arch Environ Health 52:472-475 (1997). (22.) Ronis MJ, Badger TM, Shema SJ, Roberson PK, Templer L, Ringer D, Thomas PE. Endocrine endocrine /en·do·crine/ (en´do-krin, en´do-krin) 1. secreting internally. 2. pertaining to internal secretions; hormonal. See also under system. en·do·crine adj. mechanisms underlying the growth effects of developmental lead exposure in the rat. J Toxicol Environ Health 54:101-120 (1998). (23.) Pitkin PM. Calcium metabolism calcium metabolism The constellation of ionic checks & balances that maintain Ca2+ homeostasis in the blood and tissues. See Calcium. in the pregnant and lactating lac·tate 1 intr.v. lac·tat·ed, lac·tat·ing, lac·tates To secrete or produce milk. [Latin lact female. In: Calcium Nutriture for Mothers and Children (Tsang RC, Mimouni F, eds). New York New York, state, United States New York, Middle Atlantic state of the United States. It is bordered by Vermont, Massachusetts, Connecticut, and the Atlantic Ocean (E), New Jersey and Pennsylvania (S), Lakes Erie and Ontario and the Canadian province of :Raven Press, 1992;27-37. (24.) Lai AC, Kiyomi-Ito M, Komatsuk, Niiyama Y. Effects of various levels of dietary calcium during pregnancy on maternal calcium utilization and fetal growth in rats. J Nutr Sci Vitaminol 30:285-295 (1984). (25.) Prentice A. Calcium needs and bone metabolism It is a common misconception that bones are static in nature and hardly change once an individual becomes an adult. On the contrary, bones are continuously undergoing a dynamic process of resorption and deposition known as bone metabolism. in pregnancy and lactation. In: Proceedings of the 16th International Congress of Nutrition (Fitzpatrick DW, Anderson JE, L'Abbe ML, eds). Ottawa, Canada:Canadian Federation of Biological Societies, 1998;216-218. (26.) Ramakrishnan U, Mahjrekar R, Rivera J, Gonzales-Cossio T, Martorell R. Micronutrients This is a list of micronutrients. Vitamins
(27.) Zambrana RE, Donkel-Schetter C, Collins NL, Scrimshaw scrimshaw Decoration of bone or ivory objects, such as whale's teeth and walrus tusks, with fanciful designs, traditionally carved by Anglo-American and Native American whale fishermen with a jackknife or sail needle and emphasized with black pigments (e.g., lampblack). SC. Mediators of ethnic-associated differences in infant birth weight. J Urban Health 70:102-116 (1999). (28.) Hessol WA, Fuentes-Afflick E, Bacchetti P. Risk of low birth weight infants among black and white parents. Obstet Gynecol 92:814-822 (1998). (29.) Ballew C, Khan LK, Kaufmann R, Makdad A, Miller DT, Gunter EW. Blood lead concentration and children's anthropometric dimensions in the Third National Health and Nutrition Examination Survey (NHANES III NHANES III Third National Health & Nutrition Examination Survey Public health A population-based survey conducted by the National Center for Health Statistics, designed to assess the health and nutritional status of the noninstitutionalized Americans ), 1988-1994. J Pediatr 134:623-630 (1999). (30.) Barker DJP DJP DJ Premier DJP Department of Justice and Police DJP D'Jungle People Sdn Bhd DJP Doctor of Jurisprudence DJP Desk Jet Printer DJP Digital Jet Printer , Bull AR, Osmond C, Simmonds SJ. Fetal and placental placental pertaining to or emanating from placenta. placental barrier the placental separation of maternal and fetal blood which varies in its structure and permeability between the species. size and risk of hypertension in adult life. Br Med J 301:259-262 (1990). (31.) Law CM, de Sweet M, Osmond C, Fayers PM, Barker DJP, Cruddos AM, Fall CHD CHD coronary heart disease. ChD abbr. Latin Chirurgiae Doctor (Doctor of Surgery) CHD, n.pr See disease, coronary heart. CHD canine hip dysplasia. . Initiation of hypertension in utero and its amplification throughout life. Br Med J 306:24-27 (1993). (32.) Langley-Evans S, Jackson A. Intrauterine intrauterine /in·tra·uter·ine/ (-u´ter-in) within the uterus. in·tra·u·ter·ine adj. Within the uterus. Intrauterine Situated or occuring in the uterus. programming of hypertension: nutrient-hormone interactions. Nutr Rev 54:163-169 (1996). (33.) Hertz-Picciotto I, Craft J. Review of the relation between blood lead and blood pressure. Epidemiol Rev 15:352-373 (1993). (34.) Harlan WR, Landis JR, Schmader RL, Goldstein NG, Harlan LC. Blood lead and blood pressure. Relationship in the adolescent and adult US population. JAMA 253:530-534 (1985). (35.) Hu H, Aro A, Payton M, Korrick S, Sparrow D, Weiss ST, Rufnitzky A. The relationship of bone and blood lead to hypertension. JAMA 275:1171-1176 (1996). Shenggao Han, David H. Pfizenmaier, Enid Garcia, Maria L. Eguez, Matthew Ling, Francis W. Kemp, and John D. Bogden Department of Preventive Medicine preventive medicine, branch of medicine dealing with the prevention of disease and the maintenance of good health practices. Until recently preventive medicine was largely the domain of the U.S. and Community Health, UMDNJ-New Jersey Medical School, Newark, New Jersey, USA Address correspondence to J.D. Bogden, Department of Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School, 185 South Orange Avenue, Newark, NJ USA 07103-2714. Telephone: (973) 972-5432. Fax: (973) 972-7625. E-mail: bogden@umdnj.edu Supported in part by grant HL56581 from the National Institutes of Health. Received 7 September 1999; accepted 14 December 1999. |
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