Growth and sexual development are closely interlinked in fish; however, no reports exist on potential effects of estrogen on the GH/IGF-I-axis in developing fish. We investigate whether estrogen exposure during early development affects growth and the IGF-I system, both at the systemic and tissue level. Tilapia were fed from 10 to 40 days post fertilization (DPF) with 17a-ethinylestradiol (EE 2 ). At 50, 75, 90, and 165 DPF, length, weight, sex ratio, serum IGF-I (RIA), pituitary GH mRNA and IGF-I, and estrogen receptor a (ERa) mRNA in liver, gonads, brain, and gills (real-time PCR) were determined and the results correlated to those of in situ hybridization for IGF-I. Developmental exposure to EE 2 had persistent effects on sex ratio and growth. Serum IGF-I, hepatic IGF-I mRNA, and the number of IGF-I mRNA-containing hepatocytes were significantly decreased at 75 DPF, while liver ERa mRNA was significantly induced. At 75 DPF, a transient decline of IGF-I mRNA and a largely reduced number of IGF-I mRNA-containing neurons were observed in the female brain. In both sexes, pituitary GH mRNA was significantly suppressed. A transient downregulation of IGF-I mRNA occurred in ovaries (75 DPF) and testes (90 DPF). In agreement, in situ hybridization revealed less IGF-I mRNA signals in granulosa and germ cells. Our results show for the first time that developmental estrogen treatment impairs GH/IGF-I expression in fish, and that the effects persist. These long-lasting effects both seem to be exerted indirectly via inhibition of pituitary GH and directly by suppression of local IGF-I in organ-specific cells.

The aim of this study was to evaluate whether effects of environmental estrogens on fish growth and reproduction may be mediated via modulating the growth hormone (GH)/insulin-like growth factor I (IGF-I) system. To this end, developing male and female monosex populations of tilapia were exposed to 17alpha-ethinylestradiol (EE2) at 5 and 25 ng EE2/l water from 10-day postfertilization (DPF) until 100 DPF. Under exposure to both EE2 concentrations, sex ratio shifted toward more females and body length, and weight were significantly reduced in males. The growth-reducing effect was associated with significant changes in hepatic IGF-I expression, both in males and females and with significant alterations of IGF-I mRNA and GH mRNA in the brain. The changes in IGF-I and GH mRNA were accompanied by altered estrogen receptor alpha (ERalpha) expression in brain and liver. These findings point to an influence of estrogenic exposure on the endocrine GH/IGF-I axis. In addition, the EE2 treatment resulted in significant changes of ERalpha and IGF-I expression in ovaries and testis, suggesting that the estrogens interact not only with the endocrine but also with the autocrine/paracrine part of the IGF-I system. Overall, our results provide evidence that EE2 at environmentally relevant concentrations is able to interfere with the GH/IGF-I system in bony fish and that the impairing effects of estrogens reported on fish growth and reproductive functions may rather result from a cross talk between the sex steroid and the IGF-I system than be toxicological.

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Large egg size usually boosts offspring survival, but mothers have to trade off egg size against egg number. Therefore, females often produce smaller eggs when environmental conditions for offspring are favourable, which is subsequently compensated for by accelerated juvenile growth. How this rapid growth is modulated on a molecular level is still unclear. As the somatotropic axis is a key regulator of early growth in vertebrates, we investigated the effect of egg size on three key genes belonging to this axis, at different ontogenetic stages in a mouthbrooding cichlid (Simochromis pleurospilus). The expression levels of one of them, the growth hormone receptor (GHR), were significantly higher in large than in small eggs, but remarkably, this pattern was reversed after hatching: young originating from small eggs had significantly higher GHR expression levels as yolk sac larvae and as juveniles. GHR expression in yolk sac larvae was positively correlated with juvenile growth rate and correspondingly fish originating from small eggs grew faster. This enabled them to catch up fully in size within eight weeks with conspecifics from larger eggs. This is the first evidence for a potential link between egg size, an important maternal effect, and offspring gene expression, which mediates an adaptive adjustment in a relevant hormonal axis.

Context: Nonpancreatic tumors may cause recurrent hypoglycemia known as nonislet cell tumor hypoglycemia. It is due to overproduction and secretion by the tumor of incompletely processed IGF-II, termed big IGF-II. We recently identified a patient with recurrent hypoglycemia and low insulin, but without elevated big IGF-II. Multiple small lung nodules were detected by computed tomography scan. An undifferentiated large-cell carcinoma was diagnosed from an axillary lymph node metastasis. Objective:The objective was to investigate whether the patient's hypoglycemia was due to excessive IGF-I production by the tumor.Methods: Serum IGF-I and IGF-II, insulin, and GH were measured by RIA; the distribution of IGFs between IGF binding protein complexes in serum was analyzed after neutral gel filtration. Tissue IGF-I was identified by immunohistochemistry and in situ hybridization, and by RT-PCR after RNA extraction.Results: Total and free serum IGF-I, but not total, free, and big IGF-II, was increased, and the IGF-I content of the two IGF binding protein complexes was elevated. Immunohistochemistry demonstrated IGF-I peptide in situ hybridization IGF-I mRNA in the lymph node metastasis. Combined GH/glucocorticoid treatment prevented hypoglycemia, but did not lower IGF-I. After chemotherapy with carboplatinum/etoposide, the lung nodules largely regressed, and serum IGF-I and the IGF-I content of the two binding protein complexes became normal. Hypoglycemia did not recur despite discontinuation of GH/glucocorticoid treatment. Conclusion