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Reproductive and Developmental Toxicity of Environmental Factors

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A special issue of Toxics (ISSN 2305-6304). This special issue belongs to the section "Reproductive and Developmental Toxicity".

Deadline for manuscript submissions: closed (28 February 2026) | Viewed by 16953

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Dr. Tao Chen

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Guest Editor

School of Public Health, Medical College of Soochow University, Suzhou, China
Interests: cardiac developmental toxicity; emerging contaminants; epigenetics; DNA damage
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Jisheng Nie

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Guest Editor

Department of Occupational and Environmental Health, School of Public Health, Shanxi Medical University, Xinjiannan Road 56, Taiyuan 030001, China
Interests: neurodevelomental toxicity; polycyclic aromatic hydrocarbons; epigenetics; DNA damage

Prof. Dr. Jie Zhang

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Guest Editor

Department of Toxicology, School of Public Health, Medical College of Soochow University, Suzhou, China
Interests: developmental toxicity; chronotoxicology; EDCs; epigenetics

Special Issue Information

Dear Colleagues,

Developmental periods are highly sensitive to various environmental factors, including environmental pollutants, nutrients, and other stressors. The developing heart and brain are particularly vulnerable to these influences, making early life a critical window for assessing toxic exposures. Environmental contaminants can also compromise reproductive capability. Understanding the reproductive and developmental toxicity of environmental factors is essential for evaluating their impact on human health and ecosystems, as well as for effective risk assessment and management.

In the Special Issue “Reproductive and Developmental Toxicity of Environmental Factors”, we aim to explore the incidence, effects, and mechanisms of environmental factors on fertility and prenatal/postnatal development. We invite you to submit high-quality original research papers, short communications, and reviews on the reproductive and developmental toxicity of environmental agents. Topics of interest include, but are not limited to, the following:

Reproductive and developmental toxicity mechanisms of traditional or emerging contaminants;
The impact of environmental factors on fertility and reproductive health;
The relationship between maternal exposure to environmental factors and abortion or congenital diseases;
Protective and intervention strategies against the reproductive and developmental toxicity of environmental factors.

Dr. Tao Chen
Prof. Dr. Jisheng Nie
Prof. Dr. Jie Zhang
Guest Editors

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Toxics is an international peer-reviewed open access monthly journal published by MDPI.

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Keywords

reproductive and developmental toxicity
environmental pollutants
risk assessment
environmental epidemiology
protective and intervention strategies

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Published Papers (10 papers)

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Research

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20 pages, 4048 KB

Open AccessArticle

Mixed Heavy Metal Exposure During Pregnancy Induces GDM-like Metabolic Dysfunction Associated with Glycer-Ophospholipid Metabolic Reprogramming and Altered Insig1 Expression: A Multi-Omics Study in Rats

by Tianao Sun, Zhanyue Zheng, Yongjie Ma, Minglian Pan, Yingjie Zhou, Jingxia Wei, Xinyu Yuan, Jinhao Wan, You Li and Yan Sun

Toxics 2026, 14(4), 351; https://doi.org/10.3390/toxics14040351 - 21 Apr 2026

Viewed by 680

Abstract

This study aimed to investigate whether mixed heavy metal exposure (lead, cadmium, manganese, and arsenic) during pregnancy induces gestational diabetes mellitus (GDM)-like phenotypes and to explore the associated molecular alterations. We examined the effects of exposure on metabolic disturbances using a Sprague-Dawley rat model exposed to low- and high-dose mixed heavy metals, with doses selected based on biomonitoring data. The results showed that high-dose mixed heavy metal exposure significantly increased blood glucose levels in rats, elevated the area under the curve (AUC) during the oral glucose tolerance test (OGTT), and induced insulin resistance and dyslipidemia. Concurrently, pathological examinations revealed hepatocyte steatosis, inflammatory cell infiltration, and mitochondrial abnormalities in liver tissues. Transcriptomic and metabolomic analyses identified significant disruption of the glycerophospholipid metabolic pathway following heavy metal exposure, suggesting the involvement of this pathway in the observed metabolic disturbances. Lasso regression analysis identified Insig1 as a candidate gene associated with lipid metabolic alterations, a finding subsequently validated by qPCR. Overall, mixed heavy metal exposure during pregnancy was associated with GDM-like metabolic abnormalities in rats. Disruption of glycerophospholipid metabolism and altered Insig1 expression likely contribute to these effects, providing molecular evidence linking mixed heavy metal exposure to gestational metabolic dysfunction. Full article

(This article belongs to the Special Issue Reproductive and Developmental Toxicity of Environmental Factors)

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18 pages, 2439 KB

Open AccessArticle

Cadmium-Induced Neuroendocrine Alterations: Gene Expression of the Kisspeptin–GnRH Axis and Delayed Puberty in Male Rats

by Marcela Arteaga-Silva, Eduardo Miguel Cornejo de la Concha, Daniel Adrian Landero-Huerta, Sergio Montes, Julio César Rojas-Castañeda, Rosa María Vigueras-Villaseñor, Joel Hernández-Rodríguez, Sergio Marín de Jesús, Sonia Guadalupe Pérez-Aguirre, Rocío Trilce López-Ruíz and Isabel Arrieta-Cruz

Toxics 2026, 14(3), 270; https://doi.org/10.3390/toxics14030270 - 22 Mar 2026

Viewed by 922

Abstract

Puberty is a neuroendocrine process required for sexual maturity; it is regulated by the hypothalamic–hypophysis–gonadal (HHG) axis. Kisspeptin (KISS1) plays a vital role in activating this axis by stimulating the secretion of gonadotropin-releasing hormone (GnRH). Cadmium (Cd) exposure disrupts KISS1 signaling in female rodents; its effects on hypothalamic gene expression during male puberty remain poorly understood. This study investigated the effects of Cd exposure on hypothalamic Kiss1, Kiss1r, and Gnrh1 expression, preputial separation (PS) as a marker of pubertal onset, testosterone levels, Cd concentration, and total antioxidant capacity (TAC) in the serum and hypothalamus of pubertal male Wistar rats. Animals received once a week intraperitoneal injection of CdCl₂ (1 mg/Kg body weight/100 µL) or saline (100 µL) and were euthanized on postnatal day (PND) 35 or 49. Cd exposure reduced serum testosterone levels and TAC. Also, pubertal onset was delayed. At PND 35, Cd decreased hypothalamic Kiss1 expression, whereas at PND 49, it reduced Kiss1r and Gnrh1 expression. These results suggest that Cd alters hypothalamic gene expression, which may contribute to delayed puberty and impaired sexual maturity. Our findings suggest the vulnerability of puberty to exposure to Cd, acting as an endocrine disruptor and neurotoxicant, with alterations for male reproductive maturity. Full article

(This article belongs to the Special Issue Reproductive and Developmental Toxicity of Environmental Factors)

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16 pages, 1621 KB

Open AccessArticle

Combined Repeated-Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test of Calcium Nitrate Tetrahydrate in Sprague Dawley Rats

by Ji-Woo Eom, Han-il Kang, Jae-Hyun Lee, Si-Hwan Song, Jeong-hyun Hong, Seungjin Bae, Chun-Ja Nam and Kyung-Min Lim

Toxics 2025, 13(10), 835; https://doi.org/10.3390/toxics13100835 - 30 Sep 2025

Viewed by 2394

Abstract

Calcium nitrate tetrahydrate, used in fertilizers, wastewater treatment, and concrete admixtures, has limited toxicity data despite extensive industrial use. This study evaluated its repeated-dose and reproductive/developmental toxicity in Sprague Dawley rats following OECD TG 422, which combines TG 407 and 421 to extend dosing than TG 407 and reduce animal use compared with separate studies. Rats were administered 0, 100, 300, or 1000 mg/kg/day. Males were treated for 49 days and females from 2 weeks pre-mating to postpartum day 13; the recovery group was observed for an additional 2 weeks. Endpoints included clinical signs, body weight, food consumption, hematology, serum biochemistry, organ weights, histopathology, reproductive performance, and F1 development. No systemic toxicity was observed in F0 males. Minimal prostate atrophy occurred in high-dose males but was considered non-adverse due to limited severity. One high-dose female died on PPD 1, and high-dose F1 litters showed decreased litter size, increased post-implantation loss, and a reduced live-born index. Based on these results, NOAELs were cautiously assigned 1000 mg/kg/day for repeated-dose and male reproductive toxicity and 300 mg/kg/day for female reproductive and developmental toxicity. TG 422 efficiently characterized hazards while reducing animal use, though its limited duration and scope indicate the need for complementary studies. Full article

(This article belongs to the Special Issue Reproductive and Developmental Toxicity of Environmental Factors)

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16 pages, 2809 KB

Open AccessArticle

Direct and In-Utero Exposure to Quaternary Ammonium Disinfectants Alters Sperm Parameters and mRNA Expression of Epigenetic Enzymes in the Testes of Male CD-1 Mice

by Vanessa E. Melin and Terry C. Hrubec

Toxics 2025, 13(9), 709; https://doi.org/10.3390/toxics13090709 - 23 Aug 2025

Viewed by 2264

Abstract

Quaternary ammonium compounds (QACs) are a class of chemicals used for their antimicrobial, surfactant, and antistatic properties. QACs are present in many consumer products, and people are regularly exposed to them. We have previously shown reproductive toxicity in mice exposed to the disinfectants alkyl dimethyl benzyl ammonium chloride (ADBAC) and dodecyl dimethyl ammonium chloride (DDAC). To assess the long-term reproductive impacts, a generational reproductive study was conducted. Sperm parameters were determined by CASA and epigenetic enzyme mRNA expression was determined by pathway-focused RT-PCR. Mice ambiently exposed to ADBAC+DDAC exhibited decreases in reproductive indices that persisted through the F1 generation. Male mice (F0) dosed with 120 mg/kg/day of ADBAC+DDAC exhibited decreased sperm concentration and motility that persisted through the F1 generation. Changes in the mRNA expression of chromatin-modifying enzymes in the testes were seen. Two histone acetyltransferases (Hat1 and Kat2b) were upregulated, and one lysine-specific demethylase (Kdm6b) was downregulated in the F0 generation. The DNA methyltransferase Dnmt1 was downregulated in F1 males. These changes in chromatin-modifying enzymes are known to decrease fertility and could be a mechanism for ADBAC+DDAC reproductive toxicity. In all experiments, the F2 generation was similar to the controls, showing multi-generational but not trans-generational epigenetic inheritance. Full article

(This article belongs to the Special Issue Reproductive and Developmental Toxicity of Environmental Factors)

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20 pages, 4050 KB

Open AccessArticle

LDLR H3K27ac in PBMCs: An Early Warning Biomarker for Hypercholesterolemia Susceptibility in Male Newborns Treated with Prenatal Dexamethasone

by Kexin Liu, Can Ai, Dan Xu, Wen Hu, Guanghui Chen, Jinzhi Zhang, Ning Zhang, Dongfang Wu and Hui Wang

Toxics 2025, 13(8), 651; https://doi.org/10.3390/toxics13080651 - 31 Jul 2025

Viewed by 1268

Abstract

Dexamethasone, widely used as an exogenous glucocorticoid in clinical and animal practice, has recently been recognized as an environmental contaminant of concern. Existing evidence documents its ability to induce persistent dyslipidemia in adult offspring. In this study, plasma cholesterol levels in male rats exposed to dexamethasone prenatally (PDE) were increased. Meanwhile, developmental tracking revealed a reduction in hepatic low-density lipoprotein receptor (LDLR) promoter H3K27 acetylation (H3K27ac) and corresponding transcriptional activity across gestational-to-postnatal stages. Mechanistic investigations established glucocorticoid receptor/histone deacetylase2 (GR/HDAC2) axis-mediated epigenetic programming of LDLR through H3K27ac modulation in PDE offspring, potentiating susceptibility to hypercholesterolemia. Additionally, in peripheral blood mononuclear cells (PBMC) of PDE male adult offspring, LDLR H3K27ac level and expression were also decreased and positively correlated with those in the liver. Clinical studies further substantiated that male newborns prenatally treated with dexamethasone exhibited increased serum cholesterol levels and consistent reductions in LDLR H3K27ac levels and corresponding transcriptional activity in PBMC. This study establishes a complete evidence chain linking PDE with epigenetic programming and cholesterol metabolic dysfunction, proposing PBMC epigenetic biomarkers as a novel non-invasive monitoring tool for assessing the developmental toxicity of chemical exposures during pregnancy. This has significant implications for improving environmental health risk assessment systems. Full article

(This article belongs to the Special Issue Reproductive and Developmental Toxicity of Environmental Factors)

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17 pages, 1752 KB

Open AccessEditor’s ChoiceArticle

Role of NR1D1 in Bisphenol A-Induced Anxiety-like Behavior and Inflammation in Zebrafish Larvae

by Mingjun Wu, Pinyi Chen, Yuting Wang, Xinwei Wang, Yuqianrui Bao, Liqiao Fan, Yuxiao Rao, Xiaoyao Song and Jie Zhang

Toxics 2025, 13(6), 449; https://doi.org/10.3390/toxics13060449 - 28 May 2025

Cited by 4 | Viewed by 1628

Abstract

Bisphenol A (BPA) is a widespread environmental endocrine disruptor with significant neurodevelopmental and behavioral risks. The present study explored the role of the circadian clock protein NR1D1 in mediating BPA-induced anxiety-like behavior and brain inflammation early in life. Zebrafish embryos exposed to BPA exhibited anxiety-like behavior characterized by altered motor activity patterns. Notably, BPA exposure suppressed the expression of the circadian clock gene nr1d1, accompanied by increased transcriptional and protein levels of pro-inflammatory cytokines, including IL-6, IL-1β, and TNF-α. These changes created a pro-inflammatory microenvironment that disrupted dopamine system homeostasis, contributing to the observed behavioral abnormalities. Activation of NR1D1 using GSK effectively reversed BPA-induced inflammatory responses and restored normal dopamine levels and behavioral phenotypes. These findings highlight NR1D1 as a critical regulator linking circadian rhythm disruption, neuroinflammation, and dopaminergic dysfunction to anxiety-like behavior. This study provides novel insights into the mechanisms underlying BPA-induced neurotoxicity and identifies NR1D1 as a potential therapeutic target for mitigating the adverse effects of early-life BPA exposure. Full article

(This article belongs to the Special Issue Reproductive and Developmental Toxicity of Environmental Factors)

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21 pages, 564 KB

Open AccessArticle

Air Pollution Exposure and Gestational Diabetes Mellitus Risk: A Retrospective Case–Control Study with Multi-Pollutant Analysis in Wuhan, Hubei Province

by Mengyang Dai, Jianfeng Liu, Min Hu, Feng Zhang, Yanjun Wang, Fangfang Dai, Rui Qu, Zhixiang Fang and Jing Yang

Toxics 2025, 13(2), 141; https://doi.org/10.3390/toxics13020141 - 19 Feb 2025

Cited by 2 | Viewed by 2298

Abstract

Ambient air pollution has been associated with gestational diabetes mellitus (GDM); however, evidence regarding trimester-specific effects from China remains limited. This case–control study study analyzed data from pregnant women who delivered in Wuhan, China, between 2017 and 2022 (164 GDM cases and 731 controls), integrating geographic information, air quality measurements, and maternal characteristics. Using Inverse Distance Weighting interpolation and Generalized Linear Mixed Models (GLMM), we assessed associations between air pollutant exposure and GDM across different gestational periods. Results indicated that NO₂ demonstrated the strongest association with GDM compared to other pollutants. Specifically, increased NO₂ exposure was consistently associated with higher GDM risk throughout pregnancy. PM_2.5 exposure showed significant associations during early and mid-pregnancy, while SO₂ exposure was significantly associated with GDM risk exclusively in early pregnancy. Sensitivity analyses stratified by urban maternity status and maternal age revealed the stability of the study’s findings. These findings underscore the importance of reducing air pollution exposure during pregnancy and implementing targeted interventions for high-risk populations to prevent GDM development. Full article

(This article belongs to the Special Issue Reproductive and Developmental Toxicity of Environmental Factors)

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14 pages, 1735 KB

Open AccessArticle

Association Between Fine Particle Waves and Sexual Function: A Nationwide Cross-Sectional Survey in China

by Weiqian Zhang, Rui Qu, Guan Cheng, Jingxuan Wang, Tailang Yin, Jue Liu, Dongdong Tang and Yan Zhang

Toxics 2025, 13(1), 39; https://doi.org/10.3390/toxics13010039 - 6 Jan 2025

Cited by 1 | Viewed by 2119

Abstract

Background: The effect of the long-term persistently elevated air pollutants, often referred to as air pollution waves, on sexual function has not been sufficiently addressed. Methods: This nationwide cross-sectional study involved 12,157 participants, with 5496 females and 5039 males. PM waves were characterized by daily average PM concentrations surpassing Grade II thresholds of China’s ambient air quality standards (PM_2.5 > 75 μg/m³, PM₁₀ > 150 μg/m³) for three or more consecutive days (3–8 days). Male sexual function was assessed through the International Index of Erectile Function-5 (IIEF-5) and the Premature Ejaculation Diagnostic Tool (PEDT), while female sexual function was evaluated using the Female Sexual Function Index (FSFI). A multivariate linear regression model was employed to investigate the link between PM wave exposure and sexual function. Results: Exposure to PM₁₀ waves, defined as 3 (β = −0.0145, 95%CI = −0.0280, −0.0010), 4 (β = −0.0145, 95%CI = −0.0280, −0.0010), 5 (β = −0.0193, 95%CI = −0.0371, −0.0015), 6 (β = −0.0218, 95%CI = −0.0415, −0.0021), 7 (β = −0.0243, 95%CI = −0.0458, −0.0028), and 8 (β = −0.0243, 95%CI = −0.0458, −0.0028) consecutive days, negatively impacted IIEF-5 scores and male sexual function. Moreover, depression levels, as evaluated by the PHQ-9, played a mediating role in the connection between PM₁₀ waves and IIEF-5 scores. The potentially vulnerable subgroups were the younger 20–30 and the low-income groups. Conclusions: Our results suggest for the first time that PM₁₀ waves are associated with decreased IIEF-5 scores, which are mediated by depression score PHQ-9, informing policy formulation for public health interventions and individual safeguarding. Full article

(This article belongs to the Special Issue Reproductive and Developmental Toxicity of Environmental Factors)

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Review

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27 pages, 2086 KB

Open AccessReview

Common Environmental Hazards and Male Infertility: Effects on Epididymal Immune Microenvironment

by Xin-Run Wang, Hao Li, Yi-Fan Hu, Ye-Xin Luo, Cheng-Fang Sun, Xin-Xin Zhang, Xin-Yi Cheng, Hua-Long Zhu, Yong-Wei Xiong and Hua Wang

Toxics 2026, 14(2), 171; https://doi.org/10.3390/toxics14020171 - 14 Feb 2026

Viewed by 1090

Abstract

Environmental hazard-induced male infertility has become a major public health issue. The concealment and accumulation of environmental hazards, and their interactions with the endogenous immune network, have long been underappreciated. As the central organ for sperm maturation and motility acquisition, the epididymis plays a vital role in male fertility, and the homeostasis of the epididymal immune microenvironment (EIM) is essential. Nevertheless, a systematic synthesis of common environmental hazards and their impact on EIM, which can lead to male infertility, remains lacking. This review comprehensively summarizes the composition, functionality, and key characteristics of the EIM and underscores its critical role in preserving male reproductive health. We further evaluate and delineate the disruption of EIM homeostasis resulting from major categories of environmental exposures—including chemical, physical, biological, and behavioral hazards—and discuss their shared pathophysiological mechanisms. By integrating evidence linking environmental insults, EIM dysregulation, and male infertility, this work aims to identify pivotal molecular mechanisms from an immunological perspective. The findings provide a mechanistic foundation for the development of targeted interventions and preventive strategies against environmental hazard-induced male infertility. Full article

(This article belongs to the Special Issue Reproductive and Developmental Toxicity of Environmental Factors)

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20 pages, 1161 KB

Open AccessReview

Prenatal Exposure to Tobacco Smoke and Vaping Aerosols: Mechanisms Disrupting White-Matter Formation

by Sebastián Beltran-Castillo, Juan Pablo Espinoza and Michelle Grambs

Toxics 2025, 13(12), 1071; https://doi.org/10.3390/toxics13121071 - 12 Dec 2025

Cited by 1 | Viewed by 1117

Abstract

White-matter development during fetal life represents one of the most vulnerable processes to environmental disruption, as it relies on the precisely timed proliferation, migration, and differentiation of oligodendrocyte lineage cells. Among environmental threats, exposure to toxic compounds contained in tobacco smoke and vaping aerosols represents a major yet preventable risk during pregnancy. Despite growing awareness, tobacco smoking remains widespread, and a substantial proportion of the population—including pregnant women—continues to perceive electronic nicotine delivery systems (ENDS) as less harmful, a misconception that contributes to persistent prenatal exposure. These products expose the fetus to numerous substances that readily cross the placenta and reach the developing brain, including compounds with endocrine-disrupting activity, where they interfere with white-matter development. Epidemiological and neuroimaging studies consistently reveal microstructural alterations in white matter that correlate with long-term cognitive and behavioral impairments in offspring exposed in utero. These alterations may arise from both nicotine-specific pathways and the actions of other toxicants in cigarette smoke and ENDS aerosols that cross the placenta and disrupt white-matter emergence and maturation. Preclinical research provides mechanistic insight: nicotine acts directly on nicotinic acetylcholine receptors (nAChRs) in oligodendrocyte precursor cells, disrupting calcium signaling and differentiation, while additional constituents of smoke and vaping aerosols also affect astrocyte and microglial function and disturb the extracellular milieu required for proper myelination. Full article

(This article belongs to the Special Issue Reproductive and Developmental Toxicity of Environmental Factors)

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