Publisher Correction: Dibutyl phthalate induced testicular dysgenesis originates after seminiferous cord formation in rats.

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Effects of Exposure to Acetaminophen and Ibuprofen on Fetal Germ Cell Development in Both Sexes in Rodent and Human Using Multiple Experimental Systems.

Background: Analgesic exposure during pregnancy may affect aspects of fetal gonadal development that are targeted by endocrine disruptors.

Objectives: We investigated whether therapeutically relevant doses of acetaminophen and ibuprofen affect germ cell (GC) development in human fetal testes/ovaries using and xenograft approaches.

Methods: First-trimester human fetal testes/ovaries were cultured and exposed to acetaminophen or ibuprofen (7 d).

Dibutyl phthalate induced testicular dysgenesis originates after seminiferous cord formation in rats.

Administration of dibutyl phthalate (DBP) to pregnant rats causes reproductive disorders in male offspring, resulting from suppression of intratesticular testosterone, and is used as a model for human testicular dysgenesis syndrome (TDS). DBP exposure in pregnancy induces focal dysgenetic areas in fetal testes that appear between e19.5-e21.

Experimentally induced testicular dysgenesis syndrome originates in the masculinization programming window.

The testicular dysgenesis syndrome (TDS) hypothesis, which proposes that common reproductive disorders of newborn and adult human males may have a common fetal origin, is largely untested. We tested this hypothesis using a rat model involving gestational exposure to dibutyl phthalate (DBP), which suppresses testosterone production by the fetal testis. We evaluated if induction of TDS via testosterone suppression is restricted to the "masculinization programming window" (MPW), as indicated by reduction in anogenital distance (AGD).

Analgesic exposure in pregnant rats affects fetal germ cell development with inter-generational reproductive consequences.

Analgesics which affect prostaglandin (PG) pathways are used by most pregnant women. As germ cells (GC) undergo developmental and epigenetic changes in fetal life and are PG targets, we investigated if exposure of pregnant rats to analgesics (indomethacin or acetaminophen) affected GC development and reproductive function in resulting offspring (F1) or in the F2 generation. Exposure to either analgesic reduced F1 fetal GC number in both sexes and altered the tempo of fetal GC development sex-dependently, with delayed meiotic entry in oogonia but accelerated GC differentiation in males.

Comparative effects of di(n-butyl) phthalate exposure on fetal germ cell development in the rat and in human fetal testis xenografts.

Background: Phthalate exposure induces germ cell effects in the fetal rat testis. Although experimental models have shown that the human fetal testis is insensitive to the steroidogenic effects of phthalates, the effects on germ cells have been less explored.

Objectives: We sought to identify the effects of phthalate exposure on human fetal germ cells in a dynamic model and to establish whether the rat is an appropriate model for investigating such effects.

Fetal programming of adult Leydig cell function by androgenic effects on stem/progenitor cells.

Fetal growth plays a role in programming of adult cardiometabolic disorders, which in men, are associated with lowered testosterone levels. Fetal growth and fetal androgen exposure can also predetermine testosterone levels in men, although how is unknown, because the adult Leydig cells (ALCs) that produce testosterone do not differentiate until puberty. To explain this conundrum, we hypothesized that stem cells for ALCs must be present in the fetal testis and might be susceptible to programming by fetal androgen exposure during masculinization.

Diethylstilboestrol exposure does not reduce testosterone production in human fetal testis xenografts.

In rodents, in utero exposure to exogenous estrogens including diethylstilboestrol (DES) results in major suppression of steroidogenesis in fetal testes. Whether similar effects occur in the human fetal testis is equivocal. Based on the results of the rodent studies, we hypothesised that exposure of human fetal testes to DES would result in a reduction in testosterone production.

Identification of transcription factors and coactivators affected by dibutylphthalate interactions in fetal rat testes.

Previous analysis of in utero dibutylphthalate (DBP)-exposed fetal rat testes indicated that DBP's antiandrogenic effects were mediated, in part, by indirect inhibition of steroidogenic factor 1 (SF1), suggesting that peroxisome proliferator-activated receptor alpha (PPARα) might be involved through coactivator (CREB-binding protein [CBP]) sequestration. To test this hypothesis, we have performed chromatin immunoprecipitation (ChIP) microarray analysis to assess the DNA binding of PPARα, SF1, CBP, and RNA polymerase II in DBP-induced testicular maldevelopment target genes. Pathway analysis of expression array data in fetal rat testes examined at gestational day (GD) 15, 17, or 19 indicated that lipid metabolism genes regulated by SF1 and PPARα, respectively, were overrepresented, and the time dependency of changes to PPARα-regulated lipid metabolism genes correlated with DBP-mediated repression of SF1-regulated steroidogenesis genes.

In silico analysis identifies a novel role for androgens in the regulation of human endometrial apoptosis.

Context: The endometrium is a multicellular, steroid-responsive tissue that undergoes dynamic remodeling every menstrual cycle in preparation for implantation and, in absence of pregnancy, menstruation. Androgen receptors are present in the endometrium.

Objective: The objective of the study was to investigate the impact of androgens on human endometrial stromal cells (hESC).

A Role for the orphan nuclear receptor estrogen-related receptor alpha in endometrial stromal cell decidualization and expression of genes implicated in energy metabolism.

Context: Differentiation (decidualization) of endometrial stromal cells (ESC) is an essential prerequisite for successful implantation and establishment of pregnancy.

Objective: The aim was to determine whether the orphan nuclear receptor estrogen-related receptor α (ERRα, NR3B1), and its target genes, medium chain specific acyl-CoA dehydrogenase (MCAD, ACADM), pyruvate dehydrogenase kinase 4 (PDK4), and phosphoenolpyruvate carboxykinase 2 (PEPCK, PCK2), play a role in the decidualization process.

Setting: We conducted the study at a University Research Institute.

Expression of oestrogen receptors, ERalpha, ERbeta, and ERbeta variants, in endometrial cancers and evidence that prostaglandin F may play a role in regulating expression of ERalpha.

Background: Endometrial cancer is the most common gynaecological malignancy; risk factors include exposure to oestrogens and high body mass index. Expression of enzymes involved in biosynthesis of oestrogens and prostaglandins (PG) is often higher in endometrial cancers when compared with levels detected in normal endometrium. Oestrogens bind one of two receptors (ERalpha and ERbeta) encoded by separate genes.

Estrogen receptor related beta is expressed in human endometrium throughout the normal menstrual cycle.

Background: Estrogen receptor related beta (ERRbeta, ESRRB/NR3B2) is an orphan receptor that shares significant sequence homology with estrogen receptors ERalpha and ERbeta. ERR family members are reported to exhibit constitutive transcriptional activity; however, little is known about the biological function of ERRbeta. In an attempt to delineate its role, we examined expression of ERRbeta in normal human endometrium, a tissue that undergoes cyclic remodelling under the influence of estrogen and progesterone.

Human oestrogen receptors: differential expression of ER alpha and beta and the identification of ER beta variants.

Two structurally related subtypes of oestrogen receptor (ER), known as alpha (ER alpha, NR3A1) and beta (ER beta, NR3A2) have been identified. ER beta mRNA and protein have been detected in a wide range of tissues including the vasculature, bone, and gonads in both males and females, as well as in cancers of the breast and prostate. In many tissues the pattern of expression of ER beta is distinct from that of ER alpha.

ERbeta1 and the ERbeta2 splice variant (ERbetacx/beta2) are expressed in distinct cell populations in the adult human testis.

Estrogens can regulate germ cell function. Estrogen action is mediated via high affinity ERs; two subtypes (ERalpha and ERbeta) have been identified. We have shown previously that ERbeta is expressed in nuclei of multiple human testicular cells.