Immunolike growth hormone substance in tissues from human embryos/fetuses and adults

GH immunolike reactivity was measured by RIA and IRMA tests in the extracts of tissues from human fetuses (8-32 weeks) and adults. For some fetal tissues a comparison was made with the T4 values obtained in a previous study. Both hormones were already measurable in peripheral tissues at 8 weeks of gestation. The increase in GH was faster than for T4 and it reached the zenith at approximately 20 weeks; thereafter, the GH concentration declined until delivery. In contrast, T4 progressively increased until term. Thirteen tissues were studied both in fetuses and in adults: the GH concentration was about 10 times higher in fetal tissues, with the exception of the brain and the pancreas. The brain showed the lowest GH concentration throughout fetal life and adulthood, whereas the highest GH levels were recorded in adults' pancreas, but they resulted to be artifacts since the RIA values were not confirmed by the IRMA test. In both groups of subjects the highest GH concentrations were found in kidneys, liver and small intestine; the lowest, beyond the brain, in red muscle and cartilage. Thus, the pattern of the quantitative distribution of GH in fetal tissues is the same as in adults, suggesting a functional role of the hormone in the developing human during the prenatal period, in contrast with the concept that high tissue levels of GH are a mere reflection of high GH blood levels. Moreover, in all tissues examined no correlation was found between GH and T4 concentration.     

The lack of interaction between transplanted human fetal pancreas and liver

Trophism between transplanted hepatocytes and pancreatic endocrine tissue has been demonstrated with both adult and late gestational fetal tissue. Since this effect has not been looked for with fetal tissue obtained early in pregnancy, we conducted a series of experiments transplanting human liver and pancreas, which was obtained early in the second trimester (15-20 weeks gestation), beneath the renal capsule of athymic mice. Fetal pancreatic explants increased in size after transplantation into nondiabetic mice, but their insulin content 11 weeks later was not different from that of grafts that included liver explants. Reversal of diabetes was achieved in 2 of 5 diabetic mice transplanted with pancreas alone, but none of the mice that received pancreas and liver became normoglycemic. Histological examination of grafted liver explants, which consist of hepatocytes and hematopoietic cells, showed that hepatocytes survived for only two weeks regardless of the presence of pancreatic explants. Bile ducts differentiated by this time in both groups and were still present at 7 weeks. In conclusion, there was no trophic effect observed between transplanted fetal human liver and pancreatic endocrine tissue obtained early in pregnancy; bile duct differentiation is a feature of fetal human liver xenografted into the athymic mouse.     

Cellular distribution and ontogeny of insulin-like growth factors (IGFs) and IGF binding protein messenger RNAs and peptides in developing rat pancreas

To determine the role of insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) in the development of the pancreas, and specifically of the islets of Langerhans, we have examined the cellular distribution and developmental changes in the expression of IGFs and IGFBPs in the pancreas of the fetal and neonatal rat between 19.5 days of gestation and postnatal day 28. This represents a period of substantial growth and restructuring of the beta cell component in islets of this species. IGF-I, IGF-II, and IGFBPs-1 to -6 mRNAs were localized by in situ hybridization, and peptides by immunohistochemistry, in histological sections. IGF-II mRNA was highly expressed in islet cells and some ductal epithelial cells in late fetal and early neonatal life, but was barely detectable by postnatal day 28. IGF-II peptide showed a similar distribution. IGF-I mRNA was barely detected in the fetus or neonate and was localized predominantly in the ductal and acinar tissues after postnatal day 7. IGF-I immunoreactivity was associated with some islet cells in the fetus and neonate, suggesting an endocrine rather than a paracrine source. We performed co-localization studies to assess whether the distribution of IGFs within the pancreas might be due to a sequestration by locally produced IGFBPs. The presence of mRNAs for both IGFBPs-1 and -2 was minimal in the pancreas prior to postnatal day 7, although subsequently IGFBP-1 mRNA was seen in islet cells, while IGFBP-2 mRNA was localized in both islets and acinar tissues. In contrast, both IGFBPs-1 and -2 immunoreactivities were identified in islets from late fetal life, suggesting a circulatory source for these IGFBPs during early pancreatic development. IGFBPs-3 to -5 mRNAs and immunoreactivities were identified within islet cells throughout fetal and neonatal life, with IGFBPs-3 and -5 being mainly associated with the alpha cell-rich islet mantle. The results show a compartmentalization of IGFs within pancreatic tissue, reflecting both paracrine and endocrine sources. The localization and action of IGFs in pancreas likely involves sequestration and distribution by endogenous as well as circulating IGFBPs.     

Ontogeny of insulin-like growth factors (IGF), IGF binding proteins, IGF receptors, and growth hormone receptor mRNA levels in porcine pancreas

We examined the ontogeny of mRNA levels of IGF-I and -II, IGF type 1 (IGFI-R) and type II receptors (IGFII-R), IGF binding protein-1 and -3 (IGFBP-1 and -3), GH receptor (GHR), and tissue concentrations of IGF and IGFBP in the pancreas of pigs. Tissues were collected from fetuses at 90 and 110 d of gestation and from pigs at 1, 21, 90 and 180 d of age. Northern blots were performed using total RNA hybridized with 32P-labeled cDNA probes (human IGF-I and human IGFI-R) and cRNA probes (rat IGF-II, human IGFII-R, human IGFBP-1, pig IGFBP-3, and pig GHR). There were two accelerated growth stages of the pancreas: the first one at 90 d of fetal life, which is characterized by cell hyperplasia (high ratio of DNA to body weight), and the second one at postnatal 90 d, which is attributed to cell hypertrophy (high ratios of pancreatic weight, RNA, and protein to DNA). The level of IGF-II mRNA and its tissue concentration were predominant during fetal life and low thereafter. The IGF-I mRNA level was high during fetal and early postnatal life and decreased thereafter. Messenger RNA levels of IGFI-R, IGFBP-3, and GHR and concentrations of IGFBP-1 and -2 were abundant during fetal and early postnatal life. In conclusion, IGF may be involved in various physiological periods of pancreatic development in pigs.     

Expression of type 2 11beta-hydroxysteroid dehydrogenase and corticosteroid hormone receptors in early human fetal life

In adult life, the type 2 isozyme of 11beta-hydroxysteroid dehydrogenase (11betaHSD2) protects the mineralocorticoid receptor (MR) from glucocorticoid by inactivating cortisol to cortisone. 11betaHSD2 activity has been reported in human fetal tissues, where glucocorticoids may impair fetal growth yet are also required for normal fetal development. Using digoxigenin-labeled complementary ribonucleic acid (RNA) probes and an in-house 11betaHSD2 antiserum, we have analyzed the expression of 11betaHSD2, MR, and glucocorticoid receptor (GR) in human fetal tissues of gestational age 6-17 weeks (n=15). 11BetaHSD2 expression was absent at gestational age 6+ weeks, but was expressed in abundance in many fetal tissues between 8-12 weeks. At this time, 11betaHSD2 colocalized with GR messenger RNA (mRNA) expression in metanephros, gut, muscle, spinal cord and dorsal root ganglia, periderm, sex chords of testis, and adrenal. In particular within fetal kidney, intense expression of 11betaHSD2 and GR mRNA was observed over Bowman's capsule and the vascular tufts of developing glomeruli as they migrated from the surface of the kidney to the inner cortex. Only lung and adrenal medullary rests demonstrated high levels of GR mRNA but low levels of 11betaHSD2. 11BetaHSD2 mRNA and immunoreactivity staining patterns were similar, with the exception of the fetal adrenal, where mRNA was localized to the outer definitive zone but immunoreactivity was localized to the inner fetal zone. Colocalization of 11betaHSD2 (and GR mRNA) with MR mRNA was observed principally within epithelial cells of collecting ducts, particularly after 16 weeks gestation when the pattern of distribution of 11betaHSD2 became more adult in nature. High levels of MR mRNA were observed within developing bone. The data indicate that 11betaHSD2 in fetal life principally modulates ligand access to the GR in most fetal tissues, notably glomeruli and tubules in the developing kidney, testis, and periderm, and this may be have ramifications for fetal sodium homeostasis and differentiation. The development of tissues previously shown to have a critical requirement for glucocorticoids, such as lung and adrenal medulla, is facilitated by the expression of GR mRNA, but not 11betaHSD2. The expression of MR mRNA in high abundance in bone suggests a role for corticosteroids in human bone development, and the low/absent expression of 11betaHSD2 at this site suggests that it is functionally acting as a GR.     

Studies on human sexual development. V. Concentrations of testosterone, 17-hydroxyprogesterone and progesterone in human amniotic fluid throughout gestation

Concentrations of unconjugated testosterone, 17-hydroxyprogesterone (170HP) and progesterone were measured by radioimmunoassay in amniotic fluid (AF) specimens from normal pregnancies of 9-40 weeks gestation. In two-thirds of samples from pregnancies with male fetuses. AF testosterone exceeded the upper limit found in female samples, with minimal overlap in the 12-18 week period of gestation. Although AF testosterone levels associated with male and female fetuses were both significantly lower toward term, the sex-difference persisted. Between 9-19 weeks gestation, fetal sex was also found to influence AF 170HP, a steroid thought to be predominantly of placental and fetal adrenal origin; in this case, female levels exceeded male. Awareness of the influence of sex and gestation upon AF concentrations of these steroids is an important prerequisite for their application to the prenatal diagnosis of endocrine disease (e.g., congenital adrenal hyperplasia). There was no sex difference in AF progesterone concentrations at 12-18 weeks gestation. The median progesterone concentration at 34-40 weeks was higher with female fetuses, but this difference may be related to a difference in gestational age between AF samples obtained from male and female fetuses.     

Maturational effects of cortisol on the exocrine abomasum and pancreas in fetal sheep

The role of cortisol in the prenatal development of digestive enzymes in the abomasum (prochymosin and pepsinogen) and pancreas (amylase, trypsin, chymotrypsin) has been investigated in the fetal lamb during late gestation. The abomasum and pancreas were collected from 22 unoperated control fetuses (99-145 days gestation; term, 145 +/- 2 days), from seven pairs of twins infused with either saline or cortisol for five days preceding delivery at 127-133 days, and from four 139-143-day-old fetuses adrenalectomized at 120-123 days. Developmental increases (2-8-fold) occurred in protease concentrations in the fetal abomasum and in amylase and chymotrypsin contents in the fetal pancreas. These increases paralleled the normal prepartum rise in fetal plasma cortisol. In addition, the enzyme values were significantly higher in cortisol-infused than in saline-infused fetuses (with the exception of pancreatic amylase) and were significantly lower in adrenalectomized fetuses than in control fetuses at term. The pH of abomasal fluid remained neutral (pH 6.8-8.0) during late gestation and was not affected by cortisol treatment or adrenalectomy. The results suggest that cortisol stimulates the development of the exocrine abomasum and pancreas in fetal sheep and may, thereby, increase the digestive capacity in neonatal lambs. Compared with the pig, another long-gestation species, the sheep has an early development of gastric pepsinogen but a late development of gastric acidity and pancreatic protease activities.     

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The major problem in using fetal sheep pancreas as a transplantable source of insulin-producing cells to reverse diabetes is that beta cells do not differentiate well. Glucotoxicity is a potential explanation for this because the blood glucose level of recipient mice is higher than that of fetal sheep (7 vs. 1.5 mM). To test the effect of approximating these fetal conditions blood glucose levels of recipient athymic mice were lowered for 4 weeks from 7.3 +/- 1.6 mM to a nadir of 3.7 +/- 1.7 mM by administration of insulin pellets. This resulted in a 2.7-fold increase in the percentage of beta cells and a 5.9-fold increase in the number of glucagon-containing alpha cells. The increase in endocrine cells was probably due to improved formation from undifferentiated cells, but greater proliferation of the mature cells is also a possibility. The effect was transient with endocrine cell numbers diminishing once the effect of insulin administration ceased. It is concluded that while transplanted fetal sheep pancreas may not be suitable for reversal of diabetes, it is a useful model for studying how pancreatic endocrine cells develop.     

Immunocytochemical studies on endocrine cells of alimentary tract of the pig in the embryonic and fetal period of life

The study aimed at immunocytochemical analysis of alimentary tract endocrine cells between 20th day of embryonal life and 105th day of fetal life of domestic pig. In the pancreas, presence of endocrine cells was detected already in 20th day and, at the time, the cells comprised around 3/4 all cells in primordia of the organ. Starting at that time, numerous endocrine cells produced insulin and glucagon and individual cells synthesized somatostatin and pancreatic polypeptide. In the 20th day, stomach and duodenum contained single endocrine cells but hormone production was not detected until days 27 and 30. Beginning from this days, both organs manifested rapid increase in the number of gastrin-producing cells. In each of the three organs, the number of somatostatin-producing cells exhibited most extensive changes.     

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OBJECTIVE: To evaluate the etiology and outcome of fetal hydrops of nonimmune origin diagnosed in utero during the first half of pregnancy. METHODS: We reviewed 45 cases of nonimmune fetal hydrops presenting between 11 and 17 weeks' gestation over a 4-year period. RESULTS: The median gestational age at diagnosis of fetal hydrops was 14 weeks. Placental edema was most commonly associated with generalized skin edema. Ascites was also observed in four cases, but no case presented with pleural or pericardial effusion. The fetal karyotype was abnormal in 35 cases (77.8%). Of the ten fetuses with a normal karyotype, four were classified as idiopathic, three had isolated atrioventricular septal defect, two were associated with maternal infection, and one had multiple pterygium. Fetal heart rate anomalies were found in both chromosomally normal and abnormal fetuses. All but one of the karyotypically abnormal pregnancies and five of ten euploid pregnancies were terminated. In all six pregnancies that continued, resolution occurred before mid-gestation. Three continuing euploid pregnancies resulted in fetal death, and only two had a normal outcome. CONCLUSION: Nonimmune fetal hydrops diagnosed before 18 weeks' gestation is associated with a higher incidence of aneuploidy than hydrops diagnosed during the second half of pregnancy. In most affected fetuses with a normal karyotype, spontaneous resolution occurred before 24 weeks' gestation, although the outcome was generally unfavorable.     

Levels of corticotropin-releasing hormone messenger ribonucleic acid (mRNA) in the hypothalamic paraventricular nucleus and proopiomelanocortin mRNA in the anterior pituitary during late gestation in fetal sheep

CRH regulates POMC gene expression and subsequent ACTH biosynthesis and release. In sheep, the preterm rise in fetal plasma ACTH commences at approximately 125 days gestation (dGA; 147 dGA = term), preceding the initiation of adrenocortical steroidogenesis. We hypothesized that an increase in CRH expression in the hypothalamic paraventricular nucleus (PVN) and POMC expression in the anterior pituitary in the late gestation sheep fetus may precede adrenal cortex maturation. Fetal sheep were obtained at 105-107 (n = 4), 128-130 (n = 5), and 138-140 (n = 4) dGA. Hypothalami were cryosectioned and subjected to in situ hybridization for ovine CRH mRNA. In all dGA groups, expression of CRH mRNA was observed throughout the rostrocaudal extent of the fetal PVN. The midrostral region of the fetal PVN where the dorsal and ventral divisions of the rostral PVN merge to form a single structure was selected for quantification. The number of copies of CRH probe hybridized per micron 3 were determined to estimate the quantity of hybridized CRH mRNA; the mean estimated CRH mRNA copy number per micron 3 midrostral PVN were 0.064 +/- 0.012 (105-107 dGA), 0.237 +/- 0.048 (128-130 dGA), and 0.108 +/- 0.034 (138-140 dGA; mean +/- SEM copies per micron 3 PVN). CRH mRNA signal significantly increased between 105-107 and 128-130 dGA (P < or = 0.05); 138-140 dGA levels of mRNA were not different from either 105-107 or 128-140 dGA levels. Regional variation in CRH mRNA levels were observed within the midrostral PVN between groups; at 138-140 dGA, a population of lateral midrostral PVN neurons maintain CRH mRNA levels greater than 105-107 dGA (P < 0.05), similar to those at 128-130 dGA. Fetal anterior pituitary RNA was subjected to Northern analysis for POMC mRNA. POMC mRNA levels in fetal anterior pituitaries were 14.1 +/- 2.2 (105-107 dGA), 28.9 +/- 10.9 (128-130 dGA), and 43.2 +/- 6 (138-140 dGA; mean +/- SEM arbitrary units). A significant increase (P < or = 0.05) was observed at 138-140 dGA compared to levels at 105-107 dGA. We conclude CRH mRNA levels in the fetal PVN increase coincident with increased POMC gene expression and the late gestation rise in fetal plasma ACTH. We speculate that a neuroendocrine stimulus at the fetal PVN may precipitate increased levels of CRH mRNA, initiating the maturation of the fetal hypothalamic-hypophyseal-adrenal axis, thus inducing the events of labor and delivery in sheep.     

Fetal thyroid function

Cordocentesis has permitted the study of fetal thyroid function. In normal pregnancy, fetal blood thyroid-stimulating hormone (TSH), thyroid hormones and thyroid-binding globulin increase with advancing gestation demonstrating functional maturation of the pituitary, thyroid and liver, respectively. The administration of thyroid-releasing hormone to the mother produces a rapid increase in fetal TSH from at least 25 weeks gestation. In hypoxemic growth-retarded fetuses, the concentrations of TSH are higher, and the concentrations of total and free thyroxine are lower than in appropriately grown fetuses. In anemic fetuses from red cell-isoimmunized pregnancies, serum TSH and thyroid hormone concentrations are increased. In some chromosomally abnormal fetuses, particularly those with trisomy 21, TSH is increased.     

Effects of sustained hypoxaemia with 72 hours recovery on 11beta-hydroxysteroid dehydrogenase types 1 and 2 gene expression in near-term fetal sheep

The study examined the effects of 8 h sustained hypoxaemia, with 72 h recovery, on the expression of 11beta-hydroxysteroid dehydrogenase (11beta-HSD) types 1 and 2 in near-term fetal sheep. Placental tissue and fetal liver and kidney were collected at Days 135-138 gestation 72 h after 8 h sustained hypoxaemia induced by lowering maternal inspired oxygen with (n = 9) and without (n = 6) metabolic acidosis or after 8 h normoxia (n = 6). In hypoxic fetuses with metabolic acidosis, a significant increase in the level of 11beta-HSD2 mRNA in the kidney compared with controls was correlated significantly with degree of associated fetal acidaemia, but there were no corresponding increases in the tissue level of 11beta-HSD2 activity. Hence, a time lag may exist between the mRNA and activity. Alternatively, the translation of 11beta-HSD2 mRNA may be inhibited. In contrast, levels of 11beta-HSD1 mRNA in the placenta and fetal liver were unchanged 72 h after sustained hypoxaemia. These results indicate that sustained fetal hypoxaemia with metabolic acidosis selectively up-regulates 11beta-HSD2 mRNA expression in the near-term fetal sheep kidney. This may be a re-bound effect at 72 h following an initial down-regulation as observed in a previous study.     

Pregnancy-specific alterations in the expression of the insulin-like growth factor system during early placental development in the ewe

The placenta is recognized as an important determinant of fetal growth rate, yet the factors regulating its proliferation remain poorly understood. Components of the insulin-like growth factor (IGF) system were localized in the ovine uterus using in situ hybridization between days 13-55 of gestation, the period of implantation and placentome formation. IGF-II messenger RNA (mRNA) expression was intense in the fetal mesoderm, particularly at the tips of the invading placentome villi. Moderate levels of IGF-II mRNA were also observed in the maternal caruncular stroma. In contrast, expression of IGF-1 mRNA was low (compared to estrous levels) and ubiquitous decreasing as gestation advanced. IGF-binding protein-2 (IGFBP-2 mRNA was not detected until day 29 of gestation, when it appeared restricted to the dense caruncular-like stroma lining the luminal epithelium, colocalized with IGFBP-4. High concentrations of IGFBP-4 mRNA expression were also found in the placentome capsule. IGFBP-3 mRNA expression was intense in the luminal epithelium between days 13-15 of gestation. Subsequently, levels in this region dropped significantly (P < 0.001). IGFBP-3 mRNA expression was also high in the maternal placentome villi, where photographic emulsions localized expression to blood vessel walls. Peak expression of IGF type 1 receptor (IGF-1R) mRNA was found in the deep uterine glands, with intermediate expression in the superficial uterine glands. Moderate expression of IGF-1R mRNA was initially recorded in caruncular stroma, but levels in this region decreased significantly (P < 0.001) to below the detection limit of the technique after interdigitation by the fetal allantochorion. Furthermore, IGF-1R mRNA could not be detected in any fetal placentome tissue. This study, therefore, has established the pattern of expression of the IGFs, IGF-1R, and three of the IGFBPs during establishment of the ovine placenta. It will form the basis for future work to investigate how this system is regulated and to determine the role of the IGFs in placental development.     

Physical mapping of the t(12;22) translocation breakpoints in a family with a complex type of 3/3''/4 synpolydactyly

Stress during gestation can have serious consequences on the development of the fetus. Many of these effects appear to be mediated by hormones of the hypothalamic-pituitary-adrenal (HPA) axis. Corticotropin-releasing factor (CRF), released by the hypothalamus during times of stress serves to activate release of pituitary hormones and is also present in low levels in rat plasma. Moreover, the uterus contains significant quantities of CRF at implantation sites, probably from local sources. Therefore, the possibility exists that CRF may cross the placenta and activate the fetal HPA axis. However, the ability of CRF to cross the placenta has not been demonstrated. In the present study, pregnant rats were administered radiolabeled CRF intraperitoneally, and the distribution of the labeled product was determined in the fetuses and various maternal organs. High levels of activity were observed in the pregnant female's uterus, adrenals, heart and the placentae, but only background levels of activity were detected in the maternal brain. Very low levels of activity were observed in the fetuses, indicating that the transfer of CRF across the placenta is greatly restricted. These findings suggest that maternal CRF has little or no direct effect on the developing fetus during gestational stress.     

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This study was designed to determine the effects of hypothyroidism during late fetal life in pigs on (1) the perinatal pattern of plasma levels of thyroxine (TT4), total 3,5,3'-triiodothyronine (TT3) and free T3 (FT3), and liver 5'-deiodinase activity, and (2) the early postnatal development of thermoregulation. Fetal hypothyroidism (test animals) was induced by feeding the sow a high glucosinolate rapeseed diet. Plasma levels of thyroid hormones, thyroid gland weights and liver 5'-deiodinase activity of control animals increased during late gestation (P < 0.01). The early postnatal period was characterized by a surge in thyroid hormone levels during the first 6 h (P < 0.05), followed by a transient decrease at 12 h and a second rise by 24 h after birth. This surge was much higher (P < 0.01) for TT3 than for TT4, but liver 5'-deiodinase activity did not change during the first 24 h of life. Fetal hypothyroidism was characterized by lower plasma levels of thyroid hormones (P < 0.05), and lower hepatic 5'-deiodinase activities (P < 0.01) than in control fetuses at 110 d of gestation. During the first 6 h of life, test pigs had lower levels of TT4 (P < 0.05) but exhibited a greater postnatal surge in TT3 and FT3 (P < 0.05) than did the controls. The minimal and summit metabolism of the control pigs increased markedly (P < 0.01) during the first 2 d of life, without any significant change in thermal body conductance, suggesting that this age-related improvement in thermoregulation was due to the development of the ability to produce heat.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of in utero cocaine exposure on the expression of mRNAS encoding the dopamine transporter and the D1, D2 and D5 dopamine receptor subtypes in fetal rhesus monkey

The effects of in utero cocaine exposure on the development of the mRNAs encoding the dopamine transporter (DAT) and the D1, D2 and D5 dopamine receptor subtypes were determined in fetal monkey brains at day 45 and day 60 of gestation. Pregnant monkeys were treated with cocaine 3 mg/kg or saline i.m., four times a day from day 18 of gestation until the pregnancy was terminated at day 45 or day 60. The fetal brains were dissected, and tissue RNA extracted and quantified using ribonuclease protection assay analysis. In day 45 fetal monkeys, dopamine D1 and D2 receptor subtype mRNAs and DAT mRNA were found in low quantities both in control and cocaine-treated subjects. In day 60 fetal monkeys, D1 receptor mRNA levels were highest in the frontal cortex/striatal area, and low to moderate quantities were found in diencephalic and mesencephalic fetal brain regions. Dopamine D2 receptor mRNA levels were highest in the frontal cortex/striatal area, diencephalon and the midbrain, moderate in the brainstem and low in the caudal temporal lobe and surrounding cortical areas. Dopamine D5 receptor mRNA was expressed in low quantities throughout the day 60 fetal monkey brain, whereas DAT mRNA was found in the midbrain only. In utero cocaine exposure caused a significant increase in dopamine D1, D2 and D5 receptor subtype mRNAs in the frontal cortex/striatal area of day 60 fetal monkeys. These results support the hypothesis that dopamine synthesis and release may be reduced in cocaine-treated fetuses, which results in dopamine receptor up-regulation.