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Papers by Kevin Osteen

American Journal of Reproductive Immunology, Aug 7, 2018

International Journal of Molecular Sciences

Hydroxyurea (HU), a drug for treating cancers of the blood and the management of sickle cell anem... more Hydroxyurea (HU), a drug for treating cancers of the blood and the management of sickle cell anemia, induces hypogonadism in males. However, the impact of HU on testicular architecture and function, as well as its effects on the resumption of male fertility following treatment withdrawal, remain poorly understood. We used adult male mice to determine whether HU-induced hypogonadism is reversible. Fertility indices of mice treated with HU daily for ~1 sperm cycle (2 months) were compared with those of their control counterparts. All indices of fertility were significantly reduced among mice treated with HU compared to controls. Interestingly, significant improvements in fertility indices were apparent after a 4-month withdrawal from HU treatment (testis weight: month 1 post-HU withdrawal (M1): HU, 0.09 ± 0.01 vs. control, 0.33 ± 0.03; M4: HU, 0.26 ± 0.03 vs. control, 0.37 ± 0.04 g); sperm motility (M1: HU,12 vs. 59; M4: HU, 45 vs. control, 61%; sperm density (M1: HU, 1.3 ± 0.3 vs. co...

Toxics, 2021

New bronchopulmonary dysplasia is a developmental lung disease associated with placental dysfunct... more New bronchopulmonary dysplasia is a developmental lung disease associated with placental dysfunction and impaired alveolarization. Risk factors for new BPD include prematurity, delayed postnatal growth, the dysregulation of epithelial-to-mesenchymal transition (EMT), and parental exposure to toxicants. Our group previously reported that a history of paternal toxicant exposure increased the risk of prematurity and low birth weight in offspring. A history of paternal toxicant exposure also increased the offspring’s risk of new BPD and disease severity was increased in offspring who additionally received a supplemental formula diet, which has also been linked to poor lung development. Risk factors associated with new BPD are well-defined, but it is unclear whether the disease can be prevented. Herein, we assessed whether a paternal fish oil diet could attenuate the development of new BPD in the offspring of toxicant exposed mice, with and without neonatal formula feeding. We investigat...

Reproductive Sciences, 2017

Menopause-the Journal of The North American Menopause Society, 1997

Seminars in Reproductive Medicine, 2010

Journal of Clinical Investigation, 1997

The Journal of Clinical Endocrinology & Metabolism, 1985

In mammals, insulin stimulates granulosa cell aromatase activity and steroid production and is a ... more In mammals, insulin stimulates granulosa cell aromatase activity and steroid production and is a regulating factor of oocyte maturation. To assess the role of insulin in human follicular and oocyte maturation, human follicular fluid was obtained 32-36 h after hCG administration at the time of oocyte recovery for in vitro fertilization. Follicular fluid insulin levels, measured by RIA, ranged from undetectable (less than 2 microU/ml) to 65.4 microU/ml. In women treated with human menopausal gonadotropin (n = 21), clomiphene citrate (n = 4), and human menopausal gonadotropin/clomiphene citrate (n = 14), follicular fluid insulin concentrations were 18.0 +/- 4.3 (+/- SE), 10.2 +/- 4.2, and 12.0 +/- 3.8 microU/ml, respectively (P = NS). Similarly, there was no significant difference in follicular fluid insulin concentrations in follicles with mature (n = 33) or immature (n = 6) oocytes (13.3 +/- 2.7 vs. 24.7 +/- 9.5 microU/ml) or in oocytes which eventually did (n = 35) or did not (n = 4) fertilize (16.4 +/- 3.0 vs. 3.2 +/- 0.8 microU/ml). Follicular fluid insulin levels (n = 30) correlated positively with follicular fluid progesterone levels (P less than 0.05), but not with follicular fluid estradiol or androstenedione levels or the estradiol to androstenedione ratio. The relationship of follicular fluid insulin and progesterone levels suggests that, as in other mammals, follicular fluid insulin may have a physiological role in follicular maturation.

Fertility and Sterility, 2011

Annals of the New York Academy of Sciences, 2002

Marine Drugs

Epidemiology and animal studies suggest that a paternal history of toxicant exposure contributes ... more Epidemiology and animal studies suggest that a paternal history of toxicant exposure contributes to the developmental origins of health and disease. Using a mouse model, our laboratory previously reported that a paternal history of in utero exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) increased his offspring’s risk of developing necrotizing enterocolitis (NEC). Additionally, our group and others have found that formula supplementation also increases the risk of NEC in both humans and mice. Our murine studies revealed that intervening with a paternal fish oil diet preconception eliminated the TCDD-associated outcomes that are risk factors for NEC (e.g., intrauterine growth restriction, delayed postnatal growth, and preterm birth). However, the efficacy of a paternal fish oil diet in eliminating the risk of disease development in his offspring was not investigated. Herein, reproductive-age male mice exposed to TCDD in utero were weaned to a standard or fish oil diet for one ...

Biology of Reproduction, 2001

The Journal of Clinical Endocrinology & Metabolism, 2000

Suppression of endometrial matrix metalloproteinases (MMPs) is necessary to maintain tissue stabi... more Suppression of endometrial matrix metalloproteinases (MMPs) is necessary to maintain tissue stability during the invasive events of implantation and placental development. Several laboratories have shown that inflammatory cytokines, including interleukin-1α (IL-1α), can oppose progesterone suppression of MMPs in the human endometrium. Furthermore, we have recently demonstrated colocalization of epithelial cell IL-1α and MMP-7 expression at sites of ectopic pregnancy. The current study extends these findings, revealing a previously unrecognized interrelationship between progesterone and IL-1α in regulation of MMP-3. Although IL-1α is a potent stimulator of MMP-3 in proliferative phase endometrium in organ culture, we demonstrate that progesterone exposure in vivo reduces IL-1α stimulation of MMP-3 in secretory phase tissue. This loss of sensitivity to IL-1α was duplicated in isolated stromal cells treated with progesterone in vitro, and IL-1α stimulation of MMP-3 returned in a dose-d...

Frontiers in Physiology

Women with endometriosis, the growth of endometrial glands and stroma outside the uterus, commonl... more Women with endometriosis, the growth of endometrial glands and stroma outside the uterus, commonly also exhibit adenomyosis, the growth of endometrial tissues within the uterine muscle. Each disease is associated with functional alterations in the eutopic endometrium frequently leading to pain, reduced fertility, and an increased risk of adverse pregnancy outcomes. Although the precise etiology of either disease is poorly understood, evidence suggests that the presence of endometriosis may be a contributing factor to the subsequent development of adenomyosis as a consequence of an altered, systemic inflammatory response. Herein, we will discuss the potential role of exposure to environmental toxicants with endocrine disrupting capabilities in the pathogenesis of both endometriosis and adenomyosis. Numerous epidemiology and experimental studies support a role for environmental endocrine disrupting chemicals (EDCs) in the development of endometriosis; however, only a few studies have ...

International Journal of Clinical and Experimental Pathology, 2011

Fallopian tube carcinoma (FTCA) is a very rare cancer type, but may be a useful platform for inve... more Fallopian tube carcinoma (FTCA) is a very rare cancer type, but may be a useful platform for investigating high grade serous tumors of the pelvis that originate from a serous tubal intraepithelial carcinoma (STIC) precursor. Metastatic tumors from a patient diagnosed with Stage IIIC high grade serous FTCA (P0) were transplanted via intraperitoneal (IP) injection into a small cohort of mice (passage, P1). Patient information was obtained from the medical record. Tumors were grown, harvested and re-implanted or archived through P3. The P3 cohort was treated with saline (n=8) or cisplatin, 5 mg/kg (n=8), weekly for 4 weeks. After sacrifice, tumors from each passage and treatment group were passaged further, frozen or paraffin embedded. The patient underwent optimal cytoreductive surgery for Stage IIIC high grade serous FTCA in the presence of a STIC. The FTCA, areas of STIC and normal appearing FT stained positive for p53, PAX8, pH2AX and mib-1. The patient remained in remission 9 mont...

American Journal of Obstetrics and Gynecology

ACS Infectious Diseases

Streptococcal species are gram positive bacteria responsible for a variety of infections includin... more Streptococcal species are gram positive bacteria responsible for a variety of infections including pneumonia, meningitis, endocarditis, erysipelas, necrotizing fasciitis, periodontitis, skin and soft tissue infections, chorioamnionitis, funisitis, and neonatal sepsis. In response to streptococcal infections, the host innate immune system deploys a repertoire of antimicrobial and immune modulating molecules. One important molecule that is produced in response to streptococcal infections is lactoferrin. Lactoferrin has antimicrobial properties including the ability to bind iron with high affinity and sequester this important nutrient from an invading pathogen. Additionally, lactoferrin has the capacity to alter the host inflammatory response and contribute to disease outcome. This review presents the most recent published work that studies the interaction between the host innate immune protein lactoferrin and the invading pathogen, Streptococcus.

American Journal of Obstetrics and Gynecology

783 Fetal membrane organ on chip: An innovative approach to study feto-maternal cellular interact... more 783 Fetal membrane organ on chip: An innovative approach to study feto-maternal cellular interactions Lauren S. Richardson, Kevin Osteen, George R. Saade, David Aronoff, Ramkumar Menon The University of Texas Medical Branch, Galveston, TX, Division of Infectious Diseases, Vanderbilt University Medical Center, Nashville, TN, Dept. of Pathology, Immunology, & Microbiology, Vanderbilt University, Nashville, TN OBJECTIVE: The feto-maternal interface, a vital component that helps to maintain pregnancy and contribute to parturition, is often studied in vitro in individual cell segments or as transwells (TWs) due to its complex composition. To overcome the difficulties , the Fetal membrane-on-chip (FM-O-C), consisting of amnion epithelial cells (AECs) and decidual cells cultured in a two-chamber device, was devised to better understand intercellular interactions and communications (Fig. 1A). STUDY DESIGN: FM-O-C made of silicone elastomer between a semipermeable membrane was developed. Primary AECs and decidual cells from term, nonlaboring fetal membranes were plated in the top/bottom chamber of FM-OCs respectively (Fig. 1B-D). Cells were treated with cigarette smoke extract (CSE) or dioxin two known environmental pollutants and risk factors for 48 hrs. FITC based assays tested membrane permeability (Fig. 1E) and senescence was determined by senescence-associated b-Galactosidase assay (Fig. 1F & Fig. 2B). The same cell types and treatments maintained in TWs were used for comparisons. RESULTS: Irrespective of time or treatment side, FM-O-C produced better membrane permeability than TWs. (Fig. 2A). Membrane permeability was higher in AECs treated with CSE compared to similar treatment on decidual cells. In FM-O-C, CSE and dioxininduced senescence on one side of the chamber induced similar changes on the opposite side suggesting a transfer of biochemicals between layers capable of producing changes (Fig. 2C), an effect that was minimal in TWs. CONCLUSION: FM-O-C provides better cell-cell interactions than current TWs that can be used to study fetomaternal signaling during pregnancy. Expansion of current FM-O-C model with fetomaternal interface cells can be used for cellular interactions studies, biomarker discovery, drug screening, that can advance research to reduce high risk of pregnancies.

American Journal of Reproductive Immunology, Aug 7, 2018

International Journal of Molecular Sciences

Hydroxyurea (HU), a drug for treating cancers of the blood and the management of sickle cell anem... more Hydroxyurea (HU), a drug for treating cancers of the blood and the management of sickle cell anemia, induces hypogonadism in males. However, the impact of HU on testicular architecture and function, as well as its effects on the resumption of male fertility following treatment withdrawal, remain poorly understood. We used adult male mice to determine whether HU-induced hypogonadism is reversible. Fertility indices of mice treated with HU daily for ~1 sperm cycle (2 months) were compared with those of their control counterparts. All indices of fertility were significantly reduced among mice treated with HU compared to controls. Interestingly, significant improvements in fertility indices were apparent after a 4-month withdrawal from HU treatment (testis weight: month 1 post-HU withdrawal (M1): HU, 0.09 ± 0.01 vs. control, 0.33 ± 0.03; M4: HU, 0.26 ± 0.03 vs. control, 0.37 ± 0.04 g); sperm motility (M1: HU,12 vs. 59; M4: HU, 45 vs. control, 61%; sperm density (M1: HU, 1.3 ± 0.3 vs. co...

Toxics, 2021

New bronchopulmonary dysplasia is a developmental lung disease associated with placental dysfunct... more New bronchopulmonary dysplasia is a developmental lung disease associated with placental dysfunction and impaired alveolarization. Risk factors for new BPD include prematurity, delayed postnatal growth, the dysregulation of epithelial-to-mesenchymal transition (EMT), and parental exposure to toxicants. Our group previously reported that a history of paternal toxicant exposure increased the risk of prematurity and low birth weight in offspring. A history of paternal toxicant exposure also increased the offspring’s risk of new BPD and disease severity was increased in offspring who additionally received a supplemental formula diet, which has also been linked to poor lung development. Risk factors associated with new BPD are well-defined, but it is unclear whether the disease can be prevented. Herein, we assessed whether a paternal fish oil diet could attenuate the development of new BPD in the offspring of toxicant exposed mice, with and without neonatal formula feeding. We investigat...

Reproductive Sciences, 2017

Menopause-the Journal of The North American Menopause Society, 1997

Seminars in Reproductive Medicine, 2010

Journal of Clinical Investigation, 1997

The Journal of Clinical Endocrinology & Metabolism, 1985

In mammals, insulin stimulates granulosa cell aromatase activity and steroid production and is a ... more In mammals, insulin stimulates granulosa cell aromatase activity and steroid production and is a regulating factor of oocyte maturation. To assess the role of insulin in human follicular and oocyte maturation, human follicular fluid was obtained 32-36 h after hCG administration at the time of oocyte recovery for in vitro fertilization. Follicular fluid insulin levels, measured by RIA, ranged from undetectable (less than 2 microU/ml) to 65.4 microU/ml. In women treated with human menopausal gonadotropin (n = 21), clomiphene citrate (n = 4), and human menopausal gonadotropin/clomiphene citrate (n = 14), follicular fluid insulin concentrations were 18.0 +/- 4.3 (+/- SE), 10.2 +/- 4.2, and 12.0 +/- 3.8 microU/ml, respectively (P = NS). Similarly, there was no significant difference in follicular fluid insulin concentrations in follicles with mature (n = 33) or immature (n = 6) oocytes (13.3 +/- 2.7 vs. 24.7 +/- 9.5 microU/ml) or in oocytes which eventually did (n = 35) or did not (n = 4) fertilize (16.4 +/- 3.0 vs. 3.2 +/- 0.8 microU/ml). Follicular fluid insulin levels (n = 30) correlated positively with follicular fluid progesterone levels (P less than 0.05), but not with follicular fluid estradiol or androstenedione levels or the estradiol to androstenedione ratio. The relationship of follicular fluid insulin and progesterone levels suggests that, as in other mammals, follicular fluid insulin may have a physiological role in follicular maturation.

Fertility and Sterility, 2011

Annals of the New York Academy of Sciences, 2002

Marine Drugs

Epidemiology and animal studies suggest that a paternal history of toxicant exposure contributes ... more Epidemiology and animal studies suggest that a paternal history of toxicant exposure contributes to the developmental origins of health and disease. Using a mouse model, our laboratory previously reported that a paternal history of in utero exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) increased his offspring’s risk of developing necrotizing enterocolitis (NEC). Additionally, our group and others have found that formula supplementation also increases the risk of NEC in both humans and mice. Our murine studies revealed that intervening with a paternal fish oil diet preconception eliminated the TCDD-associated outcomes that are risk factors for NEC (e.g., intrauterine growth restriction, delayed postnatal growth, and preterm birth). However, the efficacy of a paternal fish oil diet in eliminating the risk of disease development in his offspring was not investigated. Herein, reproductive-age male mice exposed to TCDD in utero were weaned to a standard or fish oil diet for one ...

Biology of Reproduction, 2001

The Journal of Clinical Endocrinology & Metabolism, 2000

Suppression of endometrial matrix metalloproteinases (MMPs) is necessary to maintain tissue stabi... more Suppression of endometrial matrix metalloproteinases (MMPs) is necessary to maintain tissue stability during the invasive events of implantation and placental development. Several laboratories have shown that inflammatory cytokines, including interleukin-1α (IL-1α), can oppose progesterone suppression of MMPs in the human endometrium. Furthermore, we have recently demonstrated colocalization of epithelial cell IL-1α and MMP-7 expression at sites of ectopic pregnancy. The current study extends these findings, revealing a previously unrecognized interrelationship between progesterone and IL-1α in regulation of MMP-3. Although IL-1α is a potent stimulator of MMP-3 in proliferative phase endometrium in organ culture, we demonstrate that progesterone exposure in vivo reduces IL-1α stimulation of MMP-3 in secretory phase tissue. This loss of sensitivity to IL-1α was duplicated in isolated stromal cells treated with progesterone in vitro, and IL-1α stimulation of MMP-3 returned in a dose-d...

Frontiers in Physiology

Women with endometriosis, the growth of endometrial glands and stroma outside the uterus, commonl... more Women with endometriosis, the growth of endometrial glands and stroma outside the uterus, commonly also exhibit adenomyosis, the growth of endometrial tissues within the uterine muscle. Each disease is associated with functional alterations in the eutopic endometrium frequently leading to pain, reduced fertility, and an increased risk of adverse pregnancy outcomes. Although the precise etiology of either disease is poorly understood, evidence suggests that the presence of endometriosis may be a contributing factor to the subsequent development of adenomyosis as a consequence of an altered, systemic inflammatory response. Herein, we will discuss the potential role of exposure to environmental toxicants with endocrine disrupting capabilities in the pathogenesis of both endometriosis and adenomyosis. Numerous epidemiology and experimental studies support a role for environmental endocrine disrupting chemicals (EDCs) in the development of endometriosis; however, only a few studies have ...

International Journal of Clinical and Experimental Pathology, 2011

Fallopian tube carcinoma (FTCA) is a very rare cancer type, but may be a useful platform for inve... more Fallopian tube carcinoma (FTCA) is a very rare cancer type, but may be a useful platform for investigating high grade serous tumors of the pelvis that originate from a serous tubal intraepithelial carcinoma (STIC) precursor. Metastatic tumors from a patient diagnosed with Stage IIIC high grade serous FTCA (P0) were transplanted via intraperitoneal (IP) injection into a small cohort of mice (passage, P1). Patient information was obtained from the medical record. Tumors were grown, harvested and re-implanted or archived through P3. The P3 cohort was treated with saline (n=8) or cisplatin, 5 mg/kg (n=8), weekly for 4 weeks. After sacrifice, tumors from each passage and treatment group were passaged further, frozen or paraffin embedded. The patient underwent optimal cytoreductive surgery for Stage IIIC high grade serous FTCA in the presence of a STIC. The FTCA, areas of STIC and normal appearing FT stained positive for p53, PAX8, pH2AX and mib-1. The patient remained in remission 9 mont...

American Journal of Obstetrics and Gynecology

ACS Infectious Diseases

Streptococcal species are gram positive bacteria responsible for a variety of infections includin... more Streptococcal species are gram positive bacteria responsible for a variety of infections including pneumonia, meningitis, endocarditis, erysipelas, necrotizing fasciitis, periodontitis, skin and soft tissue infections, chorioamnionitis, funisitis, and neonatal sepsis. In response to streptococcal infections, the host innate immune system deploys a repertoire of antimicrobial and immune modulating molecules. One important molecule that is produced in response to streptococcal infections is lactoferrin. Lactoferrin has antimicrobial properties including the ability to bind iron with high affinity and sequester this important nutrient from an invading pathogen. Additionally, lactoferrin has the capacity to alter the host inflammatory response and contribute to disease outcome. This review presents the most recent published work that studies the interaction between the host innate immune protein lactoferrin and the invading pathogen, Streptococcus.

American Journal of Obstetrics and Gynecology

783 Fetal membrane organ on chip: An innovative approach to study feto-maternal cellular interact... more 783 Fetal membrane organ on chip: An innovative approach to study feto-maternal cellular interactions Lauren S. Richardson, Kevin Osteen, George R. Saade, David Aronoff, Ramkumar Menon The University of Texas Medical Branch, Galveston, TX, Division of Infectious Diseases, Vanderbilt University Medical Center, Nashville, TN, Dept. of Pathology, Immunology, & Microbiology, Vanderbilt University, Nashville, TN OBJECTIVE: The feto-maternal interface, a vital component that helps to maintain pregnancy and contribute to parturition, is often studied in vitro in individual cell segments or as transwells (TWs) due to its complex composition. To overcome the difficulties , the Fetal membrane-on-chip (FM-O-C), consisting of amnion epithelial cells (AECs) and decidual cells cultured in a two-chamber device, was devised to better understand intercellular interactions and communications (Fig. 1A). STUDY DESIGN: FM-O-C made of silicone elastomer between a semipermeable membrane was developed. Primary AECs and decidual cells from term, nonlaboring fetal membranes were plated in the top/bottom chamber of FM-OCs respectively (Fig. 1B-D). Cells were treated with cigarette smoke extract (CSE) or dioxin two known environmental pollutants and risk factors for 48 hrs. FITC based assays tested membrane permeability (Fig. 1E) and senescence was determined by senescence-associated b-Galactosidase assay (Fig. 1F & Fig. 2B). The same cell types and treatments maintained in TWs were used for comparisons. RESULTS: Irrespective of time or treatment side, FM-O-C produced better membrane permeability than TWs. (Fig. 2A). Membrane permeability was higher in AECs treated with CSE compared to similar treatment on decidual cells. In FM-O-C, CSE and dioxininduced senescence on one side of the chamber induced similar changes on the opposite side suggesting a transfer of biochemicals between layers capable of producing changes (Fig. 2C), an effect that was minimal in TWs. CONCLUSION: FM-O-C provides better cell-cell interactions than current TWs that can be used to study fetomaternal signaling during pregnancy. Expansion of current FM-O-C model with fetomaternal interface cells can be used for cellular interactions studies, biomarker discovery, drug screening, that can advance research to reduce high risk of pregnancies.