Alpha-Fetoprotein: From a Diagnostic Biomarker to a Key Role in Female Fertility

Alpha-fetoprotein (AFP) is a well-known diagnostic biomarker used in medicine to detect fetal developmental anomalies such as neural tube defects or Down’s syndrome, or to follow up the development of tumors such as hepatocellular carcinomas. However, and despite the fact that the protein was discovered almost half a century ago, little was known about its physiological function. The study of Afp knock-out mice uncovered a surprising function of AFP: it is essential for female fertility and for expression of normal female behaviors, and this action is mediated through its estrogen binding capacity. AFP sequestrates estrogens and by so doing protects the female developing brain from deleterious (defeminizing/masculinizing) effects of these hormones

Alpha-fetoprotein controls female fertility and prenatal development of the gonadotropin-releasing hormone pathway through an antiestrogenic action

peer reviewedIt has been shown previously that female mice homozygous for an alpha-fetoprotein (AFP) null allele are sterile as a result of anovulation, probably due to a defect in the hypothalamic-pituitary axis. Here we show that these female mice exhibit specific anomalies in the expression of numerous genes in the pituitary, including genes involved in the gonadotropin-releasing hormone pathway, which are underexpressed. In the hypothalamus, the gonadotropin-releasing hormone gene, Gnrh1, was also found to be down-regulated. However, pituitary gene expression could be normalized and fertility could be rescued by blocking prenatal estrogen synthesis using an aromatase inhibitor. These results show that AFP protects the developing female brain from the adverse effects of prenatal estrogen exposure and clarify a long-running debate on the role of this fetal protein in brain sexual differentiation

Etude de la fonction de l'alpha-foetoprotéine

L’alpha-foetoprotéine (AFP) est la protéine majoritaire du sérum fœtal de mammifère. C’est une glycoprotéine produite et sécrétée par l’endoderme viscéral du sac vitellin, les hépatocytes fœtaux et dans une moindre mesure, par l’intestin fœtal. Son profil d’expression est onco-fœtal :la synthèse de cette protéine chute fortement après la naissance mais peut reprendre en cas de régénération hépatique ou en cas de tumeurs diverses. Cette protéine est capable de fixer les oestrogènes et jouerait un rôle dans la différenciation sexuelle du cerveau femelle.\Doctorat en sciences, Spécialisation biologie moléculaireinfo:eu-repo/semantics/nonPublishe

Etude de la fonction de l'alpha-foetoprotéine

L’alpha-foetoprotéine (AFP) est la protéine majoritaire du sérum fœtal de mammifère. C’est une glycoprotéine produite et sécrétée par l’endoderme viscéral du sac vitellin, les hépatocytes fœtaux et dans une moindre mesure, par l’intestin fœtal. Son profil d’expression est onco-fœtal :la synthèse de cette protéine chute fortement après la naissance mais peut reprendre en cas de régénération hépatique ou en cas de tumeurs diverses. Cette protéine est capable de fixer les oestrogènes et jouerait un rôle dans la différenciation sexuelle du cerveau femelle.\Doctorat en sciences, Spécialisation biologie moléculaireinfo:eu-repo/semantics/nonPublishe

Alpha-foetoprotein: It's all about timing

Alpha-foetoprotein (AFP) is a well known diagnostic biomarker used in medicine to detect foetal developmental anomalies such as neural tube defects or Down's syndrome, or to follow the development of tumors such as hepatocellular carcinomas. However, the role of AFP goes way further than that. AFP is involved at least in rodents in the correct differentiation of the female brain, through its estrogen binding capacity. This chapter present an overview of what is known about the regulation of the Afp gene, describes the phenotype of the AFP knock-out (AFP KO) mouse and offers an overview of other mouse models available to study estrogen function. Being in the right place, at the right time, is a key factor for alpha-foetoprotein (AFP). Firstly, because it is involved in major events occurring during narrow timewindows, such as sexual differentiation of the female brain. Secondly, because AFP is expressed in an onco-foetal way. © 2009 Nova Science Publishers, Inc. All rights reserved.SCOPUS: ch.binfo:eu-repo/semantics/publishe

Hypothalamic Expression Of Oestrogen Receptor Alpha And Androgen Receptor Is Sex, Age And Region Dependent In Mice.

Sex steroid hormones act on developing neural circuits regulating the hypothalamic-pituitary-gonadal axis and are involved in hormone-sensitive behaviours. These hormones act mainly via nuclear receptors, i.e. oestrogen receptor-alpha (ERalpha) and androgen receptor (AR). By using immunohistochemistry, we analysed the expression level of ERalpha and AR throughout perinatal life [at embryonic (E) day 19 and postnatal (P) days 5-15-25] and in adulthood in several hypothalamic nuclei controlling reproduction in both wild-type (WT) and aromatase knockout (ArKO) (which cannot convert testosterone into oestradiol) mice to determine whether there are sex differences in hypothalamic ERalpha and AR expression and if so, whether these are established by oestradiol action. As early as E19, ERalpha immunoreactivity (-ir) was observed at same expression levels in both sexes in the anteroventral periventricular nucleus (AVPv), the medial preoptic area (MPOA), the bed nucleus of the stria terminalis (BnST), the ventrolateral part of the ventromedial hypothalamic nucleus (VMHvl) and the arcuate nucleus (ARC). Sex differences (female > male) in ERalpha-ir were only observed during the prepubertal period in the BnST (P5 to P25) and the MPOA (P15), but also in adulthood in these two brain regions. Sex differences in AR-ir (male > female) were observed at P5 in the AVPv and ARC, and at P25 in the MPOA and ARC as well as in adulthood in all hypothalamic regions analysed. In adulthood, gonadectomy and hormonal treatment (oestradiol or dihydrotestosterone) also strongly modulated ERalpha-ir and AR, respectively. Taken together, sex differences in ERalpha-ir and AR-ir were observed in all hypothalamic regions analysed, but most likely do not reflect oestradiol actions since ArKO mice of both sexes showed very similar expression levels as WT mice throughout perinatal development. This article is protected by copyright. All rights reserved

Rôle clé de l’alpha-foetoprotéine dans la fertilité

info:eu-repo/semantics/publishe

Exposure to oestrogen prenatally does not interfere with the normal female-typical development of odour preferences.

The neural mechanisms controlling mate recognition and heterosexual partner preference are sexually differentiated by perinatal actions of sex steroid hormones. We previously showed that the most important action of oestrogen during prenatal development is to defeminise and, to some extent, masculinise brain and behaviour in mice. Female mice deficient in alpha-foetoprotein (AFP) due to a targeted mutation in the Afp gene (AFP-KO) do not show any female sexual behaviour when paired with an active male because they lack the protective action of AFP against maternal oestrogens. In the present study, we investigated whether odour preferences, another sexually differentiated trait in mice, are also defeminised and/or masculinised in AFP-KO females due to their prenatal exposure to oestrogens. AFP-KO females of two background strains (CD1 and C57Bl/6j) preferred to investigate male over female odours when given the choice between these two odour stimuli in a Y-maze, and thus remained very female-like in this regard. Thus, the absence of lordosis behaviour in these females cannot be explained by a reduced motivation of AFP-KO females to investigate male-derived odours. Furthermore, the presence of a strong male-directed odour preference in AFP-KO females suggests a postnatal contribution of oestrogens to the development of preferences to investigate opposite-sex odours.Comparative StudyJournal ArticleResearch Support, N.I.H. ExtramuralResearch Support, Non-U.S. Gov'tFLWINinfo:eu-repo/semantics/publishe

Association between resistance to mammary cancer development and upregulation of DNA damage response genes

info:eu-repo/semantics/publishe