Behavior and monoamine deficits in prenatal and perinatal iron deficiency are not corrected by early postnatal moderate-iron or high-iron diets in rats

Abstract

Developmental iron deficiency anemia (IDA) causes brain and behavioral deficits in rodent models, which cannot be reversed when treated at periods equivalent to later infancy in humans. This study sought to determine whether earlier iron treatment can normalize deficits of IDA in rats and what iron dose is optimal. The offspring of dams with IDA during gestation were cross-fostered at postnatal d (P) 8 to dams receiving diets with 1 of 3 iron concentrations until weaning (P21): 0.003-0.01 g/kg [totally iron deficient (TID)]; 0.04 g/kg [formerly iron deficient (FID-40)]; or 0.4 g/kg (FID-400). Always iron-sufficient control dams (CN-40) received a 0.04-g/kg iron diet. At P21, TID pups received a 0.01 g iron/kg diet; all others received a 0.04 g iron/kg diet. Hematocrit and brain iron and monoamine concentrations were assessed at P21 and P100. Pup growth, development, activity, object recognition, hesitancy, and watermaze performance were evaluated. Regional brain iron was restored by iron treatment. Regional monoamine and metabolite concentrations were elevated in FID-40 rats and reduced in FID-400 and TID rats compared with CN-40 rats. FID-40 offspring had motor delays similar to TID during lactation and FID-400 rats had elevated thigmotaxis similar to TID rats at P25 and P100 in the spatial watermaze. In conclusion, iron treatment at P8 in rats did not normalize all monoamine or behavioral measures after early IDA. Moderate iron treatment improved adult behavior, but higher iron treatment caused brain and behavioral patterns similar to TID in the short and long term.

FIGURE 1

Study design. CN-40, control; FID-40, formerly iron deficient fed 0.04-g/kg iron diet beginning at postnatal d 8; FID-400, formerly iron deficient fed 0.4-g/kg iron diet beginning at postnatal d 8; G, gestational day; P, postnatal day; TID, totally iron deficient.

FIGURE 2

Auditory startle (A), vibrissae-elicited forelimb placing (B), bar holding (C), and negative geotaxis (D) in CN-40, FID-40, FID-400, and TID rats during lactation. Values are means ± SE, n = 11–13 litters/group. *P < 0.05: CN-40 vs. TID at the specified postnatal day. CN-40, control; FID-40, formerly iron deficient fed 0.04-g/kg iron diet beginning at postnatal d 8; FID-400, formerly iron deficient fed 0.4-g/kg iron diet beginning at postnatal d 8; TID, totally iron deficient.

FIGURE 3

Time per touch in object recognition task for CN-40, FID-40, FID-400, and TID rats at P30 (A) and P80 (B). *P < 0.05: CN-40 vs. TID; ⁺P < 0.05: FID-40 vs. TID. Values are means ± SE, n = 11–13 litters/group. CN-40, control; FID-40, formerly iron deficient fed 0.04-g/kg iron diet beginning at postnatal d 8; FID-400, formerly iron deficient fed 0.4-g/kg iron diet beginning at postnatal d 8; FBlk, familiar-smelling block, FSph, familiar-smelling sphere, NBlk, novel-smelling block, NSph, novel-smelling sphere; P, postnatal day; TID, totally iron deficient.

FIGURE 4

Latency (s) to reach the platform at P25 (A), percent thigmotaxis at P25 (B), latency (s) to reach the platform at P100 (C), and percent thigmotaxis path at P100 (D) in CN-40, FID-40, FID-400, and TID rats. Diet groups without a common letter differ, P < 0.05. Values are means ± SE, n = 11–13 litters/group. CN-40, control; FID-40, formerly iron deficient fed 0.04-g/kg iron diet beginning at postnatal d 8; FID-400, formerly iron deficient fed 0.4-g/kg iron diet beginning at postnatal d 8; P, postnatal day; TID, totally iron deficient.