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Ovary |
b Laboratoire de Neuroendocrinologie du Développement, UPRES 2701, Université de Lille 1, 59655 Villeneuve d'Ascq, France
c INSERM U422, 59045 Lille, France
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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follicle-stimulating hormone, luteinizing hormone, neuroendocrinology, ovary, testis
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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From these observations, the concept of fetal programming has been advanced. Two major mechanistic hypotheses have been proposed to explain fetal programming: maternal malnutrition and prenatal glucocorticoid exposure [5, 6]. It has been proposed that overexposure of the fetus to excess glucocorticoids may be implicated in the association between restricted fetal growth and the programming of adult cardiovascular and metabolic diseases [7, 8]. Moreover, we have reported that in rats, maternal undernutrition during late gestation induces both intrauterine growth retardation and overexposure of fetuses to maternal corticosterone, which disturbs the development of their hypothalamo-pituitary-adrenal (HPA) axis [9]. Thus, the correlation between low birth weight and adult diseases could be related to the adverse glucocorticoid environment in utero for both animal models (i.e., fetal overexposure to glucocorticoids or to malnutrition). However, because during the perinatal period nutrition and glucocorticoids have powerful programming properties regarding the development of numerous systems [10, 11], long-term pathophysiological consequences can be expected in these models.
Although a metabolic link between nutrition, stress, and fertility is well documented, to our knowledge the effects of perinatal food restriction (FR) on the pituitary-gonadal axis in pups and/or adults have not yet been investigated. Indeed, severe starvation is associated with impaired reproductive function [12–14], and stress hormones of the HPA axis highly disturb the activity of the hypothalamo-pituitary-gonadal axis (reviewed in [15]). The hypothalamo-pituitary-testicular axis of the rat is already functional in fetuses during late gestation and in newborns [16, 17]. A drastic but transient surge of plasma testosterone occurs in newborn rats during the first 2 h after delivery [16–20] as well as in males of other species, including human [21]. This surge of circulating testosterone is associated with a release of pituitary LH [22] and an ephemeral increase in GnRH content of the hypothalamus [23]. In littermate newborn female rats, a late and slight increase in plasma estradiol is observed [20]. Appreciable amounts of FSH are present in the serum of perinatal rats [24]. Functional FSH receptors first appear 5 days after birth in the rat ovary [25], and FSH-stimulated cyclic AMP production in the neonatal rat ovary is observed as early as Day 4 of postnatal life [26]. The FSH is the primary gonadotropin for folliculogenesis [27], and in the ovary, the action of this hormone is restricted to granulosa cells, regardless of the state of ovarian development [28, 29].
The state of nutrition is an important factor for reproductive functions and the onset of puberty [30–32]. Leptin, which is a product of the obesity gene [33] expressed in adipose tissues, is involved in the regulation of adiposity in mammals and may act as an endocrine-signaling factor linking nutritional status to the reproductive axis. Indeed, leptin stimulates secretion of LH and FSH from the pituitary in both young and adult rats in a dose-dependent manner [34]. Serum leptin concentration increases before those of other reproductive hormones related to puberty in normal prepubertal girls [35, 36]. In prepubertal mice, earlier maturation of the reproductive tract has been reported following leptin injection [37, 38]. Chronic leptin treatment of leptin-deficient ob/ob mice restores puberty and fertility [39]. Moreover, changes in body weight, serum leptin concentration, and serum estradiol concentration are positively correlated to the age range of 3–11 wk in female rats [34].
Because maternal FR during both gestation and lactation or during lactation alone disturbs the growth of male and female rat pups from birth to weaning [40], the aim of the present study was to determine, both at birth and at weaning, the effects of maternal undernutrition during late gestation and/or lactation on pituitary-gonadal activity, gonadal development, circulating levels of leptin, fat mass, and onset of puberty.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Wistar rats (weight, 200 g) were purchased from IFFA-CREDO (L'Arbresle, France) and housed (5 rats/cage) in a room with controlled light cycle (12L:12D) and temperature (22 ± 2°C) and with free access to food (regular rat chow, no. 113, containing 22% protein, 5% fat, 53% carbohydrate; UAR, Villemoisson sur Orge, France) and tap water. After 8 days of acclimation, female rats were mated with a male for one night. The next day was considered to be Day 0 of pregnancy if spermatozoa were found in the vaginal smears. Pregnant females were then transferred into individual cages.
Animal use accreditation by the French Ministry of Agriculture (no. 04860) has been granted to our laboratory for experimentation with rats.
Feeding Regimen
Four groups of pregnant rats were studied. A group of control dams was fed ad libitum from Embryonic Day (E) 14 to E21 and during the 3 wk of lactation (from Postnatal Day [PND] 0 to PND21, with PND0 being the day of birth). Three groups of food-restricted females received 50% of ad libitum intake, as determined by the amount of food consumed by the control females during gestation and lactation in a pilot study. This FR had no effects on the litter size and on the sex ratio of the pups. The females of the first food-restricted group (Pre group) received 12 g/day of food from E14 to E21 and then were allowed to eat ad libitum during lactation. The females of the second group (Post group) were fed ad libitum until delivery and then were further exposed to FR during lactation. The females of the third group (PP group) were exposed to FR during the last week of gestation until the end of lactation (PND21). For mothers of the Post and PP groups, the food supply was gradually increased from 12 to 22 g/day (first week of lactation), from 27 to 31 g/day (second week of lactation), and from 35 to 40 g/day (third week of lactation).
Water was always available ad libitum for all experimental groups.
For studies at birth, some litters from control and FR mothers were delivered by cesarean section at term. Other litters, used for studies at weaning, were spontaneously delivered through the vagina. The litters were adjusted to eight pups per dam with respect to the sex ratio to discard the effect of litter size on the milk dispensation.
Assessment of Onset of Puberty
Four or five dams from each regimen were kept to assess the onset of puberty. After weaning at PND21, males and females were separated from their mothers, and the animals were housed one per cage. From PND40 onward, the males were inspected daily for balano-preputial separation (BPS) to assess the onset of puberty, which was defined as the age in days at which BPS occurred. From PND30 onward, the females were examined daily for vaginal opening (VO). The onset of puberty in females was defined as the time of VO.
Blood Sampling and Tissue and Gland Collection
At E21, some control and FR mothers were rapidly killed by decapitation between 0900 and 1000 h. Each litter usually contained between 8 and 12 fetuses, which were collected by cesarean section and either immediately killed or kept at 25°C for 120 min before being killed. The sex of the pups was determined by examination of the genitals at birth.
At weaning, newborns spontaneously delivered by the vagina from the four experimental groups were also killed by decapitation.
Trunk blood of the fetuses at term or of the pups at weaning was collected and put in polyethylene tubes prerinsed with EDTA. The blood samples were centrifuged at 3500 x g for 15 min at 4°C. Plasma samples were kept at -30°C until assay for circulating hormones.
The testicles, ovaries, and uteri were quickly removed, defatted, and weighed. Different fat depots (perirenal, inguinal, gonadal, and pectoral) from the left side of each pup were quickly dissected and weighed. Interscapular brown adipose tissue was also collected and weighed.
Histology of the Gonads
Testicles and ovaries were fixed for 24 h at 4°C by immersion in saturated picric acid : paraformaldehyde (40:300 [w/v]) solution and then rinsed for 24 h in 0.1 M PBS (pH 7.40) containing 20% (w/v) sucrose before being frozen in Tissue-Tek OCT Compound (Miles Scientific, Naperville, IL) using isopentane and nitrogen fluid. Serial frozen sections (thickness, 12 µm) were cut on a cryostat, mounted on gelatin-coated slides, and stained using the Mason method (hematoxylin-fuchsin). The sections were examined and photographed. Photographs of seminiferous tubules and of ovarian follicles were analyzed using a Biocom 200 image analysis system (Biocom, Les Ulis, France).
Radioimmunoassays
Plasma LH concentrations were determined by a double-antibody RIA. The standard hormone and the specific antibody were provided by the National Institute of Diabetes, Digestive, and Kidney Diseases (NIDDK, Baltimore, MD). The labeled rat LH was iodinated using the chloramine-T method. The results were expressed in terms of NIDDK-rat-LH-RP3. Sensitivity of the RIA was 0.02 ng/assay-tube; intra- and interassay variations were 3.6% and 5.9%, respectively.
Plasma FSH concentrations were determined by RIA. Standard hormone (rFSH-RP2), specific antibody (anti-rat FSH-RIA 11), and 125I-labeled rFSH were provided by the NIDDK. The results were expressed in terms of NIDDK-rat-FSH-RP2. Sensitivity of the RIA was 0.035 ng/assay-tube; intra- and interassay variations were 4.5% and 8%, respectively.
Testosterone concentrations were determined by RIA. Antitestosterone was purchased from UCB-Bioproducts (i900; Nanterre, France). Standard doses of testosterone or samples were incubated for 90 min at 4°C in the presence of a testosterone antibody (final dilution, 1:20 000 [v/v]) and [1,2,6,7-3H]testosterone (TRK 402; specific activity, 90 Ci/mmol; Amersham, Little Chalfont, U.K.) with 0.02 M sodium/potassium phosphate buffer (pH 7.40) containing 0.5% BSA, 0.9% NaCl, and 0.02% sodium azide. The incubation volume was 0.300 ml. The separation of antibody-bound testosterone and free testosterone was obtained by the addition of 1 ml of Dextran-coated charcoal suspension (25 mg of Dextran T and 250 mg of charcoal Norit in 100 ml of RIA phosphate buffer; Sigma, L'Isle d'Abeau, France). The percentage of cross-reaction at B/Bo = 0.5 was 100% with testosterone, 50% with dihydrotestosterone, 1.19% with dehydroisoandrosterone, 0.16% with corticosterone, 0.10% with deoxycorticosterone, 0.042% with progesterone, 0.0125% with 5-pregnan-3ß-ol-20-one and 17
-hydroxyprogesterone, 0.00025% with 17ß-estradiol, and 0.00002% with hydrocortisone. Binding of [3H]testosterone in the absence of competition was 80% (n = 14). Fifty percent inhibition of [3H]testosterone binding to the antibody was obtained with 25 pg of unlabeled testosterone. Intra- and interassay variabilities were 4.55% (n = 12) and 8.46% (n = 8), respectively.
Plasma estradiol concentrations were determined by RIA using a commercial kit (ESTR-CTRIA; CIS-bio International, BP 32, 91192 Gif sur Yvette, France). The minimum amount of estradiol detectable was 7 pg/ml. The antibodies used in the assay showed the following percentages of cross-reaction at B/Bo = 0.5: 100% with 17ß-estradiol, 3.5% with estriol, 1.7% with estrone, 0.15% with 2-metoxyestradiol, and less than 0.004% with estradiol-17-sulfate, estrone 3-sulfate, progesterone, testosterone, and corticosterone. As a tracer, [125I]estradiol was used. Polyclonal antiestradiol-coated tubes were incubated for 90 min at room temperature (18–25°C) with continuous shaking. Intra- and interassay variabilities were 3.5% (n = 20) and 4.9% (n = 20), respectively.
Plasma progesterone concentrations were also determined by RIA using a commercial kit (PROG-CTRIA; CIS-bio International). The minimum amount of progesterone detectable was 0.05 ng/ml. The antibodies used in the assay showed the following percentages of cross-reaction at B/Bo = 0.5: 100% with progesterone, 6.2% with deoxycorticosterone, 2.2% with 20-dihydroprogesterone, 2.1% with 6ß-dihydroprogesterone, 1.6% with 16-dihydroprogesterone, 0.7% with 5ß-dihydroprogesterone, 0.5% with 17ß-hydroxyprogesterone, 0.09% with testosterone, and less than 0.02% with estradiol, pregnenolone, and cortisol. As a tracer, [125I]progesterone was used. Polyclonal antiprogesterone-coated tubes were incubated for 2 h at room temperature (18–25°C). Intra- and interassay variabilities were 3.5% (n = 20) and 4.5% (n = 15), respectively.
Plasma leptin concentrations were measured using a rat/mouse leptin RIA kit (LEP-r61; MEDIAGNOST, Tuebingen D 72072, Germany). This RIA utilizes a high-affinity polyclonal antibody specific for leptin. Standards and 125I-labeled tracer are prepared from recombinant mouse leptin. No cross-reactivity was found with human leptin, insulin, or insulin-like growth factor (IGF)-I. Sensitivity was 6 pg/ml in undiluted samples. Intra- and interassay variabilities were 5% and 8%, respectively.
Statistical Analysis
All data are presented as mean ± SEM. Statistical analysis was performed using multiple analysis of variance followed by the Dunnett test. An unpaired Student t-test was also used when appropriate. Differences were considered to be significant at P < 0.05.
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RESULTS |
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At weaning, the body weight of mothers exposed to FR during late gestation alone (Pre group) was not significantly different from the body weight of control mothers (Pre group, 282.00 ± 6.31 g; control group, 287.25 ± 4.27 g). In contrast, the body weight of mothers exposed to FR during lactation (Post group, 245.50 ± 4.01 g) or during both gestation and lactation (PP group, 230.25 ± 7.30 g) was significantly less than the body weight of control mothers (P < 0.001). Nevertheless, all mothers survived the FR.
Influence of FR of Pregnant Rats on Fetuses at Term
According to preliminary observations, FR of pregnant rats had no effect on litter size (data not shown). However, at birth (E21), male fetuses from FR mothers showed a significant reduction of body weight (P < 0.001) without significant modification of testicular weight (Table 1).
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In fetuses from FR mothers, circulating levels of testosterone at birth (time, 0 min) were not significantly different from those of controls (Fig. 1). In both groups, testosterone levels increased similarly 2 h after birth (Fig. 1).
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Influence of FR During Gestation and/or Lactation on Newborns at Weaning
Body weight At weaning (PND21), the body weight of male pups from all experimental groups was not significantly different from that of littermate female pups (Table 2). Moreover, similar growth retardation was evident in pups of both sexes when their mothers were exposed to FR during late gestation (Pre group), lactation (Post group), or both gestation and lactation (PP group) (Table 2). However, growth retardation was more drastic when the maternal undernutrition was performed mainly during both gestation and lactation (PP group) and during lactation alone (Post group) (Table 2).
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Fat depots At weaning, male and female pups from the Post and PP groups showed a drastic reduction of all fat pads (Fig. 2). Concerning fat pads of pups from the Pre group, some differences between males and females were observed. In males, brown adipose and pectoral adipose tissue depots were significantly increased (Fig. 2B), whereas in females, only the perirenal adipose tissue depot was markedly reduced (Fig. 2A).
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Gonad weight, sex steroid (testosterone), and hypophysial gonado-stimulating hormones (LH and FSH) in male pups Newborns from the Post and PP groups showed drastic retardation of testicle growth (Table 2). In contrast, FR during late gestation alone did not affect testicle growth (Pre group) (Table 2). The testicles of newborns from the PP group showed a significant reduction of cross-sectional area (Figs. 3 and 4A) and of the intratubular lumen of the seminiferous tubules (Fig. 4C). When undernutrition was performed during lactation alone (Post group), a marked decrease of cross-sectional area, epithelial area, and intratubular lumen of the seminiferous tubules was also observed (Fig. 4). In contrast, the histology of the testicles was not affected in the Pre group (Fig. 4).
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Food restriction was unable to significantly affect circulating levels of LH (Fig. 5A) and testosterone (Fig. 5C) in male pups. In contrast, FR during both gestation and lactation (PP group) significantly reduced circulating levels of FSH in males (Fig. 5B).
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Gonad and uterine weights, sex steroids (estradiol and progesterone), and hypophysial gonado-stimulating hormones (LH and FSH) in female pups Food restriction during gestation (Pre group) did not affect ovarian weight at weaning but reduced significantly uterine weight (Table 2). Female pups from the Post and PP groups showed reduced ovarian and uterine weights (Table 2).
The ovaries of the newborns of all experimental groups contained preantral follicles (secondary follicles) and antral follicles of small (vesicular follicles) or large (graafian follicles) size (Fig. 6). In secondary follicles, the central oocyte was surrounded by several layers of granulosa cells and bounded by thecal cells, which formed a fibrous theca externa and an inner theca interna (Fig. 6B). In antral follicles, fluid appeared between the granulosa cells, and the drops coalesced to form follicular fluid within the follicular antrum (Fig. 6D). In graafian follicles, the follicular antrum was clearly developed, leaving the oocyte surrounded by a distinct and denser layer of granulosa cells, the cumulus oophorus (Fig. 6A).
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At weaning, ovarian sections of female newborns from the control group showed a majority of vesicular follicles (
60%) (Fig. 7B), slightly more than 20% of preantral follicles, and between 15 and 20% of graafian follicles (Fig. 7, A and C). In contrast, ovaries of the newborns from the Post and PP groups showed a significant increase of vesicular follicles (Figs. 6, C and D, and 7B) and a drastic reduction of graafian follicles (Figs. 6, C and D, and 7C). Moreover, FR performed during both gestation and lactation reduced noticeably the percentage of preantral follicles (Fig. 7A).
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Food restriction did not significantly affect circulating levels of LH (Fig. 8A), estradiol (Fig. 8C), and progesterone (Fig. 8D). In contrast, a drastic and significant rise of plasma FSH was observed in females from the Post and PP groups (Fig. 8B). Regardless of the maternal feeding regimen, circulating levels of LH and FSH were markedly higher in female pups than in littermate male pups (P < 0.01 for LH, P < 0.001 for FSH) (Figs. 5 and 8).
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Circulating levels of leptin in male and female pups Plasma leptin concentrations were significantly higher in female pups than in male pups from control mothers (Table 3). Maternal FR performed during late gestation (female pups from the Pre group), during lactation (male and female pups from the Post group), and during both periods (male and female pups from the PP group) significantly reduced the circulating levels of leptin in offspring at weaning (Table 3).
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Onset of puberty In both male and female pups from the Post and PP groups, the onset of puberty was significantly delayed (Table 3). In contrast, maternal FR during gestation alone (Pre group) was unable to affect significantly the timing of puberty in both male and female pups (Table 3).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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In newborn males of the control group, the surge of plasma testosterone during the first 2 h after delivery confirms previous observations reported in the rat [18, 20] and in other species, including human infants [21]. Testosterone surge is associated with a release of pituitary LH and an increase in GnRH content of the hypothalamus [23]. This transient surge of plasma testosterone during the perinatal period is of critical importance and, in adults, leads to behavioral masculinization, which is defined as increased male-typical sexual behaviors [41]. In the present study, maternal FR performed during the last week of gestation was unable to affect both testicle mass and basal plasma level of testosterone as well as the early postnatal surge of testosterone at birth. Such observation is consistent with the findings of Tonkiss et al. [42], who showed that early undernutrition facilitates rather than impairs the sexual behavior of adult male rats.
Effects of FR at Weaning and on the Onset of Puberty
Body growth In pups of both sexes, the body growth of pups from birth to weaning was slightly reduced when maternal FR was performed during the last week of gestation alone, but it was drastically reduced when maternal FR was performed during lactation or during both late gestation and lactation. Using a similar model of perinatal FR until weaning, Garofano et al. [43] showed that such marked retardation of growth is irreversible until the age of 12 mo, in spite of normal nutrition after weaning. However, the precise mechanism by which maternal malnutrition programs such growth retardation in offspring remains unknown. Postnatal growth is regulated primarily by the growth hormone (GH)-IGF-I axis [44]. Moreover, neuropeptide Y (NPY), which stimulates the secretion of somatostatin (SS), thereby indirectly inhibiting GH release, was shown to affect the GH-IGF-I axis [45]. In recent studies, Huizinga et al [46, 47] have suggested that changes in SS and NPY mRNA expressions disturb the central GH regulation and, thus, could be involved in mediation of the postnatal growth failure induced by either prenatal or early postnatal undernutrition.
Pituitary-gonadal axis In male pups at weaning, maternal FR performed during both late gestation and lactation induced a severe reduction of testicle development with a significant decrease of gonad weight, cross-sectional area, and intratubular lumen of the seminiferous tubules. Such data are consistent with the decrease in circulating levels of FSH, a gonadotropin that promotes testicular growth and spermatogenesis [48]. In contrast, plasma levels of both LH and testosterone were not significantly affected by maternal FR. When FR occurred during lactation alone, a weaker reduction of the testicle weight with histological signs of atrophy of the seminiferous tubules was also observed, in spite of a slight but not significant decrease of circulating FSH. Taken together, these results show that prenatal FR reduces only the testicular growth in male offspring at weaning. In contrast, exposure to FR during lactation or during both late gestation and lactation results in male offspring with drastic reductions of both gonadal weight and structure as well as adenopituitary FSH secretion. These alterations could imply an increased risk for later fertility problems in male pups born with low birth weight. Indeed, undernourishment during gestation and suckling in rats was reported to reduce fundamental parameters of both development and reproductive function in adult male offspring [49]. We postulate that this inappropriate testicular growth could result from a disturbed central regulatory control of FSH secretion.
Regarding human gonadal development, De Bruin et al. [50] have reported a significantly lower percentage of primordial follicles in the ovaries of growth-retarded fetuses compared with age-matched controls. This indicates that ovarian development is disturbed in cases of intrauterine growth failure and that the ovaries undergo less growth in cases of fetal malnutrition. In ewes, the ovaries of fetuses from FR mothers contained significantly more germ cells entering the initial stages of meiosis compared with controls, in which a larger proportion of germ cells had completed this process and entered meiotic arrest [51]. Present data show that in female rats, maternal FR performed during lactation or during both late gestation and lactation reduces the uterine and ovarian weights and disturbs the follicular development, which shows a greater number of antral follicles of small size but a reduced number of graafian follicles of large size at weaning. Moreover, in contrast to male offspring, the plasma FSH level was drastically increased in female offspring at weaning when maternal FR was performed during lactation or during both late gestation and lactation. However, plasma levels of LH, estradiol, and progesterone were not significantly affected at weaning by maternal FR. According to our observations, it was reported that adolescent girls born small for gestational age (SGA) show higher serum FSH level than girls with appropriate birth weight for gestational age, whereas LH, estradiol, testosterone, and sex hormone-binding globulin concentrations are similar [52]. Moreover, SGA girls have a markedly reduced uterine cross-sectional area and a strikingly reduced ovarian volume [52].
Concerning the ovaries, we could postulate that the first steps of follicular development could be stimulated by early exposure to undernutrition, whereas the latter stages of folliculogenesis could be delayed or impaired. The greater number of antral follicles in these female pups is consistent with the increased circulating levels of FSH, which is one of the most important factors in promoting folliculogenesis [48]. However, the reduced number of mature graafian follicles implies that factors involved in later follicular development are disturbed by perinatal maternal undernutrition. One hypothesis could be that in these female pups, glucocorticoids could be implicated in these later disturbances. Indeed, Tohei and Kogo [53] reported that dexamethasone, a synthetic glucocorticoid, inhibits ovarian function in immature female rats in terms of inhibin secretion and estradiol synthesis and inhibits the FSH-induced differentiation of granulosa cells [54]. In a previous study [40], we reported that maternal undernutrition during lactation or during both late gestation and lactation increases the plasma level of free glucocorticoids in weaned rats. So, we can postulate that increased circulating glucocorticoid levels in female offspring could mediate the impaired development of graafian follicles induced by maternal FR.
Concerning FSH, maternal FR induces opposite effects in offspring of both sexes at weaning, with a reduction in males and an increase in females. Synthesis and release of FSH are under the control of a great number of factors, including central and gonadal factors such as steroid hormones (reviewed in [55, 56]) and peptides, which include inhibins and activins [57, 58]. So, we can postulate that an early exposure to perinatal FR alters the central/peripheral FSH regulation in a sexually dimorphic manner. Another hypothesis could be that increased circulating levels of glucocorticoids in female pups exposed to maternal FR could promote FSH secretion. Indeed, Tohei and Kogo [53], Sander et al. [59], and Arai et al. [60] showed that dexamethasone increased FSH secretion by mechanisms that imply inhibition of inhibin secretion. Moreover, several studies have shown that a glucocorticoid treatment significantly enhances FSH release in vitro [61] and pituitary content of FSH in vivo by selectively increasing FSHß gene expression [62]. However, some other factors to complete follicular development are probably lacking.
Fat stores, leptin, and onset of puberty Leptin, an adipocyte-secreted plasma hormone involved in the control of food intake and energy expenditure that plays a key role in body-weight homeostasis [63], has recently emerged as a pivotal signal in the regulation of fertility and in the control of pituitary gonadotropins (LH and FSH) [63]. According to present data, the drastic reduction in plasma leptin level is consistent with a marked drop in fat stores of offspring from the Post and PP groups. So, we speculate that a putatively disturbed leptin control of pituitary FSH secretion may have occurred in these offspring. On the other hand, the onset of puberty in male and female pups is significantly delayed in offspring from the Post and PP groups. Our data are consistent with these of Engelbregt [32], showing that early malnutrition delays the onset of puberty in male rats. Moreover, as we previously reported, maternal FR during lactation or during both late gestation and lactation increases the plasma level of free glucocorticoids in weaned rats [40]. We could also postulate that these hormones could delay the onset of puberty. Indeed, increased fetal glucocorticoid exposure also delays puberty in postnatal life [64].
In conclusion, the consequences of early exposure to FR appear mainly when mothers are exposed to undernutrition during lactation or during both gestation and lactation rather than during gestation alone. Perinatal growth retardation induced by maternal FR has drastic consequences on gonad development in offspring of both sexes as early as weaning and probably onward. Long-term sexual alterations could be expected in this experimental model, because in humans, reduced fetal growth is associated with a reduced ovarian fraction of primordial follicles [65] and with anovulation during late adolescence [66].
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Received: 8 January 2002.
First decision: 7 February 2002.
Accepted: 22 August 2002.
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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tal environment and adult hypertension?. Lancet 1993 341:355-357[CrossRef][Medline]This article has been cited by other articles:
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E Zambrano, G. L Rodriguez-Gonzalez, C Guzman, R Garcia-Becerra, L Boeck, L Diaz, M Menjivar, F Larrea, and P. W Nathanielsz A maternal low protein diet during pregnancy and lactation in the rat impairs male reproductive development J. Physiol., February 15, 2005; 563(1): 275 - 284. [Abstract] [Full Text] [PDF]
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 S. Bandyopadhyay, J. Chakrabarti, S. Banerjee, A.K. Pal, S.K. Goswami, B.N. Chakravarty, and S.N. Kabir Galactose toxicity in the rat as a model for premature ovarian failure: an experimental approach readdressed Hum. Reprod., October 1, 2003; 18(10): 2031 - 2038. [Abstract] [Full Text] [PDF]
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