From Enrico Sertoli to freemartinism: the many phases of the master testis-determining cell†.

Sertoli cells, first identified in the adult testis by Enrico Sertoli in the mid-nineteenth century, are known for their role in fostering male germ cell differentiation and production of mature sperm. It was not until the late twentieth century with the discovery of the testis-determining gene SRY that Sertoli cells' new function as the master regulator of testis formation and maleness was unveiled. Fetal Sertoli cells facilitate the establishment of seminiferous cords, induce appearance of androgen-producing Leydig cells, and cause regression of the female reproductive tracts. Originally thought be a terminally differentiated cell type, adult Sertoli cells, at least in the mouse, retain their plasticity and ability to transdifferentiate into the ovarian counterpart, granulosa cells. In this review, we capture the many phases of Sertoli cell differentiation from their fate specification in fetal life to fate maintenance in adulthood. We also introduce the discovery of a new phase of fetal Sertoli cell differentiation via autocrine/paracrine factors with the freemartin characteristics. There remains much to learn about this intriguing cell type that lay the foundation for the maleness.

Constitutive expression of Steroidogenic factor-1 (NR5A1) disrupts ovarian functions, fertility, and metabolic homeostasis in female mice.

Steroid hormones regulate various aspects of physiology, from reproductive functions to metabolic homeostasis. Steroidogenic factor-1 (NR5A1) plays a central role in the development of steroidogenic tissues and their ability to produce steroid hormones. Inactivation of Nr5a1 in the mouse results in a complete gonadal and adrenal agenesis, absence of gonadotropes in the pituitary and impaired development of ventromedial hypothalamus, which controls glucose and energy metabolism. In this study, we set out to examine the consequences of NR5A1 overexpression (NR5A1+) in the NR5A1-positive cell populations in female mice. Ovaries of NR5A1+ females presented defects such as multi-oocyte follicles and an accumulation of corpora lutea. These females were hyperandrogenic, had irregular estrous cycles with persistent metestrus and became prematurely infertile. Furthermore, the decline in fertility coincided with weight gain, increased adiposity, hypertriglyceridemia, hyperinsulinemia, and impaired glucose tolerance, indicating defects in metabolic functions. In summary, excess NR5A1 expression causes hyperandrogenism, disruption of ovarian functions, premature infertility, and disorders of metabolic homeostasis. This NR5A1 overexpression mouse provides a novel model for studying not only the molecular actions of NR5A1, but also the crosstalk between endocrine, reproductive, and metabolic systems.

Management of Lobular Neoplasia Found on Core Needle Biopsy Performed for Calcifications Using Precise Radiologic-Pathologic Correlation.

OBJECTIVE. The purpose of our study was to evaluate the upgrade rate of calcified lobular neoplasia (LN) versus incidental noncalcified classic LN found on core needle biopsy performed for the evaluation of suspicious calcifications. MATERIALS AND METHODS. This retrospective study included 390 consecutive image-guided breast core needle biopsies with microcalcifications as the target that were performed between December 2009 and July 2017. In 81 of the 390 core biopsies, the highest-risk lesion was LN that then underwent either excision or imaging follow-up. Core biopsy results were compared with excision and imaging follow-up findings. An upgrade of LN was defined as ductal carcinoma in situ or invasive ductal or lobular carcinoma. RESULTS. Of 81 LN diagnosed on core biopsy performed for calcifications, 16 had calcifications within the LN. Fifteen of these 16 cases underwent surgical excision, and three (3/15, 20.0%) were upgraded on excision. Of the 64 core biopsies showing incidental noncalcified LN with benign concordant entities containing calcifications, 42 underwent surgical excision, and one LN (1/42, 2.4%) was upgraded. Twenty-three total lesions (one calcified LN and 22 noncalcified LN) were followed with imaging rather than excision. No cancers were detected among the follow-up group. One case was deemed to have discordant findings on radiologic-pathologic review and was sent for excision, which showed invasive cancer with tubulolobular and lobular features. CONCLUSION. Women undergoing stereotactic core needle biopsy for calcifications revealing noncalcified incidental classic LN and a benign concordant entity that could explain the presence of the target calcifications have a low risk of upgrade and may be followed with imaging. Surgical excision should be offered to women who have LN with calcifications.

Aberrant and constitutive expression of FOXL2 impairs ovarian development and functions in mice.

Development and functions of the ovary rely on appropriate signaling and communication between various ovarian cell types. FOXL2, a transcription factor that plays a key role at different stages of ovarian development, is associated with primary ovarian insufficiency and ovarian cancer as a result of its loss-of-function or mutations. In this study, we investigated the impact of aberrant, constitutive expression of FOXL2 in somatic cells of the ovary. Overexpression of FOXL2 that started during fetal life resulted in defects in nest breakdown and consequent formation of polyovular follicles. Granulosa cell differentiation was impaired and recruitment and differentiation of steroidogenic theca cells was compromised. As a consequence, adult ovaries overexpressing FOXL2 exhibited defects in compartmentalization of granulosa and theca cells, significant decreased steroidogenesis and lack of ovulation. These findings demonstrate that fine-tuned expression of FOXL2 is required for proper folliculogenesis and fertility.

Mapping lineage progression of somatic progenitor cells in the mouse fetal testis.

Testis morphogenesis is a highly orchestrated process involving lineage determination of male germ cells and somatic cell types. Although the origin and differentiation of germ cells are known, the developmental course specific for each somatic cell lineage has not been clearly defined. Here, we construct a comprehensive map of somatic cell lineage progression in the mouse testis. Both supporting and interstitial cell lineages arise from WT1+ somatic progenitor pools in the gonadal primordium. A subpopulation of WT1+ progenitor cells acquire SOX9 expression and become Sertoli cells that form testis cords, whereas the remaining WT1+ cells contribute to progenitor cells in the testis interstitium. Interstitial progenitor cells diversify through the acquisition of HES1, an indication of Notch activation, at the onset of sex determination. HES1+ interstitial progenitors, through the action of Sertoli cell-derived Hedgehog signals, become positive for GLI1. The GLI1+ interstitial cells eventually develop into two cell lineages: steroid-producing fetal Leydig cells and non-steroidogenic cells. The fetal Leydig cell population is restricted by Notch2 signaling from the neighboring somatic cells. The non-steroidogenic progenitor cells retain their undifferentiated state during fetal stage and become adult Leydig cells in post-pubertal testis. These results provide the first lineage progression map that illustrates the sequential establishment of somatic cell populations during testis morphogenesis.

Frequency and molecular characterization of invasive isolates of Streptococcus pneumoniae serotypes 6C and 6D in Colombia.

INTRODUCTION: Serogroup 6 of Streptococcus pneumoniae initially consisted of the 6A and 6B serotypes, but in recent years, the 6C and 6D serotypes were reported. The aim of this study was to determine the frequency and molecular characterization of invasive S. pneumoniae isolates serotypes 6C and 6D in Colombia, from 1994 to 2013. METHODOLOGY: All the isolates recovered during the surveillance from 1994 to 2013, and identified as 6A or 6B, were re-tested to detect the serotypes 6C and 6D. The serotyping was performed using the Quellung reaction and PCR. The susceptibility testing was performed on penicillin, erythromycin, ceftriaxone, trimethoprim/sulfamethoxazole, chloramphenicol, tetracycline and vancomycin. Molecular typing was performed using pulsed-field gel electrophoresis and multilocus sequence typing. RESULTS: From a total of 271 and 350 isolates serotyped previously as serotypes 6A and 6B, 61 (22.5%) and 15 (4.3%) were recognized as 6C and 6D, respectively. Isolates presented with low resistance to antimicrobials. Serotype 6C isolates were mainly associated with ST9007 (42.6%) and ST9008 (19.7%), and serotype 6D isolates with ST1135 (80%). CONCLUSION: This study showed the circulation of serotype 6C and 6D in Colombia between 1994 and 2013, information that is important to determine the dynamics of these recently described serotypes.

Brachial artery Doppler flux parameters before and after hot flush in Mexican postmenopausal women: preliminary report.

OBJECTIVE: To analyse brachial artery flux parameters in postmenopausal women before and after hot flush. MATERIAL AND METHODS: Two groups of postmenopausal women were studied: Group I, without vasomotor symptoms (n = 10) and Group II, with vasomotor symptoms (n = 10). In all them a brachial artery Doppler ultrasound was done, measuring before and after hyperaemic stimulus of the arterial diameter (AD), the pulsatility index (PI), and the resistive index (RI). In Group I, measurements were done at baseline and five minutes after. In Group II, measurements were at baseline, and one and five minutes after the hot-flush. Comparison between the groups was done with Mann-Whitney U test, and within the groups with Wilcoxon test. RESULTS: No differences were found among the groups in Doppler parameters. When comparing each group separately, in Group I, at baseline and at five minutes measurements, the AD was greater after the hyperaemic stimulus than before it. In group II at baseline, the PI was significantly greater after the hyperaemic stimulus than before to it. At the first and fifth minute, the AD was significantly greater after the hyperaemic stimulus than before to it. CONCLUSIONS: No differences were found between those who did not have and those who had hot flushes.

The naturally occurring luteinizing hormone surge is diminished in mice lacking estrogen receptor Beta in the ovary.

Female ESR2-null mice (betaERKO) display defects in ovarian function and are subfertile. Follicular maturation is impaired and explains smaller litters, but betaERKO also produce fewer litters, which may be partially due to inadequate ovulatory signals. To test this, the amplitude and timing of the naturally occurring luteinizing hormone (LH) surge was measured in individual intact betaERKO and wild-type (WT) mice. Vaginal cytology was evaluated daily, and blood samples were taken from mice in proestrus. The amplitude of the LH surge was severely blunted in betaERKO mice compared to WT, but pituitary LH levels revealed no differences. The betaERKO mice did not produce a preovulatory estradiol surge. To determine if the smaller LH surges and the reduced number of litters in betaERKO were due to the lack of ESR2 in the hypothalamic-pituitary axis or due to the absence of ESR2 in the ovary, ovaries were transplanted from WT into betaERKO mice and vice versa. The size of the LH surge was reduced only in mice lacking ESR2 within the ovary, and these mice had fewer litters. Fertility and size of the LH surge were rescued in betaERKO mice receiving a WT ovary. These data provide the first experimental evidence that the LH surge is impaired in betaERKO females and may contribute to their reduced fertility. ESR2 is not necessary within the pituitary and hypothalamus for the generation of a normal LH surge and for normal fertility, but ESR2 is essential within the ovary to provide proper signals.

Demographic and clinical risk factors associated with severity of lab-confirmed human leptospirosis in Colombia, 2015-2020.

BACKGROUND: Leptospirosis is a common zoonoses and is a major global public health threat. Most cases are mild, typically presenting as a non-specific acute febrile illness. However, leptospirosis can have life-threatening manifestations, including pulmonary hemorrhage syndrome, and acute kidney injury. In Colombia, notification and lab-confirmation of suspected human cases are mandatory. However, little is known about the demographic and clinical factors associated with severe leptospirosis, which could help to reduce clinical complications and mortality. Our aim was to identify risk factors associated with severe leptospirosis, intensive care unit (ICU) admission, and mortality in lab-confirmed cases in Colombia, 2015-2020. METHODS AND FINDINGS: We analyzed 201 lab-confirmed human leptospirosis cases by microagglutination test. We used a logistic regression to identify the demographic and clinical risk factors associated with severe leptospirosis, admission to ICU, and death. Most leptospirosis confirmed cases occurred in men (85.6%); the mean age was 36.7 years. We classified severe cases (43.3%) by clinical manifestations as renal (29.9%) and liver (27.4%) failure, multiple-organ failure (24.4%), septic shock (24.4%), Weil syndrome (18.4%), pulmonary hemorrhage (18.4%), and meningitis (2.5%), admitted to the ICU (30.3%), and fatal (8.5%). Clinical conditions associated with severe leptospirosis were dyspnea (OR: 5.54; 95% CI: 1.46 to 20.98), tachycardia (OR:9.69; 95% CI: 15.96 to 58.8), and rash (OR: 10.25; 95% CI: 25.01 to 42.08). CONCLUSIONS: We identified demographic characteristics and clinical symptoms associated with severe leptospirosis in Colombia. We hope these results can support clinicians in providing timely treatment to leptospirosis patients to avoid preventable medical complications or deaths.

Recovery and Characterization of Spermatozoa in a Neotropical, Terrestrial, Direct-Developing Riparian Frog (Craugastor evanesco) through Hormonal Stimulation.

The Vanishing Rainfrog (Craugastor evanesco) is an endemic and critically endangered frog species of Panama. It is suspected that 90% of the population has disappeared from the wild. Frogs were collected from the wild and brought to a Captive Breeding Program; however, accomplishing regular reproductive events for this species has been difficult. The objective of this study was to determine the effect of hormonal stimulation on the production and quality of C. evanesco spermatozoa, aiming to develop an efficient and safe sperm collection protocol as a tool to help reproduce this endangered species. Mature males received intra-peritoneal injections with one of six hormone treatments, including des-Gly10, D-Ala6, Pro-NHEt9-GnRH-A, Amphiplex or hCG. Urine samples were collected at 10 different time points post-injection. Quality assessments included sperm concentration, percentage motility, percentage forward progressive motility (FPM), osmolality, pH and morphology analysis. Our results indicate that the optimal treatment for the collection of highly concentrated sperm samples of C. evanesco is 4 µg/gbw GnRH, followed by Amphiplex and 2 µg/gbw GnRH as sub-optimal treatments and finally, 6 µg/gbw GnRH and 5 and 10 IU/gbw hCG as non-optimal treatments. GnRH-A at 4 µg/gbw and Amphiplex stimulated the production of samples with the highest sperm concentrations and quality, despite Amphiplex producing lower percentages of intact acrosome and tail. In contrast, hCG concentrations were not reliable inducers of sperm production, consistently showing lower concentrations, higher percentages of sperm abnormalities and more acidic spermic urine than that induced by Amphiplex and GnRH-A. Morphological assessments revealed that C. evanesco spermatozoa have a filiform shape with a large acrosome on the anterior part of an elongated head, a small midpiece and a long tail with two filaments joined together by an undulating membrane.

Photovoltaic Glass Waste Recycling in the Development of Glass Substrates for Photovoltaic Applications.

Because of the increasing demand for photovoltaic energy and the generation of end-of-life photovoltaic waste forecast, the feasibility to produce glass substrates for photovoltaic application by recycling photovoltaic glass waste (PVWG) material was analyzed. PVWG was recovered from photovoltaic house roof panels for developing windows glass substrates; PVWG was used as the main material mixed with other industrial waste materials (wSG). The glass was casted by air quenching, annealed, and polished to obtain transparent substrates samples. Fluorine-doped tin oxide (FTO) was deposited as back contact on the glass substrates by spray pyrolysis. The chemical composition of the glass materials was evaluated by X-ray fluorescence (XRF), the thermal stability was measured by differential thermal analysis (DTA) and the transmittance was determined by UV-VIS spectroscopy. The surface of the glass substrates and the deposited FTO were observed by scanning electron microscopy (SEM), the amorphous or crystalline state of the specimens were determined by X-ray diffraction (XRD) and the sheet resistance was evaluated by the four-point probe method. The sheet resistance of the deposited FTO on the wSG substrate was 7.84 ± 3.11 Ω/□, lower than that deposited on commercial soda-lime glass (8.48 ± 3.67 Ω/□), meaning that this material could present improved conduction of the produced electrons by the photovoltaic effect. This process may represent an alternative to produce glass substrates from waste materials that could be destined for photovoltaic applications, especially the production of ecological photovoltaic windows.

Fatal acute undifferentiated febrile illness among clinically suspected leptospirosis cases in Colombia, 2016-2019.

BACKGROUND: Acute undifferentiated febrile illness is a common challenge for clinicians, especially in tropical and subtropical countries. Incorrect or delayed diagnosis of febrile patients may result in medical complications or preventable deaths. Common causes of acute undifferentiated febrile illness in Colombia include leptospirosis, rickettsioses, dengue fever, malaria, chikungunya, and Zika virus infection. In this study, we described the acute undifferentiated febrile illness in postmortem patients reported as suspected cases of leptospirosis through the national leptospirosis surveillance in Colombia, 2016-2019. METHODOLOGY/PRINCIPAL FINDINGS: We retrospectively analyze human fresh and formalin-fixed tissue samples from fatal suspected leptospirosis cases reported by the Public Health Laboratories in Colombia. Leptospirosis confirmation was made by immunohistochemistry, real-time polymerase chain reaction (PCR) in the tissue samples. In some cases, the serum sample was used for confirmation by Microagglutination test (MAT). Simultaneously, tissue samples were tested by PCR for the most common viral (dengue, Zika, and chikungunya), bacterial (Brucella spp., and Rickettsia spp.), and parasitic (malaria). Fresh tissue samples from 92 fatal suspected leptospirosis cases were reported to the National Reference Laboratory from 22/32 departments in Colombia. We confirmed leptospirosis in 27% (25/92) of cases. Other pathogens identified by real-time PCR were Brucella spp. (10.9%), Rickettsia spp. (14.1%), and dengue (2.2%). Dengue (6.9%), hepatitis (3.5%), and Yellow Fever cases (2.2%) were detected by the pathology. All patients were negative for chikungunya and Plasmodium spp. Most cases were classified as undifferentiated febrile illnesses (45.7%; 42/92). CONCLUSIONS/SIGNIFICANCE: This study underscores the importance of early and accurate recognition of leptospirosis to prevent mortalities. Moreover, it draws attention to the existence of other febrile syndromes in Colombia, including rickettsiosis and brucellosis, that currently lack sufficient human surveillance and regular reporting. Expanding laboratory surveillance to include viruses such as Hantavirus, Mayaro virus, Oropouche virus, and West Nile virus is crucial.

Costs of dengue prevention and incremental cost of dengue outbreak control in Guantanamo, Cuba.

OBJECTIVE: To assess the economic cost of routine Aedes aegypti control in an at-risk environment without dengue endemicity and the incremental costs incurred during a sporadic outbreak. METHODS: The study was conducted in 2006 in the city of Guantanamo, Cuba. We took a societal perspective to calculate costs in months without dengue transmission (January-July) and during an outbreak (August-December). Data sources were bookkeeping records, direct observations and interviews. RESULTS: The total economic cost per inhabitant (p.i.) per month. (p.m.) increased from 2.76 USD in months without dengue transmission to 6.05 USD during an outbreak. In months without transmission, the routine Aedes control programme cost 1.67 USD p.i. p.m. Incremental costs during the outbreak were mainly incurred by the population and the primary/secondary level of the healthcare system, hardly by the vector control programme (1.64, 1.44 and 0.21 UDS increment p.i. p.m., respectively). The total cost for managing a hospitalized suspected dengue case was 296.60 USD (62.0% direct medical, 9.0% direct non-medical and 29.0% indirect costs). In both periods, the main cost drivers for the Aedes control programme, the healthcare system and the community were the value of personnel and volunteer time or productivity losses. CONCLUSIONS: Intensive efforts to keep A. aegypti infestation low entail important economic costs for society. When a dengue outbreak does occur eventually, costs increase sharply. In-depth studies should assess which mix of activities and actors could maximize the effectiveness and cost-effectiveness of routine Aedes control and dengue prevention.

[Therapeutic response and survival in patients with hairy cell leukemia in a third level institution]. / Respuesta terapéutica y supervivencia en pacientes con leucemia de células peludas en un hospital de tercer nivel.

BACKGROUND: in Mexico published casuistry concerning hairy cell leukemia (HCL) is limited. OBJECTIVE: to describe the therapeutic response and survival of patients with HCL attended in a third level public institution. METHODS: patient's data with HCL diagnosis registered between January 1989 - December 2009 were analyzed. RESULTS: twenty three patients fulfilled HCL diagnosis criteria. Median age was 44 years (range 23-75 years) and median follow-up of the cohort was 1,877 days (range 1-8,462 days). First line treatment varied along time finding complete response (CR) and partial response (PR) rates of 77.3 and 18.2%, respectively. Of all therapeutic modalities employed cladribine induced the highest response rate. Survival at 1,877 days was 82.6%. At last follow-up 65.2% of patients remain alive, 13 in CR and 2 in PR; 4 died (CR = 2, PR = 1, active disease = 1) and 4 were lost during follow-up. CONCLUSION: this study which included more patients than previous single-institution Mexican series confirm the chronic clinical behavior of HCL and that purine analogs are corner stone in the treatment of patients suffering HCL.

Somatic cell fate maintenance in mouse fetal testes via autocrine/paracrine action of AMH and activin B.

Fate determination and maintenance of fetal testes in most mammals occur cell autonomously as a result of the action of key transcription factors in Sertoli cells. However, the cases of freemartin, where an XX twin develops testis structures under the influence of an XY twin, imply that hormonal factor(s) from the XY embryo contribute to sex reversal of the XX twin. Here we show that in mouse XY embryos, Sertoli cell-derived anti-Mullerian hormone (AMH) and activin B together maintain Sertoli cell identity. Sertoli cells in the gonadal poles of XY embryos lacking both AMH and activin B transdifferentiate into their female counterpart granulosa cells, leading to ovotestis formation. The ovotestes remain to adulthood and produce both sperm and oocytes, although there are few of the former and the latter fail to mature. Finally, the ability of XY mice to masculinize ovaries is lost in the absence of these two factors. These results provide insight into fate maintenance of fetal testes through the action of putative freemartin factors.

Uterine gland formation in mice is a continuous process, requiring the ovary after puberty, but not after parturition.

Uterine gland formation occurs postnatally in an ovary- and steroid-independent manner in many species, including humans. Uterine glands secrete substances that are essential for embryo survival. Disruption of gland development during the postnatal period prevents gland formation, resulting in infertility. Interestingly, stabilization of beta-catenin (CTNNB1) in the uterine stroma causes a delay in gland formation rather than a complete absence of uterine glands. Thus, to determine if a critical postnatal window for gland development exists in mice, we tested the effects of extending the endocrine environment of pregnancy on uterine gland formation by treating neonatal mice with estradiol, progesterone, or oil for 5 days. One uterine horn was removed before puberty, and the other was collected at maturity. Some mice were also ovariectomized before puberty. The hormone-treated mice exhibited a delay in uterine gland formation. Hormone-treatment increased the abundance of uterine CTNNB1 and estrogen receptor alpha (ESR1) before puberty, indicating possible mechanisms for delayed gland formation. Despite having fewer glands, progesterone-treated mice were fertile, suggesting that a threshold number of glands is required for pregnancy. Mice that were ovariectomized before puberty did not undergo further uterine growth or gland development. Finally, to establish the role of the ovary in postpartum uterine gland regeneration, mice were either ovariectomized or given a sham surgery after parturition, and uteri were evaluated 1 wk later. We found that the ovary is not required for uterine growth or gland development following parturition. Thus, uterine gland development occurs continuously in mice and requires the ovary after puberty, but not after parturition.

Plagues, past, and futures for the Yagan canoe people of Cape Horn, southern Chile.

The manner in which the COVID-19 pandemic has affected the indigenous Yagan people of Navarino Island in southern Chile is the topic of this paper. Like other First Nation communities, these nomadic people suffered decimation and disease in successive encounters with Europeans, and then, in the mid-twentieth century, forced sedentarization by the Chilean State. More recently, the Yagan have fought the expansion of salmon aquaculture to the Island. Making use of a sociomaterial approach, we examine how the threat of past and present viruses and diseases, added to the tragic effects of colonization, become part of a broader sociohistorical debate on the right of coastal peoples to their maritories. Paradoxically, our results suggest that COVID-19 has become part of an assemblage of ethnic revitalization, opening possibilities for the Yagan clans to make some of their envisioned futures possible.

Ramsey hunt syndrome after antimonial treatment for American Cutaneous Leishmaniasis.

Ramsay Hunt Syndrome (RHS), also known as herpes zoster oticus, is caused by the reactivation of varicella zoster virus (VZV) in the geniculate ganglion of the facial nerve. Herein, we report a case of Ramsey Hunt Syndrome in a patient after antimonial treatment for Cutaneous Leishmaniasis. The patient presented with microvesicles grouped on an erythematous base, starting in the neck and ascending towards the scalp margin on the right side of the head. The patient also developed grade V peripheral facial palsy the day after initiating the herpes zoster treatment, this outcome corroborated the assumption of Ramsey Hunt Syndrome.

In utero exposure to arsenite contributes to metabolic and reproductive dysfunction in male offspring of CD-1 mice.

In utero exposure to arsenite (iAs) is known to increase disease risks later in life. We investigated the effect of in utero exposure to iAs in the drinking water on metabolic and reproductive parameters in male mouse offspring at postnatal and adult stages. Pregnant CD-1 mice were exposed to iAs (as sodium arsenite) in the drinking water at 0 (control), 10 ppb (EPA standard for drinking water), and 42.5 ppm (tumor-inducing dose in mice) from embryonic day (E) 10-18. At birth, pups were fostered to unexposed females. Male offspring exposed to 10 ppb in utero exhibited increase in body weight at birth when compared to controls. Male offspring exposed to 42.5 ppm in utero showed a tendency for increased body weight and a smaller anogenital distance. The body weight in iAs-exposed pups continued to increase significantly compared to control at 3 weeks and 11 weeks of age. At 5 months of age, iAs-exposed males exhibited greater body fat content and glucose intolerance. Male offspring exposed to 10 ppb in utero had higher circulating levels of leptin compared to control. In addition, males exposed to 42.5 ppm in utero exhibited decreased total number of pups born compared to controls and lower average number of litters sired over a six-month period. These results indicate that in utero exposure to iAs at either human relevant concentration or tumor-inducing concentration is a potential cause of developmental origin of metabolic and reproductive dysfunction in adult male mice.

Oviductal Retention of Embryos in Female Mice Lacking Estrogen Receptor α in the Isthmus and the Uterus.

Estrogen receptor α (ESR1; encoded by Esr1) is a crucial nuclear transcription factor for female reproduction and is expressed throughout the female reproductive tract. To assess the function of ESR1 in reproductive tissues without confounding effects from a potential developmental defect arising from global deletion of ESR1, we generated a mouse model in which Esr1 was specifically ablated during postnatal development. To accomplish this, a progesterone receptor Cre line (PgrCre) was bred with Esr1f/f mice to create conditional knockout of Esr1 in reproductive tissues (called PgrCreEsr1KO mice) beginning around 6 days after birth. In the PgrCreEsr1KO oviduct, ESR1 was most efficiently ablated in the isthmic region. We found that at 3.5 days post coitus (dpc), embryos were retrieved from the uterus in control littermates while all embryos were retained in the PgrCreEsr1KO oviduct. Additionally, serum progesterone (P4) levels were significantly lower in PgrCreEsr1KO compared to controls at 3.5 dpc. This finding suggests that expression of ESR1 in the isthmus and normal P4 levels allow for successful embryo transport from the oviduct to the uterus. Therefore, alterations in oviductal isthmus ESR1 signaling and circulating P4 levels could be related to female infertility conditions such as tubal pregnancy.