Role of Environmental Factors and Gonadotoxin Exposure in Unexplained Female Infertility

Fujimoto, Victor Y.; Bloom, Michael S.

doi:10.1007/978-1-4939-2140-9_15

Cited by 5 publications

(3 citation statements)

References 202 publications

(141 reference statements)

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“…Non-essential trace elements, including barium (Ba), strontium (Sr), rubidium (Rb), tin (Sn), titanium (Ti), lead (Pb), cadmium (Cd), mercury (Hg), antimonium (Sb), and arsenic (As) are ubiquitous and bioaccumulate in living organisms [1]. Industrialization, fossil fuel energy, and improvements in the agricultural industry have driven increased exposure to these elements [1,2] via occupational exposure and/or intake of industrial pollutants through diet or drinking water [3][4][5]. Exposure to these elements is particularly concerning due to their persistence in plasma and urine, unknown cumulative effects, and potency in human tissues-even slight overexposures have caused serious health complications, including fertility-related issues in animal models [6][7][8].…”

Section: Introductionmentioning

confidence: 99%

Bioaccumulation of Non-Essential Trace Elements Detected in Women’s Follicular Fluid, Urine, and Plasma Is Associated with Poor Reproductive Outcomes following Single Euploid Embryo Transfer: A Pilot Study

Palomar,

Gonzalez-Martin,

Quiñonero

et al. 2023

IJMS

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This study aims to determine the association of non-essential trace elements present in follicular fluid, plasma, and urine with reproductive outcomes of women undergoing intracytoplasmic sperm injection (ICSI), preimplantation genetic testing for aneuploidies (PGT-A) and single frozen euploid embryo transfer (SET/FET). This single-center, prospective cohort study included sixty women undergoing ICSI with PGT-A and SET/FET between 2018 and 2019. Urine, plasma and follicular fluid samples were collected on the vaginal oocyte retrieval day to simultaneously quantify ten non-essential trace elements (i.e., Ba, Sr, Rb, Sn, Ti, Pb, Cd, Hg, Sb, and As). We found several associations between the levels of these non-essential trace elements and clinical IVF parameters. Specifically, the increased levels of barium in follicular fluid were negatively associated with ovarian function, pre-implantation development and embryo euploidy, while elevated strontium concentrations in this biofluid were negatively associated with impaired blastulation and embryo euploidy. Elevated plasma strontium levels were negatively associated with ovarian function, fertilization and blastulation. Enhanced presence of other trace elements in plasma (i.e., rubidium and arsenic) were associated with a diminished ovarian function and limited the number of recovered oocytes, mature oocytes and zygotes, respectively. Fully adjusted models suggested significantly lower odds of achieving a live birth when increased concentrations of barium and tin were found in urine.

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Section: Introductionmentioning

confidence: 99%

Bioaccumulation of Non-Essential Trace Elements Detected in Women’s Follicular Fluid, Urine, and Plasma Is Associated with Poor Reproductive Outcomes following Single Euploid Embryo Transfer: A Pilot Study

Palomar,

Gonzalez-Martin,

Quiñonero

et al. 2023

IJMS

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“…Humans are exposed to mercury (Hg), a naturally ubiquitous divalent metal [4], mainly through dietary sources [5,6]. Independent studies have shown that Hg exposure has a deleterious effect on reproductive physiology [7][8][9], and gestational exposure may negatively impact fetal development [10].…”

Section: Introductionmentioning

confidence: 99%

Antioxidant Supplementation Alleviates Mercury-Induced Cytotoxicity and Restores the Implantation-Related Functions of Primary Human Endometrial Cells

Palomar

Quiñonero

Medina-Laver

et al. 2023

IJMS

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Mercury (Hg) cytotoxicity, which is largely mediated through oxidative stress (OS), can be relieved with antioxidants. Thus, we aimed to study the effects of Hg alone or in combination with 5 nM N-Acetyl-L-cysteine (NAC) on the primary endometrial cells’ viability and function. Primary human endometrial epithelial cells (hEnEC) and stromal cells (hEnSC) were isolated from 44 endometrial biopsies obtained from healthy donors. The viability of treated endometrial and JEG-3 trophoblast cells was evaluated via tetrazolium salt metabolism. Cell death and DNA integrity were quantified following annexin V and TUNEL staining, while the reactive oxygen species (ROS) levels were quantified following DCFDA staining. Decidualization was assessed through secreted prolactin and the insulin-like growth factor-binding protein 1 (IGFBP1) in cultured media. JEG-3 spheroids were co-cultured with the hEnEC and decidual hEnSC to assess trophoblast adhesion and outgrowth on the decidual stroma, respectively. Hg compromised cell viability and amplified ROS production in trophoblast and endometrial cells and exacerbated cell death and DNA damage in trophoblast cells, impairing trophoblast adhesion and outgrowth. NAC supplementation significantly restored cell viability, trophoblast adhesion, and outgrowth. As these effects were accompanied by the significant decline in ROS production, our findings originally describe how implantation-related endometrial cell functions are restored in Hg-treated primary human endometrial co-cultures by antioxidant supplementation.

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“…Studies in human and animal models show that various environmental factors-such as pollutants, smoking, diet, etc.-can diminish ovarian follicle reserve (1)(2)(3)(4). Importantly, now that diagnosis and treatment of cancers is more efficient, the ovarian follicle reserve can also be damaged in females patients by cancer treatments leading to accelerated PMF loss and resulting in infertility and premature ovarian insufficiency (POI) (1,(5)(6)(7). Treatment-induced-POI results in early menopause, an endocrine deficiency associated with osteoporosis, cardiovascular disorders, depression, and other comorbidities that require medical attention and can negatively impact the quality of survivorship (8)(9)(10)(11).…”

Section: Introductionmentioning

confidence: 99%

Chek2 Signaling Is the Key Regulator of Oocyte Survival After Chemotherapy

Emori

Boucher

Bolcun-Filas

2021

Preprint

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Radiation and chemotherapy can damage the primordial follicle reserve in female cancer patients leading to ovarian failure and infertility. Preservation of ovarian function requires treatment strategies that prevent loss of immature oocytes in primordial follicles during cancer therapy. Checkpoint kinase 2 (CHEK2) inhibition prevents loss of primordial oocytes caused by DNA damage and thus is a promising target for ovoprotective treatment against genotoxic agents. To determine which cancer treatments could benefit from ovoprotective activity of CHEK2 inhibition we investigated oocyte survival in Chek2-/- mice exposed to different chemotherapy drugs. Here, we show that loss of CHEK2 function prevents elimination of primordial oocytes damaged by cisplatin, cyclophosphamide, mafosfamide, doxorubicin, and etoposide, suggesting it could be used to reduce ovarian damage caused by wide range of drugs. Using genetic knockouts we reveal a critical role for TRP53 in oocyte response to chemotherapy drugs and show that both targets of CHEK2, TAp63 and TRP53, are activated by cisplatin and cyclophosphamide. Furthermore, we show that checkpoint kinase inhibitor and radiation- and chemotherapy sensitizer AZD7762 reduces oocyte elimination after radiation and chemotherapy treatments, despite its cytotoxic effect on ovarian somatic cells. Altogether, these findings demonstrate the role for CHEK2 as the master regulator of primordial oocyte survival or death and credential its targeting for ovoprotective treatments.

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Role of Environmental Factors and Gonadotoxin Exposure in Unexplained Female Infertility

Cited by 5 publications

References 202 publications

Bioaccumulation of Non-Essential Trace Elements Detected in Women’s Follicular Fluid, Urine, and Plasma Is Associated with Poor Reproductive Outcomes following Single Euploid Embryo Transfer: A Pilot Study

Bioaccumulation of Non-Essential Trace Elements Detected in Women’s Follicular Fluid, Urine, and Plasma Is Associated with Poor Reproductive Outcomes following Single Euploid Embryo Transfer: A Pilot Study

Antioxidant Supplementation Alleviates Mercury-Induced Cytotoxicity and Restores the Implantation-Related Functions of Primary Human Endometrial Cells

Chek2 Signaling Is the Key Regulator of Oocyte Survival After Chemotherapy

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