Endocrinology, doi:10.1210/en.2004-0473
Endocrinology Vol. 145, No. 9 4068-4072
Copyright © 2004 by The Endocrine Society
Maternal-Fetal Glucocorticoid Milieu Programs Hypothalamic-Pituitary-Thyroid Function of Adult Offspring
Jennifer Slone-Wilcoxon and
Eva E. Redei
Northwestern University Feinberg School of Medicine, The Asher Center, and Department of Psychiatry and Behavioral Sciences, Chicago, Illinois 60611
Address all correspondence and requests for reprints to: Eva E. Redei, 303 East Chicago Avenue, Ward 9-198, Chicago, Illinois 60611. E-mail: e-redei{at}northwestern.edu.
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Abstract
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To assess the role of maternal glucocorticoid milieu on the hypothalamic-pituitary-thyroid function of the offspring, we adrenalectomized (ADX) pregnant dams on gestation d 8 and implanted a placebo pellet or a continuous release 50- or 75-mg corticosterone (CORT) pellet. Maternal ADX led to realignment of the balance between maternal and fetal plasma CORT levels, resulting in an increase in CORT of fetal origin in the maternal compartment. Maternal ADX and low levels of CORT replacement had no discernable effect on maternal pituitary-thyroid measures. In contrast, the increase in fetal CORT, as a consequence of the absence of maternal glucocorticoids, decreased birth weight in neonates, decreased adult hypothalamic TRH mRNA levels, and increased plasma TSH levels in both male and female adult offspring, all of which were reversed by administration of basal levels of CORT to the pregnant ADX dam. Decreased plasma T3 concentrations in female offspring were reversed by administration of the higher levels of CORT to the ADX dams. Our data indicate that maternal glucocorticoids modulate the developing hypothalamic-pituitary-thyroid axis.
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Introduction
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GLUCOCORTICOIDS PLAY A KEY role in the development of various organ systems before birth. Glucocorticoids cross the placenta from the mother to the fetus and vice versa (1, 2), and there is evidence that elevated maternal glucocorticoids play a regulatory role in the development and activity of fetal pituitary-adrenal axis (3). Additionally, elevated glucocorticoid levels during pregnancy are associated with in utero growth retardation (4). Maternal hypocortisolemia, such as that seen in maternal Addison’s disease, also results in intrauterine fetal growth retardation and reduced birth weight (5). In animals, the removal of glucocorticoids by maternal adrenalectomy (ADX) leads to reduced neonatal body weight (6, 7) as well.
Thyroid hormones are also important for proper growth and development, and perinatal hypo (8) and hyperthyroidism (8, 9) have been shown to alter thyroid function in the adult rat offspring. Decreased levels of maternal thyroid hormones during gestation correspond to decreased birth weight, both in humans and animals (10, 11, 12). Likewise, in both humans and animals increased levels of maternal thyroid hormones lead to decreased birth weight (9, 13).
A connection between the hypothalamic-pituitary-thyroid (HPT) and the hypothalamic-pituitary-adrenal (HPA) axes has long been observed, although the mechanism of their interrelationship is still not clear. Activation of the HPA axis is associated with concomitant decreased production of TSH and inhibition of peripheral conversion of T4 to the biologically active T3 (14). This tendency is corroborated with functional analysis demonstrating that glucocorticoids regulate 5'-deiodinase activity (15, 16). The inverse relationship between TSH and ACTH secretion suggests the possibility of a direct inhibitory link connecting the HPA and HPT axes (17). Thus, changes in maternal glucocorticoid levels could affect the developing fetal HPT axis directly or indirectly by affecting the maternal HPT axis, which in turn, could affect the developing fetal HPT axis.
Although it has been previously shown that adult HPT function is perinatally programmed (8, 9, 18), no study to date has examined the long-term effects of maternal glucocorticoids on the thyroid function of the offspring. Therefore, in this study we first characterized the HPT hormonal environment in control and ADX mothers and their adult offspring. Then, we administered two different doses of corticosteroid (CORT), continuously, to ADX dams to examine the HPT function of the mother and their adult offspring. Our results suggest that maternal glucocorticoids alter HPT function in adult offspring.
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Materials and Methods
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Animals
All animal procedures were approved by the Northwestern University Animal Care and Use Committee. Adult male and female Sprague Dawley rats (viral free, 56–68 d of age; Harlan, Indianapolis, IN) were housed individually in a temperature- and humidity-controlled vivarium with regular light-dark cycles (light on at 700 h and light off at 1900 h). After 7 d of acclimatization, rats were mated by placing a female in the male cage overnight. Mating was confirmed by microscopic analysis of vaginal smears for the presence of sperm the next morning. The day sperm was found was designated as gestational d 1.
Experiment 1
Pregnant rats were divided into two experimental groups. On gestational d 8, the rats received ADX or sham ADX (SHAM), performed dorsally under anesthesia (ketamine/xylazine 87/10 mg/kg BW). ADX and SHAM dams were placed on lab chow ad libitum. All ADX dams received their diet in 0.9% NaCl instead of water to prevent sodium depletion after ADX. In experiment 1a, five pregnant rats per group were weighed and killed by decapitation on gestational d 21. Maternal trunk blood was collected. Uterine horns were placed on ice, and fetuses were removed. The sex and weight of each fetus was determined, and trunk blood samples were collected. In experiment 1b, pups of five dams per group were weaned on postnatal d 21 and group housed by sex and treatment. At 80–90 d of age, adult male and female rats from each prenatal treatment group were killed by decapitation. Trunk blood was collected into chilled tubes containing EDTA (0.25 mg/ml whole blood), and kept frozen (–80 C) in aliquots.
Experiment 2
Pregnant rats were assigned to four experimental groups. On gestational d 8, the rats received ADX or SHAM (n = 5). At the time of surgery, the ADX dams received a placebo (ADX, n = 5), 50 mg (ADX + CORT50, n = 5) or 75 mg (ADX + CORT75, n = 5), 21-d release CORT pellet (Innovative Research of America, Sarasota, FL). Dams were weighed on gestational d 21. On postnatal d 1, pups were weighed and trunk blood was collected from the mother and one male and one female from each litter. The remaining pups were then fostered to non-ADX control dams because prenatal stress has been shown to affect maternal behavior (19).
At 80–90 d of age, adult male and female rats from each prenatal treatment group were killed by decapitation. Trunk blood was collected as described in experiment 1b.
RIAs
ACTH immunoreactivity was measured as previously described (20) using [125I]ACTH (1–39) (Amersham, Piscataway, NJ). The assay sensitivity was 6.7 pg/ml. The intra- and interassay coefficients of variation were 7.6% and 8.5%, respectively.
CORT concentrations were measured as described previously (20) in unextracted plasma using [125I] CORT RIA (ICN Biomedicals, Carson, CA). For CORT, the assay sensitivity was 9.7 ng/ml. The intra- and interassay coefficients of variation were 8.6% and 9.5%, respectively.
TSH was measured as described before (20); standards and specific antiserum were obtained from the National Hormone and Pituitary Agency (NIDDK, Baltimore, MD). Rat TSH RP-2 was used for the iodination and standards. The TSH assay sensitivity was 0.9 ng/ml, and the intraassay coefficient of variation was 6.1%with an interassay coefficient of variation of 8.7%.
RIAs for total T3, free T3, and total T4 were performed using ImmunoChemcoated tubes purchased from ICN Pharmaceuticals (Costa Mesa, CA), according to protocol. The total T3 assay sensitivity was 34.7 ng/dl, and the intraassay coefficient of variation was 4.6% with an interassay coefficient of 7.2%. The free T3 assay sensitivity limit was 0.9 pg/ml, and the intraassay coefficient of variation was 5.2% with an interassay coefficient of 6.7%. The T4 assay sensitivity limit was 0.5 µg/dl, and the intraassay coefficient of variation was 4.8% with an interassay coefficient of variation of 6.3%.
RNA Isolation and Northern Analysis
Rat brains were rapidly dissected on ice and immediately placed on dry ice. Dissections used Paxinos coordinates (21): hypothalamus (anterior-posterior, –0.30 to –4.16; medial-lateral, 0–2.2; dorsal-ventral, –0.40 to 2.8). Tissues were stored at –80 C.
Extraction of total RNA was performed using Trizol reagent, according to the manufacturer’s protocol (Life Technologies, Grand Island, NY). The quality and quantity of RNA were analyzed by gel electrophoresis and spectrophotometry. Northern analysis was carried out using 8–10 µg of RNA from each sample as described before (22). The plasmid containing the ß-actin cDNA probe was kindly provided by Dr. Michael Prystowsky, Albert Einstein University (Bronx, NY). The TRH probe was generated by PCR using primers specific for the rat TRH cDNA (5'-TCTGCAGAGTCTCCACTTCGCAGACTCCAG-3'; 5'GGTGACATCAGACTCCATCCAGGGGAAGGA-3'). The generated TRH probe was 538 bp in length. Autoradiographs were scanned and analyzed using NIH Image (Wayne Rasband, National Institutes of Health, Bethesda, MD). Specific mRNA levels were normalized to the ß-actin mRNA level of each sample.
Statistics
The data were analyzed by ANOVA, a two-factor design (sex, treatment). Litter was a nested factor. The Tukey least significant difference test, with a P < 0.05, was used as a post hoc test to locate significant differences among groups. F statistics are reported in the results section; post hoc statistics are indicated in the figures.
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Results
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Experiment 1
Consistent with previous results from our laboratory (7), ADX significantly (P < 0.01) reduced maternal plasma CORT levels (data not shown). No significant differences were found in maternal plasma TSH or T3 between SHAM and ADX mothers (Table 1
). Although there were no significant differences in maternal weights (Table 1), maternal ADX significantly reduced fetal weight in both males and females [Table 1; F(1,101) = 18.3; P < 0.01]. No differences were found in total fetal litter size on gestational d 21 (data not shown). In addition, body weight tended to be decreased in ADX adult offspring compared with SHAM offspring (Table 1; P = 0.09).
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TABLE 1. Body weight, plasma TSH, and total T3 levels in mothers, fetuses (gestational d 21) and adult offspring (80–90 d of age)
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Maternal ADX significantly increased plasma TSH levels of both male and female adult offspring compared with their respective SHAM controls [surgery effect: F(1,64) = 11.3; P < 0.01]. As expected, male offspring had generally higher levels of plasma TSH than females [Table 1
; sex effect: F(1,64) = 4.5; P < 0.05]. Plasma T3 levels (Table 1) were significantly decreased in female ADX offspring compared with their SHAM counterparts, whereas no such difference was found in the male offspring [sex x surgery: F(1,64) = 12.5; P < 0.001]. No significant differences were found in plasma T4 values (females: SHAM = 2.74 ± 0.44 µg/dl, ADX = 2.11 ± 0.6 µg/dl; males: SHAM = 2.71 ± 54, ADX = 2.84 ± 0.45).
Experiment 2
To delineate the role of CORT in the effect of maternal ADX on the thyroid function of the mother and the offspring, we administered two different doses of CORT to the ADX mother. The data summarized in Table 2 show that on the day after parturition, ADX and ADX + CORT50 mothers had significantly decreased, whereas ADX + CORT75 mothers had significantly increased, plasma CORT values compared with SHAM mothers [treatment effect; F (3, 20) = 7.8; P < 0.001]. Plasma TSH levels were significantly decreased in the ADX + CORT75 mothers compared with SHAM mothers (F = 5.13; P < 0.01; Fig. 1), whereas no differences were found in T3 or T4 levels (data not shown). In addition, no significant differences were found in maternal weight on gestational d 21.
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FIG. 1. Maternal plasma TSH levels on postnatal d 1 (n = 5/group). Treatment groups include SHAM, ADX with placebo pellet (ADX), ADX with 50 mg corticosterone release pellet (ADX + CORT50), or ADX with 75 mg CORT release pellet (ADX + CORT75) dams. Values are means ± SEM. Asterisk indicates significant difference from SHAM control, P < 0.05.
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Fetal adrenal hypersecretion, compensating for the lack of maternal glucocorticoids, led to significantly increased neonatal plasma CORT levels in both ADX and ADX + CORT50 pups compared with SHAM pups [treatment effect: F(3,37) = 6.5; P < 0.001; Table 2], but offspring of ADX+CORT75 mothers had plasma CORT levels identical with those of SHAM controls. Plasma T4 was undetectable in the neonatal blood at this time point, and we did not have enough neonatal plasma to measure TSH. Neonatal weight was significantly reduced in both male and female ADX pups on postnatal d 1 compared with their respective SHAM controls, and this decreased body weight was normalized by both low and high doses of CORT replacement to the ADX mother [treatment effect: F(3,269) = 27; P < 0.001; Table 2]. The observed sex difference in neonatal body weight was within expected parameters [sex effect: F(1,269) = 4.9; P < 0.05]. There were no significant differences in neonatal litter size or the sex ratio between treatment groups (data not shown).
Maternal ADX led to a decrease in adult body weight, which was reversed by both doses of CORT replacement. However, post hoc analysis showed this difference to be significant only between ADX and ADX + CORT75 offspring [treatment effect: F(1,134)] = 2.7; P < 0.05; Table 3]. Basal plasma ACTH levels, which were higher in males than in females [sex effect: F(1,46) = 29.0; P < 0.001], were significantly decreased in ADX and ADX + CORT50 females, but only the ADX females had increased basal plasma CORT levels compared with SHAM females [sex x treatment: F(3,46) = 3.4; P < 0.05]. Whereas ACTH was significantly increased in ADX + CORT75 males compared with SHAM males [sex x treatment: F(3,46) = 12.2; P < 0.001], no significant differences were found in basal plasma CORT levels (Table 3).
Confirming results of experiment 1, basal plasma TSH levels were significantly increased in the adult ADX group compared with those of SHAM controls [Table 3; treatment effect, F(3,48) = 6; P < 0.01], whereas only ADX females had significantly decreased total and free T3 compared with SHAM females [Table 3; total T3: sex x treatment, F(3,48) = 2.7; P < 0.05; free T3: F(3,48) = 3.1; P < 0.05]. Both low and high CORT treatment normalized TSH levels in adult offspring, whereas the higher dose of CORT was needed to reverse the decreased total and free T3 found in ADX females. No significant differences were observed in basal plasma T4 values between groups (females: SHAM = 2.75 ± 0.24 µg/dl, ADX = 2.17 ± 0.41 µg/dl, ADX + CORT50 = 2.42 ± 0.3 µg/dl, ADX + CORT75 = 3.12 ± 0.32; males: SHAM = 2.17 ± 0.28 µg/dl, ADX = 2.5 ± 0.36 µg/dl, ADX + CORT50 = 2.5 ± 0.31 µg/dl, ADX+CORT75 = 2.71 ± 0.27).
No sex differences were found in hypothalamic TRH mRNA levels in any treatment group, so male and female data were combined (Fig. 2). TRH mRNA levels were lower in the hypothalamus of adult offspring of ADX mothers compared with SHAM offspring [F(1,36) = 3.8; P < 0.05]. However, this lower TRH expression was normalized by both doses of CORT replacement to the mother because hypothalamic TRH mRNA in ADX + CORT50 and ADX + CORT75 offspring did not differ significantly from SHAM controls.
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FIG. 2. Levels of TRH mRNA in the hypothalamus of rats (80–90 d of age, n = 8–10/group). No sex differences were found in TRH mRNA levels in any of the brain regions, so male and female data are pooled. TRH mRNA levels were normalized to the ß-actin mRNA level of each sample. Values are means ± SEM. Asterisk indicates significant difference from SHAM control, P < 0.05.
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Discussion
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The main findings of the present study suggest that maternal glucocorticoids permanently imprint adult HPT function. The complete lack of glucocorticoids of maternal origin led to decreased birth weight in both male and female neonates. The decreased birth weight, elevated TSH levels, and suppressed hypothalamic TRH expression found in male and female adult offspring of ADX mothers were normalized by maternal CORT administration using a CORT dose corresponding to low basal levels. In contrast, only the higher dose of CORT reversed the decrease in plasma T3 values in ADX females. These data suggest that HPT function is developmentally programmed and dependent on the maternal glucocorticoid milieu.
Decreased maternal CORT or subsequently increased fetal CORT may affect the developing HPT axis directly rather then via altering maternal HPT function. This suggestion is supported by the lack of apparent HPT dysfunction in ADX and ADX + CORT50 dams whose offspring nevertheless shows altered HPT function. In contrast, plasma TSH in the ADX + CORT75 mothers was suppressed without any discernable effect on the adult offspring HPT function. Because increased ACTH and/or cortisol inhibit TSH secretion (14, 23), increased maternal CORT may lead to this suppressed TSH, which does not effect the offspring’s HPT function.
It is important to note that plasma CORT levels of the ADX + CORT75 dams are only moderately high. The 75-mg CORT pellet produced CORT levels in the pregnant dams that were in the elevated basal, rather than the stress, CORT range. This seems to be a very important point because plasma CORT levels in the neonates of ADX + CORT75 mothers were not different from those of SHAM neonates, suggesting that placental 11ß-hydroxysteroid dehydrogenase (type 2) may protect the fetus from moderately high levels of maternal CORT. Consequently, these maternal CORT levels did not lead to fetal growth retardation or to alterations in the adult offspring’s HPT function, indicating that it is the fetal/neonatal glucocorticoid milieu that programs HPT function.
The adult HPT axis responded to variations in maternal glucocorticoid milieu in a sex- and dose-specific manner. Overall, the observed sex differences in HPT hormone levels, namely higher plasma TSH levels, but lower plasma T3 levels in males than females, correspond to previous findings (24), whereas others found no sex differences in HPT function (25). Plasma T3 was lower in the ADX female offspring and required the higher CORT replacement to the mother to be brought back to SHAM levels. The cause of the sex differences in plasma T3 levels and the differences in HPT responsiveness to varying doses of prenatal CORT require further studies.
Hypothalamic TRH mRNA levels were decreased in the male and female offspring of ADX mothers despite decreased peripheral T3 levels in the females. Because TRH expression is negatively regulated by T3 (26), the inappropriately lower levels of TRH RNA may reflect altered sensitivity to T3 in female offspring of ADX dams. In addition, the increased TSH and normal T3 values in male ADX offspring and the normal TSH but decreased T3 in both male and female offspring of ADX + CORT50 dams could be due to altered TSH bioactivity in these offspring. Studies with TRH –/– mice suggest that TRH is essential for the maintenance of normal biological activity of circulating TSH (27) and normal feedback regulation of the TSH gene by thyroid hormone (28). As adults, these TRH –/– mice have elevated plasma TSH and decreased thyroid hormone levels (27). Although not that extreme, this HPT profile resembles our findings in ADX offspring.
Although experimental hypothyroidism of the mother has been show to effect the development of the HPA function of the offspring (29), little work has been done on the prenatal programming effects of experimental hypo- or hypercorticosteronemia on HPT function. Glucocorticoids can alter the development and activity of fetal pituitary-adrenal axis (3), leading to long-term alterations in the HPA function of the adult offspring (3). Thus, it is possible that alterations in adult HPT function after maternal CORT manipulations are secondary to changes in offspring HPA activity. However, basal HPA measures of the adult offspring do not support this hypothesis because they are not inversely related to those of the HPT axis. Alternatively, maternal ADX may lead to decreased body weight, which in turn can alter HPT function of the offspring. Because we found decreased body weight in both ADX fetuses and adults, the role of decreased body weight in resetting the HPT axis in response to altered maternal glucocorticoid milieu cannot be excluded. Regardless of the complexity of the mechanisms, this study indicates that decreased maternal glucocorticoids alter HPT functioning in the adult hypothalamus and pituitary. Further studies are necessary to assess the functional responsivity of the HPT axis in adult offspring after maternal ADX, the mechanism of vulnerability of the developing HPT axis to prenatal environmental alterations, and the connection between the HPT and HPA programming.
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Footnotes
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This work was supported by National Institute on Alcohol Abuse and Alcoholism Grants AA07389 (to E. R.) and AA05587 (to J. S.-W.).
Abbreviations: ADX, Adrenalectomy/adrenalectomized; CORT, corticosterone; HPA, hypothalamic-pituitary-adrenal; HPT, hypothalamic-pituitary-thyroid; SHAM, SHAM ADX.
Received April 13, 2004.
Accepted for publication June 11, 2004.
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Abstract
Introduction
