iron and manganese uptake by offspring of lactating mice fed a high aluminum diet

ELSEVIER Toxicology 109 (1996) I I I - 118

Iron and manganese uptake by offspring of lactating mice fed a high aluminum diet

Mari S. Golub*, Bin Han, Carl L. Keen

Depurtment of Internul Medicine, University of Californiu Duvis, Davis, CA 95616. USA

Received 14 November 1995; accepted 3 January 1996

Abstract

High dietary Al can result in lowered tissue Mn and Fe concentrations in weanling mice. Possible mechanisms underlying this effect of Al (altered milk Fe and Mn content, altered absorption or retention of Fe and Mn) were investigated in this experiment. To determine if milk composition was changed, milk was analyzed for Fe and Mn at 0, 3, 7, and 12 days postnatal. To determine if Al influenced absorption and/or retention of Fe and Mn, a single milk meal containing 54Mn and 59Fe was administered by gavage to I2 day old pups and tissues were obtained 6 and 24 h later. Pup body and tissue weights were not affected by the high Al diet. Milk from dams fed high Al diets (1000 pg Al/g, n = 11, AllOOO) had similar Fe and Mn concentrations as milk from dams fed a control diet (7 fig Al/g, n = I I), although Al concentrations were higher. Absorption and tissue distribution of “Mn and 5yFe, as determined at the 6 h timepoint, were unaffected by maternal diet group (control n = 16, AL1000 n = 10). However, total retention of both 54Mn and 59Fe was 8-10% lower in the AL1000 pups 24 h after gavage (P = 0.030 for Mn and 0.017 for Fe). These data suggest that high dietary Al during development alters the ability of nursing mouse pups to retain absorbed Fe and Mn.

Keywords: Milk; Lactation; Mice; Aluminum; Iron; Manganese

1. Introduction

Earlier studies showed that neurobehavioral

tests (grip strength, temperature sensitivity and negative geotaxis) were altered in mouse wean-

lings who had suckled dams fed a high aluminum

diet (1000 pg Al/g) (Golub et al., 1992b). Wean- lings had similar brain and liver Al concentra-

tions as controls, but had lower brain and liver Mn concentrations, and lower liver Fe concentrations, than controls. This suggested that Fe

*Corresponding author, Tel.: + 1(916)752-5119; Fax: + 1(916)752-2880; email [email protected].

and Mn uptake during lactation could be influenced by the Al content of the dam’s diet.

Given the diverse and important roles that Fe and Mn play in CNS development, Al effects on these essential trace minerals might be involved

in the neurobehavioral effects. Two related Fe-binding proteins, transferrin

and lactoferrin, are involved in the transfer of Fe

from blood to milk (Moutafchiev and Sirakov,

1990) and with the intestinal absorption as well as the cellular uptake of Fe by various tissues (Conrad et al., 1994). In mice, fransferrin is the major iron-binding milk protein (Lee et al.. 1987), while lactoferrin, a related protein, is more

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112 M.S. Gduh er d. ITo.vicolog~ 109 (1996) III-118

important in other species including humans. Transferrin and lactoferrin also bind Mn, although mechanisms of excretion into milk and the absorption of protein bound Mn from milk have not been as thoroughly studied. AI also has a high affinity for transferrin (over 80% of Al in serum is bound to transferrin), and presumably also for lactoferrin. These relationships suggest that Al could interfere with transferrin/lactoferrin-mediated Fe and Mn uptake during lactation. While many minerals (Ca, Mg, Zn) are primarily accrued during intrauterine life in rodents (Romeu et al., 1986), Fe and Mn tissue levels increase rapidly during mid to late lactation, indicating that milk can be an important source of these elements. Interference with tissue accu- mulation could affect the ontogeny of Fe- and Mn-dependent processes during this time period.

The present experiments were designed to determine whether reduced weanling tissue Fe and Mn concentrations in Al exposed mice could be attributed to, (1) lower milk Fe and Mn concentrations, (2) reduced Fe and Mn absorption, and/or (3) reduced Fe and Mn retention. Al, Fe and Mn in milk and pup tissues were quantified on days 0, 3, 7, and 12 postnatal and absorption and retention of Fe and Mn isotopes from milk were studied on day 12 postnatal. These studies were conducted early in lactation when trace element intake is entirely dependent on milk.

2. Methods

2.1. Animals All procedures followed the Guide for the Care

and Use of Laboratory Animals (USPHS, 1985) and were approved by the UC Davis Animal Use and Care Administrative Advisory Committee. Pregnant mice (NIH Swiss Webster, Harlan Sprague Dawley) were fed diets containing 7 pg Al/g (control) or 1000 pg Al/g (ALlOOO) during gestation and lactation (the control diet was fed to all animals for l-2 weeks before mating). The experimental diets were based on sprayed egg white as the protein source to avoid metal ligands in grain-based diets. They contained the NRC recommended levels of all nutrients, and

were prepared in pelleted form by a commercial supplier (Dyets, Inc). Distilled deionized water was provided ad libitum in plastic bottles to minimize trace metal contamination. On the day of birth, litters were reduced to 8 if larger; litters of <6 pups were not used.

2.2. Milk collection and administration Milk was collected from the stomachs of

mouse pups shortly after nursing (Reis et al., 1991). This method ensures that the milk obtained is identical to that normally consumed by the pup without introduction of changes in composition that can be induced by artificial milking (Keen et al., 1980). For milk collection, the dam was separated from her litter for 4 h to ensure that the dam would have an adequate milk supply and that the pups would have an empty stomach and a good suckle response. Pups were kept in a beaker on a warm heating pad to maintain body temperature. Pups were then allowed to suckle for 60 min (1300-1400 h), separated from the dam and killed immediately. Stomach contents (curdled milk) were removed intact from each stomach, pooled and frozen for later analysis. For the absorption/retention experiment, milk was thawed, homogenized in distilled deionized water (1 g milk to 2 g water) to produce a smooth slurry, and incubated with isotope (‘9Fe, 8.3 &i//lg and “4Mn 30.5 &i/pg) for 1 h prior to administration. Labeled milk (0.2 ml, 60 ng 59Fe, 16 ng 54Mn, 0.5 $i for each isotope) was administered by gavage using a small size ball tip needle.

2.3. Tissue collection and milk and tissue analyses Pups were killed at 0, 3, 7 and 12 days post-

natal; brain and liver were obtained at the time of milk collection and frozen for analysis of Al, Fe and Mn concentration by electrothermal atomic absorption spectrophotometry (ETAAS, Therm0 Jarrell Ash) (Golub et al., 1992a). Pups fed the labeled milk meal for the absorption/ retention study were killed by decapitation after a 6-h or 24-h interval. Trunk blood (approxi- mately 100 mg) was collected on filter paper, and the brain and liver were removed. The intestinal

M.S. Goluh rl al. IToxicolog~ 109 (1996) IIILIIX 113

tract was washed with distilled water to remove any contents and a portion of the small intestine was collected to determine whether isotope was retained in the gastric mucosa. The dissection used plastic or stainless steel materials to avoid trace metal contamination. The remainder of the body, including the head, was reserved for analysis. Tissues (brain, liver, blood, small intestine, body) were transferred to scinitillation vials and counted with a gamma counter (MINAXI Auto Gamma 5000 series) after optimizing the energy windows for each respective isotope (59Fe, lOOO- 1150 nm; 54Mn, 780-900 nm). Isotope content of brain, liver, blood, small intestine and body, and

total recovered isotope, were determined for each

PUP.

2.4. Statistics Measures taken at several timepoints using the

pups from the same litter were analyzed by repeated measure ANOVA with diet (control, ALlOOO) and timepoint as the factors. Measures at one timepoint were analyzed by ANOVA with diet as the independent variable. Correlations were also calculated between various dependent variables. Statistical significance was indicated by P < 0.05.

50

45

40

cn35 ;js 825 ;20

15 10

5 n

MILK BRAIN LIVER

”

D,O Da;3 Da;? Da;12

.O

._ Day 0 Day3 Day7 Day12

18

fa 16: Mn

0” 2 12 g 10

6

4

2

f-j Day0 Day3 Day7 Day12

4.0

z.5

3.0

25

20

1.5

1.0

.5

Mn

!F J A

Day0 Day3 Day7 Day12 OJ

Day 0 Day 3 Day 7 Day 12

Fig I. Al. Fe and Mn content of milk, pup brain and pup liver during early lactation. Groups fed diets containing 7 (control) or

IWO (ALIOOO) pg Al/g diet are compared. Element concentrations were obtained from assay of whole brain and liver and stomach

milk contents by electrothermal absorption/atomic absorption spectrophotometry and are expressed per g wet weight.

Mean i S.E.M. for each group (n = 8-12/group/age) are presented.

Fl?

.30 *3si L .2s

.20

.C

Day0 D&3 Da;7 D,12

o- Day0 Day3 Day7 Day12

114 M.S. Goluh et al. ITv.~icolog_v 109 (1996) III-118

3. Results 3.2. Fe and Mn absorption and retention

3. I. Milk Fe and Mn concentration On day 0, 3, 7 and 12, two pups from each

litter, one male and one female, were selected for determination of milk and tissue trace elements. As reported previously, the high Al diet did not produce general toxicity in dams or pups. There were no differences between diet groups in maternal weight gain during pregnancy or in litter size or pup weights at birth, 3, 7, or 12 days postnatal. There was no postnatal mortality in either group.

To study Fe and Mn absorption and retention, litters from control (n = 6) and AL1000 dams (n = 5) were culled to 8 at birth. On day 8 milk was collected from two pups per litter and pooled within diet groups. On day 12 the milk from the appropriate diet group with added 59Fe and 54Mn was administered to two pups per litter (n = 12 control, n = 10 ALlOOO). The pooled milk from AL1000 dams contained 20% more Al than that from controls.

Temporal patterns of milk, brain and liver Al, Fe and Mn during early lactation are shown in Fig. 1. Milk Al in the AL1000 group followed a similar pattern as milk Mn, rising markedly on day 12. On day 12, there was a significant correlation between milk Al and Mn (r = 0.52, P = 0.012). Milk Al concentrations of the AL1000 group were generally higher than those of controls throughout lactation as indicated by repeated measures ANOVA (F = 4.42, P = 0.049). There was also a significant interac- tion between diet and timepoint (F = 4.73, P < 0.005); the only individual timepoint at which

milk Al was significantly higher in the AL1000 group was at day 12 (F = 9.66, P = 0.0056). There were no differences at any timepoint in milk Fe and Mn concentrations of AL1000 dams and controls. There was no correlation between litter size and milk trace element concentration at any timepoint.

Absorption of 59Fe and 54Mn at 6 h was 78% and 14% of the administered dose, respectively. As was anticipated for these essential trace elements, the amount of isotope retained at 24 h was similar to the amount absorbed at 6 h (Fig. 2). Total body absorption of Mn and Fe isotope at 6 h did not differ between diet groups, but total body retention of both Fe and Mn was lower in the AL1000 group than in controls at 24 h (Mn, F = 5.28, P = 0.030; Fe, F = 6.55, P = 0.017).

Concentrations of Al, Mn and Fe were also determined in brain and liver of pups from whom milk was obtained. Repeated measures ANOVA indicated a significant change across timepoints for all 3 elements. Al followed a similar developmental pattern as Fe in brain and liver, declining markedly from birth to day 3 postnatal in brain and more gradually in liver. Brain Al declined significantly from birth to 3 days of age in the Al group (F = 3.94, P < 0.003) but not in controls (F = 2.21, P = 0.063). In contrast, brain and liver Mn concentrations rose from birth to day 12 postnatal. There were no diet group differences in brain or liver Al, Fe or Mn concentrations at any timepoint.

While total radioactivity was similar at 6 and 24 h, tissue distribution was different at the two timepoints (Table 1). Radioactivity from each isotope was lower at 24 than at 6 h in the remainder of the body (after removal of brain, liver and small intestine) (P < 0.001). Mn in the remainder of the body was lower in the AL1000 group than in controls at 24 h (F = 6.34, P = 0.019) while the group difference in Fe did not reach significance (P = 0.06). Only the remainder of the body demonstrated significantly lower Fe and Mn retention in the Al group than in controls; this was not seen for brain or liver. In the small intestine, Mn decreased markedly from 6 to 24 h in both groups (P < O.OOOl), while Fe decreased only in the control group (P = 0.001). Notably, radioactivity in the brain increased significantly from 6 to 24 h in both groups for both isotopes (P < 0.0001). A similar pattern was seen in blood (P < 0.0001). In liver, Fe concentrations did not change, but Mn concentrations declined in the control group only (t = 2.47, P = 0.026) from 6 to 24 h. The tissue distribution data suggested that decreased retention of total radioactivity in the AL1000 group was not limited to any one tissue.

M.S. Goluh et (11. I To.uicolog_v 109 (1996) Ill-It8 115

Fe

absorption

Mn

retention

absorption retention

Fig. 2. Absorption and retention of 5YFe and “‘Mn administered in a single milk meal on day 12 postnatal. Absorption and retention were measured 6 and 24 h, respectively, after the milk meal. Total isotope counts from all samples were determined and converted to ng of administered element. Mean + S.E.M. for each group (control, n = 12 pups, ALIOOO, n = IO pups) are presented.

4. Discussion

This experiment demonstrates that retention of Fe and Mn from a milk mea! is reduced by about 10% in suckling offspring of mouse dams fed excess dietary A!. Milk concentration and absorption of Fe and Mn were not influenced by

dietary A!. Retention was studied at 12 days postnatal because this is the latest postnatal age at which a!! mineral intake can be anticipated to come from milk. Although isotope retention was lower in the AL1000 group, brain and liver concentrations of Fe and Mn as measured by bulk analysis did not differ from controls on day 12. Reduced retention of Fe and Mn, if continued into late lactation, could .be responsible for the lower tissue levels of Fe and Mn seen in A! exposed offspring at the time of weaning in previous experiments (Golub et a!., 1992b, 1993). Also higher concentrations of A! in milk and diet in late lactation could increase the effect on retention. Since brain uptake of Fe in rats and mice is highest in late lactation (Taylor and Morgan, 1990), this is likely to be a more sensi- tive period for A! interference with Fe uptake.

Reduced Fe and Mn retention could be due to an elevated body burden of A! in’ the nursing pups that interfered with tissue uptake or binding of these elements. However, this and previous (Golub et a!., 1992b, 1993) experiments have not documented higher A! concentrations in mouse pup tissues when dams were fed a high A! diet. Failure of nursing offspring to accumulate tissue A! from milk was also noted in rabbit and rat offspring nursing dams injected with A! (Yokel, 1984; Muller et a!., 1992). A second explanation is that A! competes with Fe and Mn for serum transferrin transport. However, relative serum concentrations of A! and Fe and affinity con- stants for transferrin do not support the likeli- hood of this explanation. A third possible mechanism would be interference by Al with cellular uptake of Fe and Mn. Dysregulation of cellular Fe and Mn uptake by A! transferrin has been demonstrated in vitro (McGregor et a!., 1990, 1994; Golub et a!., 1996).

The Al diet used in this experiment is high in that it exceeds estimated average human intake (Greger, 1985) by an order of magnitude but is only about 5-fold higher than the A! content of commercial rodent chow as determined in our laboratory and by others (Gawlick et al., 1987). The estimated maximum human intake (based on high dose antacid therapy) is 71 mg/kg/day (Lione, 1983) as compared to a maximum intake

116 M.S. Goluheral.IToxicolog~~109 (1996) Ill-II8

Table 1 Isotope recovered after 6 and 24 h in different body regions

“Fe (ng) 54Mn (ng)

6 h (absorption) 24 h (retention) 6 h (absorption) 24h (retention)

Body’ Control 34.2 k 1.13” 30.7 f 1.09 1.14 + 0.07 I .57 * 0.059 AL1000 34.2 + 1.86 26.6 + 1.06 1.23 f 0.17 1.41 k 0.032

Intestine Control 2.30 k 0.10 1.85 It 0.13 0.366 + 0.036 0.147 * 0.010 AL1000 1.96 + 0.27 1.86 rt 0.09 0.380 f 0.106 0.150 + 0.016

Brain Control 0.426 f 0.01 I 0.586 + 0.028 0.008 + 0.0005 0.026 f 0.002 ALlOtXl 0.426 f 0.027 0.558 * 0.025 0.009 * O.ooo8 0.027 f 0.003

Liver Control 4.84 ) 0.28 5.24 f 0.35 0.661 f 0.032 0.504 * 0.054 AL1000 4.32 + 0.24 4.45 + 0.40 0.550 + 0.069 0.494 + 0.027

Blood’ Control 6.33 f 0.66 9.93 + 0.94 0.043 + 0.004 0.065 f 0.006 AL1000 6.20 + 0.70 10.69 + 0.91 0.044 + 0.004 0.069 f 0.006

Statistical comparisons between groups and timepoints are presented in the text. “Remainder of the body after removal of brain, liver, small intestine and trunk blood. bMean f S.E.M. ‘Whole blood.

of 420 mg Al/kg/day by lactating mouse dams in this study. The high Al dietary content did not produce any detectable sign of general toxicity, such as slower growth, in dams or pups. It should be noted that pup tissue Al concentrations in this experiment were lower than previously reported (Golub et al., 1992b, 1993). This can be attributed to the lower Al content of the control diet (7 vs. 25 pg AI/g diet), which was also fed to AL1000 dams before mating. We have decreased the Al content of control diet to the lowest attainable level using purified ingredients to match the estimated Al content of human diets.

The Al content of mouse milk in this study did not increase dramatically in response to the 1000 ,ug Al/g diet and was comparable to ranges reported for human milk and formula. The median (range) for Al concentration in the milk of control mouse dams across lactation was 6 (3-23) nmol/g and for the Al-exposed dams 15 (7-25) nmoi/g. The range of Al concentrations has been reported in human breast milk at 0.1-3 nmol/g (assuming 1 ml weighs 1 g), in cow’s milk based formula at l-4 nmol/g and in soy based formula at 20-24 nmol/g (Baxter et al., 1991). Al absorption by neonates and infants has not been studied, but serum Al concentrations have been

shown to vary with the Al content of milk/formula (Hawkins et al., 1994). Gastrointestinal absorption of Al in adults is low (< 1%) and varies with the form of Al but is similar in humans and most laboratory species (Wilhelm, 1990).

Al appears to resemble Fe in the pattern of concentrations in pup brain and liver in the early postnatal period. The decrease in Fe in brain in early lactation has also been described in rats (Taylor and Morgan, 1990), and has been shown to be associated with brain transferrin concentrations. Milk Fe (Keen et al., 1981) and transferrin (Nicholas and Hartmann, 1991) concentrations decrease sharply in early lactation in rats, but this pattern was not seen in the present experiment with mice.

Milk Al had constant values across the 0, 3 and 7 day timepoints, but increased strikingly on day 12 gestation in the AL1000 group. This same increase on day 12 was seen for Mn. In rats, Mn has been shown to decrease in early lactation and to increase again after day 20 (Keen et al., 1981), a different pattern than was recorded here for mice. Changes in milk Al during lactation have not been previously reported in rodents, although some data are available for humans

h4. S. Golub er al. I Toxico1og.v 109 (1996) I I I - I18 111

(Feeley et al., 1983) and guinea pigs (Anderson, 1990). The similar developmental pattern, and the correlation between milk Al and Mn at 12 days postnatal, suggests that a similar mechanism is responsible for the increase in the two elements; this mechanism might involve changes in the concentration of milk proteins that bind both elements, but specific information on this is not yet available.

Aluminum is ubiquitous in tissues and bodily fluids and has been documented in milk of several species, including humans (Feeley et al., 1983; Anderson, 1992; Tanaka et al., 1994). Al content of milk has only been a toxicity concern in the case of uremic infants (Freundlich et al., 1985). The nutritional significance of milk Al concentrations is unclear, but the present experiment suggests attention to Fe and Mn metabolism is warranted. Fe and Mn are important for growth, immunity and brain function and for the normal ontogeny of metalloenzymes and bio- chemical processes such as hematopoiesis and oxidant defense. While it seems unlikely that Al could cause frank Fe or Mn deficiencies, subop- timal utilization of these minerals during critical developmental periods might occur.

Acknowledgements

The authors appreciate the help of Tammy Sakanashi in planning and conduct of this experiment, and of Joel Commisso for trace element analysis. Supported by NIH grant ES04190.

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iron and manganese uptake by offspring of lactating mice fed a high aluminum diet

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