Reproductive Toxicity Research Articles

Dietary Nannochloropsis oculata could ameliorate cadmium chloride-induced reproductive toxicity in Barki rams: Antioxidant, MAP3K8, and inflammatory pathways

The experiment was intended to explore the protecting effects of Nannochloropsis oculate on the induced cadmium reproductive toxicity in rams. Twenty mature Barki rams were randomly allocated into four groups, each containing five rams: group I (control), group II (received 3 % dietary N. oculate), group III (received 1 mg/Kg/day cadmium chloride (CdCl2), and group IV (received 3 % dietary N. oculate and 1 mg/Kg/day CdCl2). Semen ejaculates and blood samples were collected. Testicular volume and reaction time were assessed with every semen collection. Ejaculates were analyzed for semen criteria. Rams were subjected to a castration process to analyze the anti-oxidative status, including total antioxidant capacity (TAC) and superoxide dismutase (SOD), and inflammatory markers in the testicular homogenate. Testicular histopathology was performed on testicular sections. Gene expression of p38 Mitogen-Activated Protein Kinase (MAPK) was assessed. Alga-treated rams revealed significant improvement in semen criteria, testicular weight, and testosterone hormone as compared to other groups. The levels of testicular antioxidant markers and interleukin-10 elevated significantly in the alga group, while interleukin-12 increased in the CdCl2 group. Alga+CdCl2 rams showed significant amelioration in the previous parameters equated to the CdCl2 group. CdCl2 rams exhibited a significant fold upgrade in MAPK of compared with other groups. Testicular histopathology revealed marked alterations in the testicular architecture of CdCl2, while administration of alga recovered the testicular architecture. In conclusion, administration of N. oculate ameliorated semen criteria, testicular antioxidant capacity as well as testicular histopathology that was declared by the expression of MAPK38.

Exposure to organophosphate esters and early menopause: A population-based cross-sectional study

Organophosphate esters (OPEs), increasingly used as new flame retardants and plasticizers in various products, have been found to have reproductive toxicity with overt endocrine disruption potential, yet the relationship between OPEs and early menopause remains unexplored. In the present study, we included 2429 women who participated in the U.S. National Health and Nutrition Examination Survey data (2011–2020) and had data of five urinary OPE metabolite levels and information of menopause characteristics, to investigate the associations of OPEs exposure with premature ovarian insufficiency (POI) and age of menopause. Multivariable adjusted linear and logistic regression were used to assess the associations of urinary OPE metabolites with age of menopause and POI, respectively. Quantile g computation (QGC) models were used to assess the relative contribution of individual metabolites to associations of OPE metabolites mixture. After adjusting for covariates, urinary bis(2-chloroethyl) phosphate (BCEP) concentration was inversely associated with menopause age (β = - 0.21; 95% confidence interval (CI): 0.41, - 0.002). Higher urinary BCEP level (>median) was associated with earlier age at menopause (β = −1.14, 95% CI: 1.83, - 0.46), and elevated odds of having POI (OR = 1.93; 95% CI: 1.02, 3.66). These associations were robust to the further adjustment of cardiometabolic diseases and related traits (e.g., body mass index). Further QGC analyses confirmed that BCEP was the dominant metabolite contributing most to the associations of OPEs mixture with age of menopause (weight = 49.5%) and POI (weight = 75.1%). No significant associations were found for the other four OPE metabolites. In this cross-sectional study, urinary BCEP level was associated with earlier menopause and increased odds of POI, highlighting the potential negative impacts of this chemical and its parent compound tris(2-chloroethyl) phosphate on ovarian function. Further studies are required to validate our findings and reveal potential underlying mechanisms.

Long-term impact of Hurricane Maria on point-of-use drinking water quality in Puerto Rico and associated potential adverse health effects

Drinking water security in Puerto Rico (PR) is increasingly challenged by both regulated and emerging anthropogenic contaminants, which was exacerbated by the Hurricane Maria (HM) due to impaired regional water cycle and damaged water infrastructure. Leveraging the NIEHS PROTECT (Puerto Rico Testsite for Exploring Contamination Threats) cohort, this study assessed the long-term tap water (TW) quality changes from March 2018 to November 2018 after HM in PR, by innovatively integrating two different effect-based quantitative toxicity assays with a targeted analysis of 200 organic and 22 inorganic pollutants. Post-hurricane PR TW quality showed recovery after >6-month period as indicated by the decreased number of contaminants showing elevated average concentrations relative to pre-hurricane samples, with significant difference of both chemical and toxicity levels between northern and southern PR. Molecular toxicity profiling and correlation revealed that the HM-accelerated releases of certain pesticides and PPCPs could exert increased cellular oxidative and/or AhR (aryl hydrocarbon receptor)-mediated activities that may persist for more than six months after HM. Maximum cumulative ratio and adverse outcome pathway (AOP) assessment identified the top ranked detected TW contaminants (Cu, Sr, V, perfluorooctanoic acid) that potentially associated with different adverse health effects such as inflammation, impaired reproductive systems, cancers/tumors, and/or organ toxicity. These insights can be incorporated into the regulatory framework for post-disaster risk assessment, guiding water quality control and management for public health protection.

Protective effect of rutin on acrylamide induced ovarian inflammation, oxidative stress, DNA damage, and hormonal changes: Based on in silico and in vivo study.

Acrylamide (AA) is a carcinogenic compound that affects people due to its frequent use in laboratories and industry as well as the high-temperature cooking of foods with high hydrocarbon content. AA is known to cause severe reproductive abnormalities. The main aim of this study is to evaluate the protective effect of rutin (RU), a phytoactive compound, against AA-induced reproductive toxicity in female rats. Initially, rats were exposed to AA (40 mg/kg for 10 days). Therapy of RU was given after AA intoxication consecutively for 3 days. After 24 h of the last treatment, all the animals were sacrificed. The study evaluated reproductive hormones, oxidative stress markers, membrane-bound enzymes, DNA damage, histological findings, and an in silico approach to determine the protective efficacy of RU. The results indicated that RU significantly protected against inflammation, oxidative stress, and DNA damage induced by AA, likely due to its antioxidant properties.

Chronic Polystyrene Microplastic Exposure Reduces Testosterone Levels in Mice through Mitochondrial Oxidative Stress and BAX/BCL2-Mediated Apoptosis.

Microplastics (MPs) have emerged as a major environmental issue. They have been found to cause significant reproductive toxicity and lower testosterone levels in adult males, though the exact mechanisms remain unclear. In this study, C57bl/6 mice were orally exposed to saline or varying doses (0.25, 0.5, and 1 mg/day) of 5 μm polystyrene MPs (PS-MPs) for 4 weeks, and TM3 mouse Leydig cells were treated with different concentrations of PS-MPs. Our results found that exposure to PS-MPs significantly reduced testosterone levels and impaired the synthesis function of testicular steroids. In vitro, PS-MPs reduced steroid synthesis in Leydig cells. Treatment with PS-MPs significantly increased the apoptosis rate and BAX/BCL2 ratio in Leydig cells. Additionally, GSH-px and SOD activities decreased, while MDA levels increased, along with a rise in mitochondrial ROS. In conclusion, chronic PS-MP exposure reduced testosterone levels in mice through mitochondrial oxidative stress and BAX/BCL2-mediated apoptosis. This study offers new insights into the health risks posed by MPs.

The use of weight-of-evidence approaches to characterize developmental toxicity risk for therapeutic monoclonal antibodies in humans without in vivo studies

Regulatory guidance for global drug development relies on animal studies to evaluate safety risks for humans, including risk of reproductive toxicity. Weight-of-evidence approaches (WoE) are increasingly becoming acceptable to evaluate risk. A WoE for developmental risk of monoclonal antibodies (mAbs) was evaluated for its ability to retrospectively characterize risk and to determine the need for further in vivo testing based on the remaining uncertainty. Reproductive toxicity studies of 65 mAbs were reviewed and compared to the WoE. Developmental toxicities were absent in 52/65 (80%) mAbs. Lack of toxicity was correctly predicted in 29/52 (56%) cases. False positive and equivocal predictions were made in 9/52 (17%) and 14/52 (27%) cases. For 3/65 (5%) mAbs, the findings were equivocal. Of mAbs with developmental toxicity findings (10/65, 15%), the WoE correctly anticipated pharmacology based reproductive toxicity without any false negative predictions in 9/10 (90%) cases, and in the remaining case (1/10, 10%) an in vivo study was recommended due to equivocal WoE outcome. Therefore, this WoE approach could characterize presence and absence of developmental risk without animal studies. The current WoE could have reduced the need for developmental toxicity studies by 42% without loss of important patient information in the label.

Micro/Nanoplastic Exposure on Placental Health and Adverse Pregnancy Risks: Novel Assessment System Based upon Targeted Risk Assessment Environmental Chemicals Strategy.

Micro/nanoplastics (MNPs), as emerging pollutants, have been detected in both the maternal and fetal sides of the placenta in pregnant women, and their reproductive toxicity has been demonstrated in in vivo and in vitro experimental models. The Targeted Risk Assessment of Environmental Chemicals (TRAEC) strategy has been innovatively devised to facilitate valid risk assessment, encompassing a comprehensive evaluation of reliability, correlation, outcome fitness, and integrity across four dimensions based on the included published evidence and our own findings. This study serves as an application case of TRAEC, with 40 items of research evidence on the toxicity of MNPs to the placenta, which were rigorously screened and incorporated into the final scoring system. The final score for this TRAEC case study is 5.63, suggesting a moderate-to-low risk of reproductive toxicity associated with MNPs in the placenta, which may potentially increase with decreasing particle size. It is essential to emphasize that the findings also report original data from assays indicating that exposure to high-dose groups (100 μg/mL, 200 μg/mL) of 50 nm and 200 nm polystyrene nanoplastics (PS-NPs) induces HTR8/SVneo cell cycle arrest and cell apoptosis, which lead to reproductive toxicity in the placenta by disrupting mitochondrial function. Overall, this study employed the TRAEC strategy to provide comprehensive insight into the potential reproductive health effects of ubiquitous MNPs.

Ameliorative action of eugenol on nitrate induced reproductive toxicity in male rats

There is a great concern for studies to prevent nitrate (NO3) induced male reproductive toxicity as it might lead to infertility. Therefore, the study was aimed to investigate the ameliorative effects of eugenol on NO3 induced male reproductive toxicity in wistar rats. Adult male rats were randomly divided into five groups (n=5). The first group was served as control, the second and third group of rats were treated with 100 mg/kg bw of sodium nitrate (NaNO3) and NO3 contaminated ground water respectively. The fourth and fifth group of rats were orally intubated with eugenol (100 mg/kg bw) and then exposed to NaNO3 and NO3 contaminated ground water respectively. The treatment was continued for 52 days. Nitrate exposure significantly decreased the sperm motility, testicular 3-beta-hydroxysteroid dehydrogenase activity, serum concentration of testosterone, activities of superoxide dismutase and catalase in testis and spermatozoa and different categories of germ cells in stage VII of spermatogenesis. Further, there was significant increase in sperm abnormality and levels of nitrite (NO2) and malondialdehyde in testis and spermatozoa of NO3 treated rats. In addition, NO3 exposure distorted the histological architecture of seminiferous tubules of testis. It was established that NO3 induced high production of NO2 affected spermatogenesis, steroidogenesis and sperm motility. However, in the present study, pretreatment of eugenol prevented NO3 induced reproductive alterations by decreasing the level of NO2. These findings clearly showed the protective action of eugenol against NO3 induced oxidative stress in male reproductive system.

Rumen Microbiota Transplantation Alleviates Gossypol Diet-Induced Reproductive, Liver, and Intestinal Damage in Male Mice.

Ruminants exhibit stronger tolerance to gossypol, an anti-nutritional factor, compared to monogastric animals. We transplanted Hu sheep rumen microbiota into male mice to investigate the role of rumen microbiota in animal gossypol tolerance. Thirty specific-pathogen-free (SPF) male C57BL/6 mice were randomly divided into three groups: normal diet (CK group), gossypol diet (FG group), and rumen microbiota transplantation (FMT group, gossypol diet). The pathological changes in the liver and small intestine of the mice, the organ coefficient, and sperm parameters were analyzed. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in the blood and lactate dihydrogen-X (LDH-X) levels in the testicular tissue were also measured. The results showed that body weight, feed intake, sperm concentration, sperm motility, and LDH-X levels in the FMT group increased (p < 0.05) compared with the FG group, while the enzyme activities of ALT, AST, and AST/ALT decreased (p < 0.05). In the FMT group, the injury to liver cells was alleviated, the structure of the small intestine was intact, and the villus height and the ratio of villus height to crypt depth (V/C) were higher than those in the FG group (p < 0.05). And there were no differences in various organ coefficients and sperm deformity rates among the three groups (p > 0.05), but compared with the FG group, mice in the FMT group showed tendencies closer to those in the CK group. Rumen microbiota transplantation relieved the reproductive toxicity and liver damage induced by gossypol in male mice and improved the tolerance of recipient animals to gossypol. Additionally, rumen microbes improved the intestinal structural integrity of recipients.

Biochemical Characterization and Application of Zearalenone Lactone Hydrolase Fused with a Multifunctional Short Peptide.

Zearalenone (ZEN) is an estrogenic mycotoxin causing reproductive toxicity in livestock. Currently, lactone hydrolases are used in the enzymatic degradation of ZEN. However, most lactone hydrolases suffer from low degradation efficiency and poor thermal stability. ZHD518, as a documented neutral enzyme for ZEN degradation, exhibits high enzymatic activity under neutral conditions. In this study, a multifunctional peptide S1v1-(AEAEAHAH)2 was fused to the N-terminus of ZHD518. Compared with the wild-type enzyme, the peptide fusion significantly enhanced protein expression by 1.28 times, enzyme activity by 9.27 times, thermal stability by 37.08 times after incubation at 45 °C for 10 min and enzyme stability during long-term storage. Moreover, ZEN concentrations in corn bran, corn germ meal, and corn gluten powder decreased from 5.29 ± 0.04, 5.31 ± 0.03, and 5.30 ± 0.01 μg/g to 0.48 ± 0.05, 0.48 ± 0.06, and 0.21 ± 0.04 μg/g, respectively, following a 60 min treatment with S1v1-GS-ZHD518, resulting in degradation rates of 90.98, 91.00, and 95.32%, respectively. In conclusion, the properties of S1v1-GS-ZHD518, such as its efficient degradability, high temperature resistance and storage resistance, offer the possibility of its application in food or feed.

Transgenerational reproductive toxicity induced by carboxyl and amino charged microplastics at environmental concentrations in Caenorhabditis elegans: Involvement of histone methylation

Microplastics, recognized as emerging contaminants, are commonly observed to be charged in the environment, potentially exerting toxic effects on various organisms. However, the transgenerational reproductive toxicity and underlying mechanisms of polystyrene (PS), particularly carboxyl-modified PS (PS-COOH) and amino-modified PS (PS-NH2), remain largely unexplored. In this study, the parental generation (P0) of Caenorhabditis elegans was subjected to environmental concentrations (0.1–100 μg/L) of PS, PS-COOH, and PS-NH2, with subsequent generations (F1–F4) cultured under normal conditions. Exposure to PS-NH2 at concentrations of 10–100 μg/L exhibited more pronounced reproductive toxicity compared to PS or PS-COOH, resulting in decreased brood size, egg ejection rate, number of fertilized eggs, and cell corpses per gonad. Similarly, maternal exposure to 100 μg/L of PS-NH2 induced more severe transgenerational reproductive effects in C. elegans. Significant increases in H3 on lysine 4 dimethylation (H3K4me2) and H3 on lysine 9 trimethylation (H3K9me3) levels were observed in the subsequent generation, concurrent with the transgenerational upregulation of set-30 and met-2 following parental exposure to PS, PS-COOH, and PS-NH2. Correlation analyses revealed significant associations between the expression of these genes with the reproductive ability. Molecular docking studies suggested that PS-NH2 exhibited higher affinity for SET-30 and MET-2. Further analysis demonstrated that transgenerational effects on reproduction were absent in set-30(gk315) and met-2(n4256) mutants, highlighting the pivotal role of set-30 and met-2 in mediating the transgenerational effect. This study provides novel insights into the environmental risks associated with negatively and positively charged microplastics.

Rosolic acid as a novel activator of the Nrf2/ARE pathway in arsenic-induced male reproductive toxicity: An in silico study

Male reproductive toxicity as a result of arsenic exposure is linked with oxidative stress and excessive generation of reactive oxygen species (ROS). It leads to an imbalance between ROS production and antioxidant defense mechanisms ultimately resulting in male infertility. The nuclear factor erythroid 2 (NFE2)-related factor 2 (Nrf2) is a transcription factor that responds to cellular stressors controlling the oxidative state, mitochondrial dysfunction, inflammation, and proteostasis. This study aims to investigate the potential of Rosolic acid (ROA) to act as a novel Nrf2 activator by mitigating oxidative stress to combat arsenic-induced male reproductive toxicity. The protein and ligands were prepared in the BIOVIA Discovery Studio, followed by protein-ligand docking using auto dock vina integrated with the PyRx-Virtual Screening Tool. Then the ADME properties were analyzed using the SwissADME tool to get a clear idea about the physicochemical properties, lipophilicity, water solubility, pharmacokinetics, and drug likeliness of ROA. It was followed by molecular dynamics simulation (MDS) studies using GROMACS. The 3D and 2D interaction maps revealed the interactions of Keap 1 with ROA. Keap1-ROA complex was found to have a binding energy of −7.8 kcal/mol. ROA showed 0 violations for Lipinski and 0 alerts each for PAINS and Brenk and a bioavailability score of 0.55. The BOILED-Egg representation showcases that ROA is predicted as passively crossing the blood-brain barrier (BBB). The MDS described 2FLU-ROA as a stable system. This work portrays that ROA can be a potent Nrf2 activator by exhibiting an inhibitory activity against the Keap1 protein and thus mitigating oxidative stress in arsenic-induced male reproductive toxicity.

IMPACT OF REAL-LIFE ENVIRONMENTAL EXPOSURES ON REPRODUCTION: Evidence for reproductive health effects following exposure to hydraulic fracturing chemical mixtures.

Unconventional oil and natural gas (UOG) operations, particularly hydraulic fracturing, have revolutionized oil and gas production, using and containing complex mixtures of chemicals that may impact reproductive health. While there is growing evidence for effects on births in hydraulic fracturing/UOG regions and good mechanistic evidence for potential reproductive toxicity, there is much research still needed to make firm conclusions about these practices and reproductive health. Unconventional oil and natural gas (UOG) operations have emerged over the last four decades to transform oil and gas production in the United States and globally by unlocking previously inaccessible hydrocarbon deposits. UOG development utilizes many compounds associated with conventional oil and gas, as well as some specific to UOG extraction, particularly during hydraulic fracturing (HF). While research is increasing on UOG chemicals and their mixtures, this review discusses the current evidence for reproductive toxicity following exposures to UOG/HF mixtures. These complex chemical mixtures have been demonstrated to interact with numerous mechanisms known to influence reproductive health. A growing number of environmental and controlled laboratory testing studies have reported adverse reproductive health effects in animals exposed to various UOG chemical mixtures. An expanding body of epidemiological literature has assessed adverse birth outcomes, although none has directly examined reproductive measures such as time to pregnancy, semen quality, and other direct measures of fertility. The existing literature provides moderate evidence for decreased birth weights, increased risk of small for gestational age and/or preterm birth, increased congenital abnormalities, and increased infant mortality, though importantly, studies are widely variable in methods used. Most studies utilized distance from UOG operations as an exposure proxy and did not measure actual chemical exposures experienced by those living near these operations. As such, while there is growing evidence for effects on births in these regions and good mechanistic evidence for potential reproductive toxicity, there is much research still needed to make firm conclusions about UOG development and reproductive health.

Multigenerational toxicity of microplastics derived from two types of agricultural mulching films to Folsomia candida

Degradation and fragmentation of mulching films represents an increasing source of microplastics (MPs, plastic particles 1 μm to 5 mm in size) to agricultural soils. MPs have been shown to affect many soil invertebrates, including springtails. However, these studies typically use test materials representing less environmentally relevant particle types, such as pristine uniform MPs, which do not represent the large range of particle sizes and morphologies found in the field. This study aimed at providing insight into the adverse effects of MPs originating from agricultural mulching films, by using artificially aged MPs derived from both biodegradable (starch-polybutadiene adipate terephthalate (PBAT)) blend, as well as conventional (linear low-density polyethylene (LLDPE)) plastic polymers. The soil dwelling springtail Folsomia candida was exposed to these MPs for five generations in order to elucidate population effects due to possible reproduction toxicity, endocrine disruption, mutagenesis or developmental toxicity. F. candida were exposed to 0, 0.0016, 0.008, 0.04, 0.2, 1, 2, 3, 4 and 5 % (w/w dry soil) MPs in Lufa 2.2 soil, which includes concentrations within the range of environmental relevance. Juveniles produced at each concentration were transferred to the next generation, with the parental, F2 and F4 generations being exposed for four weeks and F1 and F3 generations for five weeks. No concentration-dependent effects on F. candida survival or reproduction were observed in exposures to either of the MPs, in any of the generations. These results suggest that the particular MPs used in this study, derived from mulching films used on agricultural soils, may not be potent toxicants to F. candida, even after long-term exposure and at elevated concentrations.

Bisphenol A and bisphenol AF co-exposure induced apoptosis of human ovarian granulosa cells via mitochondrial dysfunction

Bisphenol A (BPA) is a synthetic chemical primarily utilized in the manufacturing of polycarbonate plastics and epoxy resins that are present in various consumer products. While the BPA impacts on female reproductive toxicity have been widely investigated, very little is currently identified about the mixed toxicity of BPA and bisphenol AF (BPAF), another common BPA derivative that is used in many industrial applications. In this study, we assessed the effect of co-exposure of BPA (30 and 50 μM) and BPAF (3 and 5 μM) on mitochondrial dysfunction in human granulosa cells (KGN cells) for 24 h. Our results exhibited that high-concentration bisphenol individual or their mixture exposure of KGN cells induced significant mitochondrial dysfunction by reducing mitochondrial mass, reducing ATP production, and damaging the mitochondrial respiratory chain. In addition, we found that the combination of BPA and BPAF significantly induced mitochondrial stress by increasing calcium levels and the production of ROS in mitochondria. Mitochondrial stress induced by BPA and BPAF was determined to be a mechanism that promoted cell apoptosis after pretreating the cells with the mitochondrial-targeted antioxidant and the calcium chelator. Our results provide novel evidence of the cytotoxicity of mixtures of different bisphenol compounds.

Ethylene oxide suppresses boar sperm function during capacitation

Ethylene oxide (E.O) is an epoxide compound, and it has been utilized as a sterilizer or production of ether compounds in several industries. Although the toxic effects of E.O on bacteria and mammals have been reported, its effects on male reproductive toxicity during sperm capacitation are not fully understood. Therefore, this study was designed to evaluate the effects of E.O exposure during sperm capacitation. Boar spermatozoa were treated with various E.O concentrations (0, 0.1, 1, 10, and 100 μМ). After exposure, sperm motility, motion kinematics, capacitation status, intracellular ATP levels, cell viability, expression levels of protein kinase A (PKA) activation, and tyrosine phosphorylation were evaluated. Results revealed that E.O exposure significantly decreased sperm motility, motion kinematics, and intracellular ATP levels but significantly increased the capacitated spermatozoa. In addition, the PKA activation and tyrosine phosphorylation were abnormally changed. According to our results, E.O may cause toxic effects on sperm function during capacitation, which induces male reproductive toxicity. Consequently, we suggest that male reproductive toxicity should be considered when using E.O.

Exposome Profiling of Environmental Pollutants in Seminal Plasma and Novel Associations with Semen Parameters.

Indicators of male fertility are in decline globally, but the underlying causes, including the role of environmental exposures, are unclear. This study aimed to examine organic chemical pollutants in seminal plasma, including both known priority environmental chemicals and less studied chemicals, to identify uncharacterized male reproductive environmental toxicants. Semen samples were collected from 100 individuals and assessed for sperm concentration, percent motility, and total motile sperm. Targeted and nontargeted organic pollutant exposures were measured from seminal plasma using gas chromatography, which showed widespread detection of organic pollutants in seminal plasma across all exposure classes. We used principal component pursuit (PCP) on our targeted panel and derived one component (driven by etriadizole) associated with total motile sperm (p < 0.001) and concentration (p = 0.03). This was confirmed by the exposome-wide association models using individual chemicals, where etriadizole was negatively associated with total motile sperm (FDR q = 0.01) and concentration (q = 0.07). Using PCP on 814 nontargeted spectral peaks identified a component that was associated with total motile sperm (p = 0.001). Bayesian kernel machine regression identified one principal driver of this association, which was analytically confirmed to be N-nitrosodiethylamine. These findings are promising and consistent with experimental evidence showing that etridiazole and N-nitrosodiethylamine may be reproductive toxicants.

Human risk assessment through development and application of a physiologically based toxicokinetic model for 4-tert-octylphenol

4-tert-octylphenol (4-tert-OP) is an ecologically hazardous substance, and exposure to it in the environment has been consistently reported in the past. Despite the hazards and widespread exposure to 4-tert-OP, tools for scientific assessment of 4-tert-OP exposure risk level in humans are lacking. The main purpose of this study was to develop a physiologically-based-toxicokinetic (PBTK) model for 4-tert-OP and to perform quantitative risk assessment of 4-tert-OP in various population groups using the established model. Based on the results of toxicokinetic experiments on male rats, the PBTK model for 4-tert-OP was established and verified, and this was converted to a model for humans through interspecies extrapolation. Based on the previously reported no-observed-adverse-effect-levels for rats, it was possible to estimate the 4-tert-OP reference dose in humans through reverse dosimetry using the model. Biomonitoring data derived from various population groups were applied to the human PBTK model to calculate external exposures and margin of safety for 4-tert-OP for each population group. The PBTK model established in this study adequately explained the toxicokinetic experimental values at acceptable levels and was able to quantitatively predict the 4-tert-OP exposure level in the testes related to male reproductive toxicity. In addition, the degree of external exposure to 4-tert-OP could be scientifically estimated based on biomonitoring values derived from various biological matrices. The reference doses for systemic and reproductive toxicity caused by 4-tert-OP in male humans were calculated to be 0.16 and 1.12 mg/kg/day, respectively. The mean external exposure to 4-tert-OP in each population group estimated based on plasma and urine biomonitoring data was 0.04–66.24 mg/kg/day, showing very large exposure diversity between groups. Exposure risks to 4-tert-OP in populations ranged from safe to risky, suggesting the need for continued monitoring and risk management of 4-tert-OP worldwide. This study provides valuable scientific insight regarding the 4-tert-OP human risk assessment.

Prenatal exposure to Benzo[a]pyrene affects maternal–fetal outcomes via placental apoptosis

Prenatal exposure to Benzo[a]pyrene (BaP) has been suggested to increase the risk of adverse pregnancy outcomes. However, the role of placental apoptosis on BaP reproductive toxicity is poorly understood. We conducted a maternal animal model of C57BL/6 wild-type (WT) and transformation-related protein 53 (Trp53) heterozygous knockout (p53KO) mice, as well as a nested case–control study involving 83 women with PB and 82 term birth from a birth cohort on prenatal exposure to BaP and preterm birth (PB). Pregnant WT and p53KO mice were randomly allocated to BaP treatment and control groups, intraperitoneally injected of low (7.8 mg/kg), medium (35 mg/kg), and high (78 mg/kg) doses of 3,4-BaP per day and equal volume of vegetable oil, from gestational day 10.5 until delivery. Results show that high-dose BaP treatment increased the incidence of preterm birth in WT mice. The number of fetal deaths and resorptions increased with increasing doses of BaP exposure in mice. Notably, significant reductions in maternal and birth weights, increases in placental weights, and decrease in the number of livebirths were observed in higher-dose BaP groups in dose-dependent manner. We additionally observed elevated p53-mediated placental apoptosis in higher BaP exposure groups, with altered expression levels of p53 and Bax/Bcl-2. In case–control study, the expression level of MMP2 was increased among women with high BaP exposure and associated with the increased risk of all PB and moderate PB. Our study provides the first evidence of BaP-induced reproductive toxicity and its adverse effects on maternal–fetal outcomes in both animal and population studies.

Lactating exposure to microplastics at the dose of infants ingested during artificial feeding induced reproductive toxicity in female mice and their offspring

Microplastics (MPs) pollution poses a global environmental challenge with significant concerns regarding its potential impact on human health. Toxicological investigations have revealed multi-system impairments caused by MPs in various organisms. However, the specific reproductive hazards in human contexts remain elusive, and understanding the transgenerational reproductive toxicity of MPs remains limited. This study delves into the reproductive toxicity resulting from lactational exposure to polystyrene MPs (PS-MPs) in female mice, extending the inquiry to assess the reproductive effects on their offspring bred by rigorous natural mating. The MPs dosage corresponds to the detected concentration in infant formula prepared using plastic bottles. By systematically evaluating the reproductive phenotypes of F0 female mice from birth to adulthood, we found that female mice exposed to PS-MPs exhibited delayed puberty, disturbed estrous cyclicity, diminished fertility, elevated testosterone, abnormal follicle development, disrupted ovarian steroidogenesis, and ovarian inflammation. Importantly, the observed inheritable reproductive toxicity manifested with gender specificity, showcasing more pronounced abnormalities in male offspring. Specifically, reproductive disorders did not manifest in female offspring; however, a significant decrease in sperm count and viability was observed in PS-MPs-exposed F1 males. Testicular transcriptomics analysis of F1 males significantly enriched pathways associated with reproductive system development and epigenetic modification, such as male germ cell proliferation, DNA methylation, and histone modification. In summary, real-life exposure to PS-MPs impaired the reproductive function of female mice and threateningly disrupted the spermatogenesis of their F1 male offspring, which raises serious concerns about inter- and trans-generational reproductive toxicities of MPs in mammals. These findings underscore the potential threats of MPs to human reproductive health, emphasizing the need for continued vigilance and research in this critical area.