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Reproductive Toxicity of Chemicals

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Toxicology".

Deadline for manuscript submissions: 30 December 2025 | Viewed by 2533

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Dr. Maria Laura Zenclussen

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Guest Editor

Instituto de Salud y Ambiente del Litoral (ISAL, UNL-CONICET), Facultad de Bioquímica y Ciencias Biológicas, Universidad Nacional del Litoral (UNL), Santa Fe 3000, Argentina
Interests: immunology; flow cytometry; inflammation; cell culture biotechnology

Special Issue Information

Dear Colleagues,

The importance of reproductive health to society cannot be overlooked as there is increasing evidence of declining fertility in both women and men. Increased and continuous exposure to anthropogenic chemicals that are present in the environment has been linked to impaired fertility. In addition, reproductive toxicity from chemical exposure may also manifest as changes in the onset of puberty, sexual behavior and pregnancy-related complications with possible adverse effects on the embryo, fetus and offspring. Given the importance of reproductive health for society, the hazard identification of toxicants is of outmost importance. These chemicals may act as toxicants to specific cells of the reproductive system, or even act as endocrine disruptors, interfering with normal hormone activity. This special issue is dedicated to the impact of chemicals on the reproductive system and welcomes all studies that will help to clarify the molecular mechanisms involved in the toxicity of chemicals and how they affect the reproductive system of both males and females.

Dr. Maria Laura Zenclussen
Guest Editor

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Keywords

reproductive health
fertility
anthropogenic chemicals
impaired fertility
reproductive toxicity
embryo
toxicants
hormone disruption
chemical exposure

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Published Papers (5 papers)

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Research

23 pages, 11418 KB

Open AccessArticle

Bisphenol A Interferes with Mast Cell-Mediated Promotion of Cellular Processes Critical for Spiral Artery Remodeling

by Federica Romanelli, Ningjuan Zhang, Mario Bauer, Beate Fink, Ana Claudia Zenclussen, Anne Schumacher and Nicole Meyer

Int. J. Mol. Sci. 2025, 26(19), 9706; https://doi.org/10.3390/ijms26199706 (registering DOI) - 5 Oct 2025

Abstract

Mast cells (MCs) belong to the cell network that regulates uterine spiral artery remodeling (uSAR), a critical vascular adaptation supporting placental development and fetal growth. Our previous in vitro study demonstrated that human MCs promote trophoblast invasion, as well as uterine vascular smooth muscle cells (uVSMCs) migration and transition to a synthetic phenotype—essential steps for a successful uSAR. Although MCs are known targets of bisphenol A (BPA), a widespread endocrine-disrupting chemical, its impact on their supportive role in uSAR is unknown. In this study, we used murine cell lines to investigate whether BPA (0.1–100 µM) affects MC-mediated promotion of cellular processes critical for uSAR. Our results showed that BPA exposure hindered MCs’ ability to promote trophoblast invasion and the switch in uVSMCs’ synthetic phenotype and migration. The highest concentrations of BPA altered the expression of genes related to MCs activation and proliferation, and of those involved in trophoblasts invasion. In contrast, low doses induced the expression of pro-inflammatory mediators in MCs without detectable effect on trophoblasts at the transcriptional level. These findings confirmed MCs as key mediators of uSAR, and identified BPA as a disruptor of their function, emphasizing its potential harmful impact on reproductive health. Full article

(This article belongs to the Special Issue Reproductive Toxicity of Chemicals)

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14 pages, 1358 KB

Open AccessArticle

The Endocrine-Disrupting Chemical Benzophenone-3 in Concentrations Ranging from 0.001 to 10 µM Does Not Affect the Human Decidualization Process in an In Vitro Setting

by Kristin Krausser, Julia Howanski, Beate Fink, Mario Bauer, Florence Fischer, Federica Romanelli, Ana Claudia Zenclussen and Anne Schumacher

Int. J. Mol. Sci. 2025, 26(19), 9314; https://doi.org/10.3390/ijms26199314 - 24 Sep 2025

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Abstract

Endocrine-disrupting chemicals such as benzophenone-3 (BP-3) can have severe consequences for human reproduction by affecting critical processes during pregnancy. To shed further light on potential harmful BP-3 actions, our current study addressed the impact of BP-3 on decidualization and trophoblast invasion. Decidualization was initiated in human endometrial stromal cells (THESC) upon treatment with a mixture of cAMP, progesterone, and estradiol. In parallel to hormonal treatment, the cells were exposed to different BP-3 concentrations ranging from 0.001 µM to 10 µM. The expression of decidualization and invasion markers was determined. Moreover, trophoblastic spheroids derived from JEG-3 cells were transferred to decidualized THESC after BP-3 exposure, and spheroid attachment and invasion were analyzed. Hormonal treatment successfully initiated decidualization in THESC, which was confirmed by increased prolactin levels and IGFBP1 and NCOA-3 mRNA expression. Notably, BP-3 exposure did not affect these markers. Furthermore, BP-3 changed neither THESC proliferation nor viability nor the frequency of cells expressing MMP2/9 or TIMP1/3. Trophoblastic spheroid attachment and outgrowth into THESC were not altered through any of the BP-3 concentrations applied. Our results do not provide evidence for an influence of BP-3 on the decidualization process and the capability of trophoblast cells to adhere and invade into endometrial stromal cells. Full article

(This article belongs to the Special Issue Reproductive Toxicity of Chemicals)

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20 pages, 3658 KB

Open AccessArticle

Epigallocatechin-3-Gallate Enhances Antioxidant Activity and Improves Testicular and Epididymal Histology in Cadmium-Exposed Prepubertal Rats

by Sonia Guadalupe Pérez-Aguirre, Rosa María Vigueras-Villaseñor, Herlinda Bonilla-Jaime, Sergio Montes, Sonia Galván-Arzate, Joel Hernández-Rodríguez, Sergio Marín de Jesús, Leticia Carrizales-Yañez, Julio Cesar Rojas-Castañeda and Marcela Arteaga-Silva

Int. J. Mol. Sci. 2025, 26(17), 8264; https://doi.org/10.3390/ijms26178264 - 26 Aug 2025

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Abstract

The prepubertal period represents a critical stage of development, where the reproductive system is susceptible to toxicants such as cadmium (Cd). Cd induces oxidative stress, causes alterations in the antioxidant enzymes and testosterone concentration, and affects reproductive organs. (–)-Epigallocatechin-3-gallate (EGCG), a polyphenol with antioxidant properties, has been studied for its protective effects. We evaluated the effects of EGCG on antioxidant activity and improvement of testicular and epididymal histology in Cd-exposed prepubertal rats. Twenty-eight male Wistar rats, on postnatal day (PND) 21, were distributed into four groups: Ctrl (saline), Cd (1 mg/kg CdCl₂), EGCG (10 mg/kg), and Cd+EGCG (1 mg/kg CdCl₂ + 10 mg/kg EGCG). Treatments were administered intraperitoneally from PND 21 to 49. After euthanasia, blood, testes, and epididymides were collected for Cd content, testosterone concentration, antioxidant activity, and histological evaluation. Cd exposure increased blood Cd, reduced testosterone, impaired antioxidant activity, and caused epithelial disorganization in both organs. In contrast, co-administration of EGCG significantly lowered Cd accumulation, restored testosterone concentration and antioxidant enzymes, and preserved histological integrity of testes and epididymides. These findings demonstrate that EGCG exerts protective effects against Cd-induced reproductive damage during the prepubertal period, suggesting its potential therapeutic use to counteract Cd toxicity in reproductive development. Full article

(This article belongs to the Special Issue Reproductive Toxicity of Chemicals)

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18 pages, 3748 KB

Open AccessArticle

Sulfur-Containing Heterocyclic Aromatic Hydrocarbons Alter Estrogen Metabolism and Cause DNA Damage and Apoptosis in Granulosa Cells

by Genevieve A. Perono, Thane Tomy, Kara Loudon, Laiba Jamshed, Bianca Garlisi, Sylvia Lauks, Cielle Lockington, Celina Ruan, Gregg T. Tomy, James J. Petrik, Philippe J. Thomas and Alison C. Holloway

Int. J. Mol. Sci. 2025, 26(16), 8004; https://doi.org/10.3390/ijms26168004 - 19 Aug 2025

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Abstract

The expansion of the Alberta Oil Sands Region (AOSR) has increased the deposition of petroleum-derived chemicals into the surrounding environment. Among these, polycyclic aromatic compounds (PACs), including sulfur-containing heterocyclic hydrocarbons, have been detected in exposed local wildlife, yet the reproductive toxicity and genotoxicity of this suite of PACs remain largely unexplored. This study examined the effects of dibenzothiophene (DBT) and its alkylated congener, 2,4,7-trimethyldibenzothiophene (2,4,7-DBT), on estradiol (E2) synthesis and metabolism in granulosa cells (SIGCs). Cells were exposed to DBT or 2,4,7-DBT for 24 h at concentrations detected in AOSR wildlife tissues (0, 0.1, 1 and 10 nM). We measured the gene expression of markers involved in E2 synthesis, signaling and metabolism, E2 output via ELISA and E2 metabolite production via HPLC-MS/MS. Exposure to 2,4,7-DBT, but not DBT, shifted E2 metabolism towards 4-OHE2, a genotoxic E2 metabolite. DNA damage was assessed by γH2Ax expression, alongside DNA repair (Parp1) and survival markers (pAKT). Interestingly, both DBT and 2,4,7-DBT increased DNA damage and triggered apoptosis via a caspase-independent mechanism. Given the critical role of granulosa cells in steroidogenesis and fertility, these findings highlight the endocrine-disruptive effects of sulfur-containing heterocyclic PACs and their potential to compromise reproductive health in exposed mammals. Full article

(This article belongs to the Special Issue Reproductive Toxicity of Chemicals)

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18 pages, 1922 KB

Open AccessArticle

Genomic and Cytotoxic Damage in Wistar Rats and Their Newborns After Transplacental Exposure to Hibiscus sabdariffa Hydroalcoholic Extract

by Yelin Tobanche Mireles, Ana Lourdes Zamora-Pérez, Marisol Galván Valencia, Susana Vanessa Sánchez de la Rosa, Fuensanta del Rocío Reyes Escobedo and Blanca Patricia Lazalde-Ramos

Int. J. Mol. Sci. 2025, 26(15), 7448; https://doi.org/10.3390/ijms26157448 - 1 Aug 2025

Viewed by 459

Abstract

Hibiscus sabdariffa (Hs) is a tropical plant with a wide range of therapeutic properties; however, few studies have evaluated its potential adverse effects. In the present study, the cytotoxic and genotoxic effects of the hydroalcoholic extract of Hs (EHHs) dried calyces administered during gestation were assessed in Wistar rats and their newborns using the micronucleus assay in peripheral blood and the quantification of malondialdehyde (MDA) in various tissues. Three different doses of EHHs (500, 1000, and 2000 mg/Kg) were administered orally to five pregnant Wistar rats per group during the final days of gestation (days 16–20). Blood samples were collected every 24 h during the last six days of gestation and from the neonates at birth, along with tissue samples for MDA quantification. EHHs induced myelosuppression in the mothers and genotoxicity in their newborns, as well as cytotoxicity, evidenced by increased MDA levels in serum, liver, and kidneys of the mothers, and in the liver, kidneys, brain, and muscle tissues of the neonates. These findings provide important insights into the safety profile of Hs, and its use is therefore recommended only under the supervision of a qualified healthcare professional. Full article

(This article belongs to the Special Issue Reproductive Toxicity of Chemicals)

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