A new experimental model for the investigation of sequential hermaphroditism

The stunning sexual transformation commonly triggered by age, size or social context in some fishes is one of the best examples of phenotypic plasticity thus far described. To date our understanding of this process is dominated by studies on a handful of subtropical and tropical teleosts, often in wild settings. Here we have established the protogynous New Zealand spotty wrasse, Notolabruscelidotus, as a temperate model for the experimental investigation of sex change. Captive fish were induced to change sex using aromatase inhibition or manipulation of social groups. Complete female-to-male transition occurred over 60 days in both cases and time-series sampling was used to quantify changes in hormone production, gene expression and gonadal cellular anatomy. Early-stage decreases in plasma 17β-estradiol (E2) concentrations or gonadal aromatase (cyp19a1a) expression were not detected in spotty wrasse, despite these being commonly associated with the onset of sex change in subtropical and tropical protogynous (female-to-male) hermaphrodites. In contrast, expression of the masculinising factor amh (anti-Müllerian hormone) increased during early sex change, implying a potential role as a proximate trigger for masculinisation. Collectively, these data provide a foundation for the spotty wrasse as a temperate teleost model to study sex change and cell fate in vertebrates.

Morphological and morphometric changes and epithelial apoptosis are induced in the rat epididymis by long-term letrozole treatment

The epididymis is an organ that plays a key role in sperm maturation. The aim of this study was to examine the association between the chronic treatment of mature male rats with letrozole and morphological evaluation and morphometric values of epididymis as well as changes in the number of apoptotic cells in epididymal epithelium. Adult rats were treated with letrozole for 6 months and the epididymis weight, morphology, morphometric values and the number of apoptotic cells in the epithelium were examined. Long-term aromatase inhibition resulted in presence of intraepithelial clear vacuoles, hyperplasia of clear cells and a hyperplastic alteration in the epithelium known as a cribriform change. Moreover, changes in diameters of the epididymal duct and the epididymal lumen and changes in the epididymal epithelium height were observed. The number of apoptotic epithelial cells was increased in letrozole-treated group. It can be indicated that chronic treatment with letrozole can affect morphology, morphometric values and apoptosis in the epididymis of adult male rats. Observed changes are similar to that observed in the aging processes and may also be important for patients treated with aromatase inhibitors.

ESR1 mutation as an emerging clinical biomarker in metastatic hormone receptor-positive breast cancer

In metastatic hormone receptor-positive breast cancer, ESR1 mutations are a common cause of acquired resistance to the backbone of therapy, estrogen deprivation by aromatase inhibition. How these mutations affect tumor sensitivity to established and novel therapies are active areas of research. These therapies include estrogen receptor-targeting agents, such as selective estrogen receptor modulators, covalent antagonists, and degraders (including tamoxifen, fulvestrant, and novel agents), and combination therapies, such as endocrine therapy plus CDK4/6, PI3K, or mTORC1 inhibition. In this review, we summarize existing knowledge surrounding the mechanisms of action of ESR1 mutations and roles in resistance to aromatase inhibition. We then analyze the recent literature on how ESR1 mutations affect outcomes in estrogen receptor-targeting and combination therapies. For estrogen receptor-targeting therapies such as tamoxifen and fulvestrant, ESR1 mutations cause relative resistance in vitro but do not clearly lead to resistance in patients, making novel agents in this category promising. Regarding combination therapies, ESR1 mutations nullify any aromatase inhibitor component of the combination. Thus, combinations using endocrine alternatives to aromatase inhibition, or combinations where the non-endocrine component is efficacious as monotherapy, are still effective against ESR1 mutations. These results emphasize the importance of investigating combinatorial resistance, challenging as these efforts are. We also discuss future directions and open questions, such as studying the differences among distinct ESR1 mutations, asking how to adjust clinical decisions based on molecular surveillance testing, and developing novel therapies that are effective against ESR1 mutations.

Assessment of androgenic response potential of effluents using in vitro and in vivo methods

The androgenic potential of a New Zealand pulp mill effluent (PME) and a Canadian PME was assessed along with a New Zealand sewage treatment plant effluent (STP) using a combination of in vivo and in vitro methods. The in vitro methods included: (1) a fish-based androgen receptor binding assay, (2) a fish-based aromatase inhibition activity assay, and (3) an analysis of gonadal sex steroid levels in exposed female mosquitofish ( Gambusia affinis ) ovaries by radioimmunoassay. The in vivo method included a quantifiable analysis of anal fin ray length for female mosquitofish exposed to the effluents. Effluent extracts for the Canadian PME and New Zealand STP were found to have low in vitro androgenic potential compared to upstream reference extracts. All effluent extracts (Canadian PME, New Zealand PME and STP) showed a low degree of in vitro aromatase inhibition potential compared to upstream reference extracts. In vivo analysis showed no androgenic potential of the New Zealand PME and STP. The in vitro androgen receptor assay and in vivo mosquitofish bioassay did show androgenic responses for androstenedione (AD) and 1,4-androsta-diene-3,17-dione (ADD), which are two products of the microbial conversion of β-sitosterol (a plant sterol commonly found in PME) by Mycobacterium smegmatis . Also, the potential of the mosquitofish bioassay to determine anti-androgenic effects in effluents was demonstrated.

Assessment of androgenic response potential of effluents using in vitro and in vivo methods

The androgenic potential of a New Zealand pulp mill effluent (PME) and a Canadian PME was assessed along with a New Zealand sewage treatment plant effluent (STP) using a combination of in vivo and in vitro methods. The in vitro methods included: (1) a fish-based androgen receptor binding assay, (2) a fish-based aromatase inhibition activity assay, and (3) an analysis of gonadal sex steroid levels in exposed female mosquitofish ( Gambusia affinis ) ovaries by radioimmunoassay. The in vivo method included a quantifiable analysis of anal fin ray length for female mosquitofish exposed to the effluents. Effluent extracts for the Canadian PME and New Zealand STP were found to have low in vitro androgenic potential compared to upstream reference extracts. All effluent extracts (Canadian PME, New Zealand PME and STP) showed a low degree of in vitro aromatase inhibition potential compared to upstream reference extracts. In vivo analysis showed no androgenic potential of the New Zealand PME and STP. The in vitro androgen receptor assay and in vivo mosquitofish bioassay did show androgenic responses for androstenedione (AD) and 1,4-androsta-diene-3,17-dione (ADD), which are two products of the microbial conversion of β-sitosterol (a plant sterol commonly found in PME) by Mycobacterium smegmatis . Also, the potential of the mosquitofish bioassay to determine anti-androgenic effects in effluents was demonstrated.