Treatment of pregnant rats with haloperidol delays the onset of sexual maturation in female offspring

AbstractFetal programming by androgen excess is hypothesized as one of the main factors contributing to the development of polycystic ovary syndrome (PCOS). PCOS is more than a reproductive disorder, as women with PCOS also show metabolic and other endocrine alterations. Since both ovarian and reproductive functions depend on energy balance, the alterations in metabolism may be related to reproductive alterations. The present study aimed to evaluate the effect of androgen excess during prenatal life on ovarian fuel sensors and its consequences on steroidogenesis. To this end, pregnant rats were hyperandrogenized with testosterone and the following parameters were evaluated in their female offspring: follicular development, PPARG levels, adipokines (including leptin, adiponectin, and chemerin as ovarian fuel sensors), serum gonadotropins (LH and FSH), the mRNA of their ovarian receptors, and the expression of steroidogenic mediators. At 60 days of age, the prenatally hyperandrogenized (PH) female offspring displayed both an irregular ovulatory phenotype and an anovulatory phenotype with altered follicular development and the presence of cysts. Both PH groups showed altered levels of both proteins and mRNA of PPARG and a different expression pattern of the adipokines studied. Although serum gonadotropins were not impaired, there were alterations in the mRNA levels of their ovarian receptors. The steroidogenic mediators Star, Cyp11a1, Cyp17a1, and Cyp19a1 were altered differently in each of the PH groups. We concluded that androgen excess during prenatal life leads to developmental programming effects that affect ovarian fuel sensors and steroidogenesis in a phenotype-specific way.

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Sexual maturation and fertility of male and female mice exposed prenatally and postnatally to trivalent and hexavalent chromium compounds

Reproduction Fertility and Development ◽

10.1071/r97001 ◽

1998 ◽

Vol 10 (2) ◽

pp. 179 ◽

Cited By ~ 37

Author(s):

M. H. Al-Hamood ◽

A. Elbetieha ◽

H. Bataineh

Keyword(s):

Hexavalent Chromium ◽

Sexual Maturation ◽

Potassium Dichromate ◽

Reproductive Toxicity ◽

Female Offspring ◽

Male Offspring ◽

Experimental Conditions ◽

Male And Female ◽

Female Mice ◽

Chromium Compounds

The reproductive toxicity of trivalent and hexavalent chromium compounds was investigated in male and female mice exposed to 1000 ppm chromium chloride and potassium dichromate via their mother during gestational and lactational periods. Fertility was reduced in male offspring exposed to either trivalent or hexavalent chromium compounds. Body weights and weights of testes, seminal vesicles and preputial glands were reduced in trivalent-exposed male offspring. The exposure of female mice offspring to trivalent and hexavalent chromium compounds delayed sexual maturation. Fertility was reduced in female offspring exposed to either trivalent or hexavalent chromium compounds. The exposure of female mice to hexavalent chromium compound reduced the number of implantations and viable fetuses respectively. Body weight and weights of ovaries and uteri were reduced in trivalent-exposed female offspring. The results indicate that under our experimental conditions, the exposure of male and female mice offspring to either trivalent or hexavalent chromium compounds during gestational and lactational periods impair reproductive functions and fertility in adulthood.

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Modest maternal protein restriction fails to program adult hypertension in female rats

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00037.2003 ◽

2005 ◽

Vol 289 (4) ◽

pp. R1131-R1136 ◽

Cited By ~ 139

Author(s):

Lori L. Woods ◽

Julie R. Ingelfinger ◽

Ruth Rasch

Keyword(s):

Renin Angiotensin System ◽

Female Gender ◽

Female Offspring ◽

Protein Restriction ◽

Female Rats ◽

Male Rats ◽

Pregnant Rats ◽

Angiotensin System ◽

Low Protein ◽

Maternal Protein Restriction

Modest maternal dietary protein restriction in the rat leads to hypertension in adult male offspring. The purpose of this study was to determine whether female rats are resistant to developing the increased blood pressure seen in male rats after maternal protein restriction. Pregnant rats were fed a normal protein (19%, NP) or low-protein (8.5%, LP) diet throughout gestation. Renal renin protein and ANG II levels were reduced by 50–65% in male LP compared with NP pups, but were not suppressed in female LP compared with female NP. Mean arterial pressure in conscious, chronically instrumented adult female offspring (22 wk) was not different in LP (LP: 120 ± 3 mmHg vs. NP: 121 ± 2 mmHg), and glomerular filtration rate was also not different in LP vs. NP. The number of glomeruli per kidney was similar in adult LP and NP female offspring (LP: 26,050 ± 2,071 vs. NP: 26,248 ± 1,292, NP), and individual glomerular volume was also not different (LP: 0.92 ± 0.11 106μm3, LP vs. NP: 1.07 ± 0.11 106μm3); the total volume of all glomeruli per kidney was also not significantly different. Thus female rats are relatively resistant to the programming for adult hypertension by perinatal protein restriction that we have described in males. This resistance may be due to the fact that modest maternal protein restriction does not reduce the number of glomeruli with which females are endowed as it does in males. The intrarenal renin-angiotensin system during development may play a key role in this protective effect of female gender.

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Prenatal programming of adult blood pressure: role of maternal corticosteroids

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00455.2004 ◽

2005 ◽

Vol 289 (4) ◽

pp. R955-R962 ◽

Cited By ~ 80

Author(s):

Lori L. Woods ◽

Douglas A. Weeks

Keyword(s):

Blood Pressure ◽

Food Intake ◽

Female Offspring ◽

Common Mechanism ◽

Long Term Effects ◽

Pregnant Rats ◽

Body Weights ◽

Glucocorticoid Administration ◽

Blood Pressures

Both maternal glucocorticoid administration and maternal dietary protein or food restriction in pregnancy cause fewer nephrons and hypertension in the adult offspring. The purpose of these studies was to determine the extent to which nutritional factors contribute to programming of offspring hypertension by maternal glucocorticoids. Pregnant rats were treated with dexamethasone (100 μg·kg−1·d−1sc) on days 1–10 (ED) or days 15–20 (LD) of pregnancy. Additional groups of pregnant animals were pair fed to the early (EDPF) and late (LDPF) dexamethasone-treated groups, and another group was untreated or given vehicle (C). The dams treated with dexamethasone reduced their food intake and lost or failed to gain a normal amount of weight during treatment; body weights of ED dams caught up to normal after the treatment period, whereas those of LD dams did not. In adulthood (∼21 wks), chronically instrumented male offspring of ED had normal blood pressures (125 ± 2 mmHg vs. 126 ± 1 mmHg in C), whereas LD offspring were hypertensive (136 ± 3 mmHg). However, LDPF offspring were equally hypertensive (134 ± 2 mmHg). Glomerular filtration rates normalized to body weight were not significantly different among groups. Qualitatively similar results were found in female offspring. Thus the long-term effects of maternal glucocorticoid administration at this dose on offspring’s blood pressure may, in large part, be accounted for by the reduction in maternal food intake. These data suggest that maternal glucocorticoids and maternal food or protein restriction may, at least in part, share a common mechanism in programming offspring for hypertension. The window of sensitivity of future offspring blood pressure to either maternal insult coincides with nephrogenesis in the rat, suggesting that impaired renal development could play an important role in this programming.

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Gestational Zearalenone Exposure Causes Reproductive and Developmental Toxicity in Pregnant Rats and Female Offspring

Toxins ◽

10.3390/toxins9010021 ◽

2017 ◽

Vol 9 (1) ◽

pp. 21 ◽

Cited By ~ 28

Author(s):

Xin Gao ◽

Lvhui Sun ◽

Niya Zhang ◽

Chong Li ◽

Jiacai Zhang ◽

...

Keyword(s):

Developmental Toxicity ◽

Female Offspring ◽

Pregnant Rats

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Estrogen normalizes maternal HFD induced cardiac hypertrophy in offspring by regulating AT2R

Journal of Endocrinology ◽

10.1530/joe-20-0562 ◽

2021 ◽

Author(s):

Fangyuan Chen ◽

Haili Yu ◽

Haichuan Zhang ◽

Runzhu Zhao ◽

Kaifang Cao ◽

...

Keyword(s):

Cardiac Hypertrophy ◽

Glucocorticoid Receptors ◽

Female Offspring ◽

Left Ventricular ◽

Normal Diet ◽

Angiotensin Ii Receptor ◽

Pregnant Rats ◽

Glucocorticoid Response ◽

17Β Estradiol ◽

Induced Changes

Our previous study has demonstrated maternal high-fat diet (HFD) caused a sex-dependent cardiac hypertrophy in adult male, but not female offspring. The present study tested the hypothesis that estrogen normalizes maternal HFD-induced cardiac hypertrophy by regulating angiotensin II receptor (ATR) expression in adult female offspring. Pregnant rats were divided into normal diet (ND) and HFD (60% kcal fat) groups. Ovariectomy (OVX) and 17β-estradiol (E2) replacement were performed on 8-week-old female offspring. Maternal HFD had no effect on left ventricular (LV) wall thickness, cardiac function and molecular markers of cardiac hypertrophy function in sham groups. However, maternal HFD caused cardiac hypertrophy of offspring in OVX groups, which was abrogated by E2 replacement. In addition, maternal HFD had no effect on ERα and ERβ in sham groups. In contrast, HFD significantly decreased ERα, but not ERβ in OVX groups. In sham groups, there was no difference in the cardiac ATR type 1 (AT1R) and ATR type 2 (AT2R) between ND and HFD offspring. HFD significantly increased AT2R, but not AT1R in OVX groups. Furthermore, maternal HFD resulted in decreased glucocorticoid receptors (GRs) binding to the glucocorticoid response elements at the AT2R promoter, which was due to decreased GRs in hearts from OVX offspring. These HFD-induced changes in OVX groups were abrogated by E2 replacement. These results support a key role of estrogen in the sex difference of maternal HFD-induced cardiac hypertrophy in offspring, and suggest that estrogen protects female offspring from cardiac hypertrophy in adulthood by regulating AT2R.

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Effects of Developmental Exposure to Mixtures of Environmental Contaminants on the Hepatic Metabolism of Estradiol-17β in Immature Female Sprague Dawley Rats

International Journal of Toxicology ◽

10.1177/1091581812457431 ◽

2012 ◽

Vol 31 (5) ◽

pp. 454-466 ◽

Cited By ~ 2

Author(s):

Daniel Desaulniers ◽

K. Leingartner ◽

G. Pelletier ◽

G.-H. Xiao ◽

W. J. Bowers

Keyword(s):

Messenger Rna ◽

High Performance ◽

Environmental Contaminants ◽

Hepatic Metabolism ◽

Female Offspring ◽

Estrogen Metabolism ◽

High Dose ◽

Sprague Dawley ◽

Pregnant Rats ◽

Estradiol 17Β

Exposure to environmental contaminants induces the activation of cytochrome P450s (CYP) which lead to the hydroxylation of contaminants and endogenous hormones such as estrogens. The hydroxylation of estrogens forms catecholestrogens (CEs), one of them being the mutagenic 4-hydroxyestradiol-17β (4−OH−E2). Catecholestrogens are transformed by catechol -o-methyltransferases (COMTs) into nonreactive methoxyestrogens. To investigate the hepatic metabolism of estradiol-17β in female offspring at postnatal day (PND) 21, pregnant rats were dosed daily from gestation day 1 until PND 21 with 2 dose levels of organochlorine pesticides (OCPs; 0.019 or 1.9 mg/kg per d), methylmercury (MeHg; 0.02 or 2 mg/kg per d), polychlorinated biphenyls (PCBs; 0.011 or 1.1 mg/kg per d), or a mixture (M; 0.05 or 5 mg/kg per d) including all 3 groups of chemicals. Concentrations of organochlorines in the mixture M were based on their proportions in serum of the Canadian Arctic population. The messenger RNA (mRNA) expressions of CYP and COMT were analyzed by quantitative reverse transcriptase–polymerase chain reaction (qRT-PCR). High-performance thin layer chromatography and phosphor imaging were used to measure the transformation of 14C substrates into estrogen metabolites. The low-dose treatments or the MeHg groups had no effect. The high-dose OCP, PCB, and M group increased the production of 2-OH-E2 and 6α-OH-E2, while only the PCB and M groups increased the 2-OH-CE/methoxyestrogen ratio. In all groups, the cytosolic COMT activity exceeded the microsomal production rate of 4-OH-E2. Although the M treatment included the PCB and OCP mixtures, it did not modify the estrogen metabolism more than did the PCB mixture alone. This endocrine disruption information contributes to our understanding of chemical interactions in the toxicology of chemical mixtures.

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Prenatal Inflammation Dampens Neurogenesis and Enhances Serotonin Transporter Expression in the Hippocampus of Adult Female Rats

Medical Principles and Practice ◽

10.1159/000499658 ◽

2019 ◽

Vol 28 (4) ◽

pp. 352-360 ◽

Cited By ~ 2

Author(s):

Abdeslam Mouihate ◽

Samah Kalakh ◽

Rawan AlMutairi ◽

Abdelrahman Alashqar

Keyword(s):

Adult Female ◽

Female Offspring ◽

Hippocampal Neurogenesis ◽

Female Rats ◽

Pregnant Rats ◽

Plus Maze ◽

Age Dependent ◽

Prenatal Inflammation ◽

The Impact ◽

Transporter Expression

Background/Aims: Prenatal exposure to lipopolysaccharide (LPS) dampens hippocampal neurogenesis. This effect is associated with increased anxiety-like behavior in adult offspring. Furthermore, blocking serotonin transporters (SERT) promotes adult neurogenesis. Previous studies were performed largely in males. Therefore, we explored the impact of prenatal LPS on neurogenesis, SERT expression in the hippocampus, and anxiety-like behavior in female rats during prepubertal and adulthood stages. Materials and Methods: Timed pregnant rats were injected with either saline or LPS (100 µg/kg, i.p.) on gestational days 15, 17, and 19. Newly born neurons were monitored by immunohistochemistry, and anxiety-like behavior was monitored using the elevated plus maze and open-field test. SERT expression in the hippocampus was assessed by Western blot and immunofluorescence. Results: Prenatal LPS led to reduced hippocampal neurogenesis in adult but not in prepubertal female offspring. This reduced neurogenesis was associated with enhanced hippocampal expression of SERT protein. However, there was no significant impact of prenatal LPS on anxiety-like behavior. Conclusions: Prenatal LPS-induced reduction in neurogenesis was dissociated from anxiety-like behavior in adult female rats. Furthermore, the long-lasting impact of prenatal LPS on neurogenesis in female offspring was age-dependent.

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Tryptophan ingestion by pregnant rats induces pituitary and mammary tumours in the adult female offspring

Human Reproduction ◽

10.1093/humrep/14.8.2155 ◽

1999 ◽

Vol 14 (8) ◽

pp. 2155-2161 ◽

Cited By ~ 1

Author(s):

Cristo Santana ◽

Lorenzo Martin ◽

Francisco Valladares ◽

Lucio Diaz-Flores ◽

Celsa Santana-Herrera ◽

...

Keyword(s):

Adult Female ◽

Female Offspring ◽

Pregnant Rats ◽

Mammary Tumours

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Excess maternal salt or fructose intake programmes sex-specific, stress- and fructose-sensitive hypertension in the offspring

British Journal Of Nutrition ◽

10.1017/s0007114515004936 ◽

2015 ◽

Vol 115 (4) ◽

pp. 594-604 ◽

Cited By ~ 14

Author(s):

Clint Gray ◽

Sheila M. Gardiner ◽

Matthew Elmes ◽

David S. Gardner

Keyword(s):

Blood Pressure ◽

Heart Rate ◽

Salt Intake ◽

Maternal Diet ◽

Cardiovascular Function ◽

Female Offspring ◽

Male Offspring ◽

Pregnant Rats ◽

Salt Loading ◽

Male And Female

AbstractThe Western diet is typically high in salt and fructose, which have pressor activity. Maternal diet can affect offspring blood pressure, but the extent to which maternal intake of excess salt and fructose may influence cardiovascular function of the offspring is unknown. We sought to determine the effect of moderate maternal dietary intake of salt and/or fructose on resting and stimulated cardiovascular function of the adult male and female offspring. Pregnant rats were fed purified diets (±4 % salt) and water (±10 % fructose) before and during gestation and through lactation. Male and female offspring were weaned onto standard laboratory chow. From 9 to 14 weeks of age, cardiovascular parameters (basal, circadian and stimulated) were assessed continuously by radiotelemetry. Maternal salt intake rendered opposite-sex siblings with a 25-mmHg difference in blood pressure as adults; male offspring were hypertensive (15 mmHg mean arterial pressure (MAP)) and female offspring were hypotensive (10 mmHg MAP) above and below controls, respectively. Sex differences were unrelated to endothelial nitric oxide activity in vivo, but isolation-induced anxiety revealed a significantly steeper coupling between blood pressure and heart rate in salt-exposed male offspring but not in female offspring. MAP of all offspring was refractory to salt loading but sensitive to subsequent dietary fructose, an effect exacerbated in female offspring from fructose-fed dams. Circadian analyses of pressure in all offspring revealed higher mean set-point for heart rate and relative non-dipping of nocturnal pressure. In conclusion, increased salt and fructose in the maternal diet has lasting effects on offspring cardiovascular function that is sex-dependent and related to the offspring’s stress–response axis.

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