Combined pesticides in field doses weaken honey bee (Apis cerana F.) flight ability and analyses of transcriptomics and metabolomics.

Imidacloprid, chlorpyrifos, and glyphosate rank among the most extensively employed pesticides worldwide. The effects of these pesticides and their combined on the flight capability of Apis cerana, and the potential underlying mechanisms remain uncertain. To investigate these effects, we carried out flight mill, transcriptome, and metabolome experiments. Our findings reveal that individual acute oral treatments with pesticides, specifically 20 µL of 10 ng/g imidacloprid (0.2 ng per bee), 30 ng/g chlorpyrifos (0.6 ng per bee), and 60 ng/g glyphosate (1.2 ng per bee), did not impact the flight capability of the bees. However, when bees were exposed to a combination of two or three pesticides, a notable reduction in flight duration and distance was observed. In the transcriptomic and metabolomic analyses, we identified 307 transcripts and 17 metabolites that exhibited differential expression following exposure to combined pesticides, primarily associated with metabolic pathways involved in energy regulation. Our results illuminate the intricate effects and potential hazards posed by combined pesticide exposures on bee behavior. These findings offer valuable insights into the synergistic potential of pesticide combinations and their capacity to impair bee behavior. Understanding these complex interactions is essential for comprehending the broader consequences of pesticide formulations on honey bee populations.

Adenosine triphosphate alleviates high temperature-enhanced glyphosate toxicity in maize seedlings.

Extracellular ATP plays a key role in regulating plants stress responses. Here, we aimed to determine whether ATP can alleviate the glyphosate toxicity in maize seedlings under high temperature by regulating antioxidant responses. Foliar spraying with 100 µM glyphosate inhibited the growth of maize seedlings at room temperature (25 °C), leading to an increase in shikimic acid accumulation and oxidative stress (evaluated via lipid peroxidation, free proline, and H2O2 content) in the leaves, all of which were further exacerbated by high temperature (35 °C). The growth inhibition and oxidative stress caused by glyphosate were both alleviated by exogenous ATP. Moreover, the glyphosate-induced antioxidant enzyme activity and antioxidant accumulation were attenuated by high temperature, while ATP treatment reversed this inhibitory effect. Similarly, qPCR data showed that the relative expression levels of antioxidant enzyme-related genes (CAT1, GR1, and γ-ECS) in maize leaves were upregulated by ATP before exposure to GLY. Moreover, high temperature-enhanced GLY residue accumulation in maize leaves was reduced by ATP. ATP-induced detoxification was attenuated through NADPH oxidase (NOX) inhibition. Higher NOX activities and O2•- production were noted in ATP-treated maize leaves compared to controls prior to GLY treatment, indicating that the extracellular ATP-induced alleviation of GLY toxicity was closely associated with NOX-dependent reactive oxygen species signalling. The current findings present a new approach for reducing herbicide toxicity in crops exposed to high temperatures.

[Glyphosate and human health]. / Glyphosate et santé humaine, une plongée en eaux troubles.

At this time of environmental crisis, pesticides represent a major threat to the environment and to human health alike. The widely used herbicide glyphosate is suspected of acting as a mutagen, a carcinogen as well as a neurotoxic substance for the professionals who use it. This possibly also holds true for the population at large. Despite increasing warnings from the independent scientific community, this product was granted provisional registration for Europe in 2017, and the decision has been postponed to 2022 with a report on the decision by that date. In fact, EU and US public authorities - who in theory are guarantors of public health - seem to put up with biased expert committees, falsification of science and attacks against a WHO health protection agency, as they keep relying on administrative pseudo-science as a basis for their decisions.

À l'heure de la crise environnementale, les pesticides sont la cause d'une atteinte majeure à l'environnement et à la santé humaine. Le glyphosate, herbicide très répandu, est soupçonné d'être un mutagène, un carcinogène et un neurotoxique pour les professionnels qui l'utilisent et peut-être aussi pour la population générale. Malgré les alertes toujours plus nombreuses du monde scientifique indépendant, ce produit a obtenu son homologation provisoire pour l'Europe en 2017 et la décision prévue en 2022 a été reportée. Les pouvoirs publics de l'Union européenne et des États-Unis ­ garants en principe de la santé publique ­ semblent s'accommoder de comités d'experts sous influence, de falsification de la science et d'attaques contre une agence de protection sanitaire de l'OMS et s'appuient sur une pseudoscience administrative pour fonder leurs décisions.

Structural characterization and in silico toxicity prediction of degradation impurities of roxadustat.

Roxadustat is the first drug approved for anemia due to chronic kidney disease. Drug degradation profile is very crucial for assessing the quality and safety of the drug substances and their formulations. Forced degradation studies are conducted for quick prediction of drug degradation products. Forced degradation of roxadustat was carried out as per ICH guidelines, and nine degradation products (DPs) were observed. These DPs (DP-1 to DP-9) were separated using the reverse phase HPLC gradient method with an XBridge column (250 mm × 4.6 mm, 5 µm). The mobile phase consisted of 0.1% formic acid (solvent A) and acetonitrile (solvent B) at a flow rate of 1.0 ml/min. The chemical structures of all the DPs were proposed by using LC-Q-TOF/MS. DP-4 and DP-5, the two major degradation impurities, were isolated, and NMR was used to confirm their chemical structures. Based on our experiments, the roxadustat was found stable to thermal degradation in solid state and oxidative conditions. However, it was unstable in acidic, basic, and photolytic conditions. A very remarkable observation was made about DP-4 impurity. DP-4 was generated as a common degradation impurity in alkaline hydrolysis, neutral hydrolysis as well as photolysis conditions. DP-4 has a similar molecular mass to roxadustat but is structurally different. DP-4 is chemically, (1a-methyl-6-oxo-3-phenoxy-1,1a,6,6a-tetrahydroindeno [1,2-b] aziridine-6a-carbonyl) glycine. In silico toxicity study was conducted using Dereck software to gain the best knowledge of the drug and its degradation products towards carcinogenicity, mutagenicity, teratogenicity, and skin sensitivity. A further study using molecular docking confirmed the potential interaction of DPs with proteins responsible for toxicity. DP-4 shows a toxicity alert due to the presence of aziridine moiety.

Mammary gland development in male rats perinatally exposed to propiconazole, glyphosate, or their mixture.

This study aimed to assess whether perinatal exposure to propiconazole (PRO), glyphosate (GLY) or their mixture (PROGLY) alters key endocrine pathways and the development of the male rat mammary gland. To this end, pregnant rats were orally exposed to vehicle, PRO, GLY, or a mixture of PRO and GLY from gestation day 9 until weaning. Male offspring were euthanized on postnatal day (PND) 21 and PND60. On PND21, GLY-exposed rats showed reduced mammary epithelial cell proliferation, whereas PRO-exposed ones showed increased ductal p-Erk1/2 expression without histomorphological alterations. On PND60, GLY-exposed rats showed reduced mammary gland area and estrogen receptor alpha expression and increased aromatase expression, whereas PRO-exposed ones showed enhanced lobuloalveolar development and increased lobular hyperplasia. However, PROGLY did not modify any of the endpoints evaluated. In summary, PRO and GLY modified the expression of key molecules and the development of the male mammary gland individually but not together.

Alterations in cell viability, reactive oxygen species production, and modulation of gene expression involved in mitogen-activated protein kinase/extracellular regulating kinase signaling pathway by glyphosate and its commercial formulation in hepatocellular carcinoma cells.

Glyphosate (N-phosphonomethyl glycine) is a non-selective, organophosphate herbicide widely used in agriculture and forestry. We investigated the possible toxic effects of the glyphosate active compound and its commercial formulation (Roundup Star®) in the human hepatocellular carcinoma (HepG2) cell line, including their effects on the cytotoxicity, cell proliferation, reactive oxygen species (ROS) levels, and expression of oxidative stress-related genes such as HO-1, Hsp70 Nrf2, L-FABP, and Keap1. MTT and NRU tests indicated that the IC50 values of Roundup Star® were 219 and 140 µM, respectively, and because glyphosate failed to induce cell death at the studied concentrations, an IC50 value could not be determined for this cell line. Roundup Star at concentrations of 50 and 100 µM significantly increased (39.58% and 52%, respectively) cell proliferation, which 200 µM of glyphosate increased by 35.38%. ROS levels increased by 27.97% and 44.77% for 25 and 100 µM of Roundup Star and 32.74% and 38.63% for 100 and 200 µM of glyphosate exposure. In conclusion, Roundup Star and glyphosate significantly increased expression levels of selected genes related to the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signaling pathway. This suggests that ROS production and the MAPK/ERK signaling pathway may be key molecular mechanisms in the toxicity of glyphosate in liver cells.

Glyphosate-triggered hepatocyte ferroptosis via suppressing Nrf2/GSH/GPX4 axis exacerbates hepatotoxicity.

Glyphosate (GLY) exposure has been reported to damage organs in animals, in particular the liver, due to increased reactive oxygen species (ROS). Ferroptosis is defined as a new type of cell death that is characterized by the increase of ROS. The purpose of this study was to elucidate whether the relationship between ferroptosis and GLY-induced hepatotoxicity is of significance to enlarge the knowledge about GLY toxicity and consequences for human and animal health. To this end, in this study, we investigated the role of ferroptosis in GLY-induced hepatotoxicity both in vivo and in vitro. The results showed that GLY exposure triggered ferroptosis in L02 cells, but pretreatment with ferroptosis inhibitor ferrostatin (Fer-1) rescued ferroptosis-induced injury, thereby indicating that ferroptosis plays a key role in GLY-induced hepatotoxicity. Moreover, N-acetylcysteine, a glutathione (GSH) synthesis precursor, reversed GLY-triggered ferroptosis damage, thus indicating that GSH exhaustion may be a prerequisite for GLY-triggered hepatotoxicity. Mechanistically, GLY inhibited GSH biosynthesis via blocking the phosphorylation and nuclear translocation of Nrf2, which resulted in GSH depletion-induced hepatocyte ferroptosis. In a mouse model, GLY exposure triggered ferroptosis-induced liver damage, which can be rescued by pretreatment with Fer-1 or tBHQ (a specific agonist of Nrf2). To our knowledge, this is the first study to reveal that GLY-triggered hepatocyte ferroptosis via suppressing Nrf2/GSH/GPX4 axis exacerbates hepatotoxicity, which expands our knowledge about GLY toxicity in animal and human health.

Glyphosate infiltrates the brain and increases pro-inflammatory cytokine TNFα: implications for neurodegenerative disorders.

BACKGROUND: Herbicides are environmental contaminants that have gained much attention due to the potential hazards they pose to human health. Glyphosate, the active ingredient in many commercial herbicides, is the most heavily applied herbicide worldwide. The recent rise in glyphosate application to corn and soy crops correlates positively with increased death rates due to Alzheimer's disease and other neurodegenerative disorders. Glyphosate has been shown to cross the blood-brain barrier in in vitro models, but has yet to be verified in vivo. Additionally, reports have shown that glyphosate exposure increases pro-inflammatory cytokines in blood plasma, particularly TNFα. METHODS: Here, we examined whether glyphosate infiltrates the brain and elevates TNFα levels in 4-month-old C57BL/6J mice. Mice received either 125, 250, or 500 mg/kg/day of glyphosate, or a vehicle via oral gavage for 14 days. Urine, plasma, and brain samples were collected on the final day of dosing for analysis via UPLC-MS and ELISAs. Primary cortical neurons were derived from amyloidogenic APP/PS1 pups to evaluate in vitro changes in Aß40-42 burden and cytotoxicity. RNA sequencing was performed on C57BL/6J brain samples to determine changes in the transcriptome. RESULTS: Our analysis revealed that glyphosate infiltrated the brain in a dose-dependent manner and upregulated TNFα in both plasma and brain tissue post-exposure. Notably, glyphosate measures correlated positively with TNFα levels. Glyphosate exposure in APP/PS1 primary cortical neurons increases levels of soluble Aß40-42 and cytotoxicity. RNAseq revealed over 200 differentially expressed genes in a dose-dependent manner and cell-type-specific deconvolution analysis showed enrichment of key biological processes in oligodendrocytes including myelination, axon ensheathment, glial cell development, and oligodendrocyte development. CONCLUSIONS: Collectively, these results show for the first time that glyphosate infiltrates the brain, elevates both the expression of TNFα and soluble Aß, and disrupts the transcriptome in a dose-dependent manner, suggesting that exposure to this herbicide may have detrimental outcomes regarding the health of the general population.

Effects of glyphosate and glyphosate-based herbicides like Roundup™ on the mammalian nervous system: A review.

Glyphosate is the active ingredient in glyphosate-based herbicides (GBHs), such as Roundup™, the most widely used herbicides in the world. Glyphosate targets an essential enzyme in plants that is not found in animals. However, both glyphosate and GBHs are rated as Group 2A, probable human carcinogens, and also have documented effects on reproduction, acting as endocrine disruptive chemicals. We have reviewed reports of the effects of glyphosate and GBHs on mammalian nervous system function. As with several other herbicides, GBHs exposure has been associated with an increased risk of Parkinson's Disease and death of neurons in the substantia nigra. There is also some evidence implicating Roundup™ in elevated risk of autism. Other studies have shown the effects of GBHs on synaptic transmission in animal and cellular studies. The major mechanism of action appears to be oxidative stress, accompanied by mitochondrial dysfunction. In addition, some gut bacteria utilize the enzyme used by plants, and glyphosate and GBHs use has been shown to alter the gut microbiome. There is a large and growing body of evidence that the gut microbiome alters susceptibility to great number of human diseases, including nervous system function. The weight of the evidence indicates that in addition to cancer and reproductive effects, glyphosate and GBHs have significant adverse effects on the brain and behavior and increase the risk of at least some serious neurological diseases.

Molecular and Histological Effects of Glyphosate on Testicular Tissue of the Lizard Podarcis siculus.

The expansion of agriculture produces a steady increase in habitat fragmentation and degradation due to the increased use of pesticides and herbicides. Habitat loss and alteration associated with crop production play an important role in reptile decline, among which lizards are particularly endangered. In this study, we evaluated testicular structure, steroidogenesis, and estrogen receptor expression/localization after three weeks of oral exposure to glyphosate at 0.05 and 0.5 µg/kg body weight every other day in the field lizard Podarcis siculus. Our results show that glyphosate affected testicular morphology, reduced spermatogenesis, altered gap junctions and changed the localization of estrogen receptors in germ cells, increasing their expression; the effects were mostly dose-dependent. The result also demonstrates that glyphosate, at least at these concentrations, did not influence steroidogenesis. Overall, the data indicate that this herbicide can disturb the morphophysiology of the male lizard's reproductive system, with obviously detrimental effects on their reproductive fitness. The effects of glyphosate must be considered biologically relevant and could endanger the reproductive capacity not only of lizards but also of other vertebrates, including humans; a more controlled and less intensive use of glyphosate in areas devoted to crop production would therefore be advisable.

Hematological effects of glyphosate in mice revealed by traditional toxicology and transcriptome sequencing.

The herbicide glyphosate is being used worldwide. Hematological toxicity caused by glyphosate exposure has been reported, but the underlying mechanisms remain unclear. In this study, classical toxicology methods and RNA sequencing were performed to explore the molecular mechanisms related to glyphosate hematotoxicity. We found that 500 mg/kg b.w. glyphosate-based herbicide (GBH) significantly decreased leukocyte, neutrophil, lymphocyte and monocyte counts, as well as inhibited colony-forming abilities of CFU-GM, CFU-G and CFU-GEMM. RNA sequencing identified 82 and 48 differentially expressed genes (DEGs) in BM cells after treatment with 250 mg/kg and 500 mg/kg GBH, respectively. Meanwhile, GO and KEGG analyses revealed that the MAPK signaling pathway, hematopoietic cell lineage and cytokine-cytokine receptor interactions were vital pathways involved in GBH-induced toxicity in BM cells. Notably, Nr4a, Fos, Thbs1 and tnfrsf19 contributed to the hematotoxicity of GBH by regulating hematopoietic stem cell functions. In summary, our efforts enhance the understanding of the glyphosate hematotoxic responses and facilitate future studies on its corresponding mechanisms.

The study of human serum metabolome on the health effects of glyphosate and early warning of potential damage.

Glyphosate is one of the most widely used herbicide with high efficiency, low toxicity and broad-spectrum. In recent decades, increasing evidence suggests that glyphosate may cause adverse health effects on human beings. However, until now, there is little data on the human metabolic changes. Since occupational workers are under greater health risks than ordinary people, the understanding regarding the health effects of glyphosate on occupational workers is very important for the early warning of potential damage. In this study, serum metabolic alterations in workers from three chemical factories were analyzed by gas chromatography-mass spectrometry (GC-MS) to assess the potential health risks caused by glyphosate at the molecular level. It was found that the levels of 27 metabolites changed significantly in the exposed group compared to the controls. The altered metabolic pathways, including amino acid metabolism, energy metabolism (glycolysis and TCA cycle) and glutathione metabolism (oxidative stress), etc., indicated a series of changes occur in health profile of the human body after glyphosate exposure, and the suboptimal health status of human may further evolve into various diseases, such as Parkinson's disease, renal and liver dysfunction, hepatocellular carcinoma, and colorectal cancer. Subsequently, 4 biomarkers (i.e., benzoic acid, 2-ketoisocaproic acid, alpha-ketoglutarate, and monoolein) were identified as potential biomarkers related to glyphosate exposure based on the partial correlation analyses, linear regression analyses, and FDR correction. Receiver-operating curve (ROC) analyses manifested that these potential biomarkers and their combinational pattern had good performance and potential clinical value to assess the potential health risk associated with glyphosate exposure while retaining high accuracy. Our findings provided new insights on mechanisms of health effects probably induced by glyphosate, and may be valuable for the health risk assessment of glyphosate exposure.

Changes in defense capacity to infectious hematopoietic necrosis virus (IHNv) in rainbow trout intergenerationally exposed to glyphosate.

Glyphosate, the most widely used herbicide active substance worldwide, has raised many scientific, political and public debates in the context of its recent re-registration in the European Union, highlighting in particular a lack of data concerning its potential generational effects. In this study, we investigated the intergenerational toxicity of this active substance used alone or coformulated in glyphosate-based herbicides (GBHs) on the ability of rainbow trout (Oncorhynchus mykiss) to face a viral challenge. Juvenile trout from parents exposed for eight months to four different chemical exposure conditions (non-exposed control, pure glyphosate, Roundup Innovert®, and Viaglif Jardin® were experimentally infected with the infectious hematopoietic necrosis virus (IHNv). Various enzymatic and hemato-immunological markers were assessed before and after the viral challenge. Chemical contamination with GBHs strongly modulated viral trout susceptibility. Pure glyphosate induced a cumulative mortality of 35.8%, comparable to the control (37.0%), which was significantly reduced with Roundup Innovert® (-9.9%) and increased (+14.8%) with Viaglif Jardin®. No modification was observed for the biomarkers analysed for any conditions. These results demonstrate that the nature of the co-formulants associated to glyphosate in GHBs can modulate the susceptibility of fish to pathogens.

Synergistic effects of glyphosate- and 2,4-D-based pesticides mixtures on Rhinella arenarum larvae.

Glyphosate and 2,4-D are two herbicides commonly used together. Since there is little information about the interactions between these pesticides, the aim of this study was to evaluate the single and joint lethal toxicity of the glyphosate-based herbicide (GBH) ATANOR® (43.8% of glyphosate, isopropylamine salt) and the 2,4-D-based herbicide (2,4-DBH) Así Max 50® (602000 mg/L of 2,4-D) on Rhinella arenarum larvae. Equitoxic and non-equitoxic mixtures were prepared according to the recommendation for their combination and analyzed with a fixed ratio design at different exposure times and levels of lethality (LC10, LC50, and LC90). GBH (504h-LC50=38.67 mg ae/L) was significantly more toxic than 2,4-DBH (504h-LC50=250.31 mg ae/L) and their toxicity was time-dependent. At 48h, the equitoxic mixture toxicity was additive and from the 96h was antagonistic at LC10 and LC50 effect level. The non-equitoxic mixture toxicity was additive at LC10 effect level from the 48h to the 168h, and synergistic from the 240h. At LC50 and LC90 effect level, the mixture interaction resulted synergistic for all exposure times. This is the first study to report the synergistic interactions between GBH and 2,4-DBH on amphibians, alerting about its negative impact on aquatic ecosystems.

Urinary glyphosate concentration in pregnant women in relation to length of gestation.

Human exposure to glyphosate-based herbicides (GBH) is increasing rapidly worldwide. Most existing studies on health effects of glyphosate have focused on occupational settings and cancer outcomes and few have examined this common exposure in relation to the health of pregnant women and newborns in the general population. We investigated associations between prenatal glyphosate exposure and length of gestation in The Infant Development and the Environment Study (TIDES), a multi-center US pregnancy cohort. Glyphosate and its primary degradation product [aminomethylphosphonic acid (AMPA)] were measured in urine samples collected during the second trimester from 163 pregnant women: 69 preterm births (<37 weeks) and 94 term births, the latter randomly selected as a subset of TIDES term births. We examined the relationship between exposure and length of gestation using multivariable logistic regression models (dichotomous outcome; term versus preterm) and with weighted time-to-event Cox proportional hazards models (gestational age in days). We conducted these analyses in the overall sample and secondarily, restricted to women with spontaneous deliveries (n = 90). Glyphosate and AMPA were detected in most urine samples (>94 %). A shortened gestational length was associated with maternal glyphosate (hazard ratio (HR): 1.31, 95 % confidence interval (CI) 1.00-1.71) and AMPA (HR: 1.32, 95%CI: 1.00-1.73) only among spontaneous deliveries using adjusted Cox proportional hazards models. In binary analysis, glyphosate and AMPA were not associated with preterm birth risk (<37 weeks). Our results indicate widespread exposure to glyphosate in the general population which may impact reproductive health by shortening length of gestation. Given the increasing exposure to GBHs and the public health burden of preterm delivery, larger confirmatory studies are needed, especially in vulnerable populations such as pregnant women and newborns.

Response of the nuclear xenobiotic receptors to alleviate glyphosate-based herbicide-induced nephrotoxicity in weaned piglets.

Glyphosate-based herbicides (GBHs) are widely used worldwide. Glyphosate (GLP) is the main active component of GBHs. The presence of GBH residues in the environment has led to the exposure of animals to GBHs, but the mechanisms of GBH-induced nephrotoxicity are not clear. This study investigated the effects of GBHs on piglet kidneys. Twenty-eight healthy female hybrid weaned piglets (Duroc × Landrace × Yorkshire) with an average weight of 12.24 ± 0.61 kg were randomly divided into four treatment groups (n=7 piglets/group) that were supplemented with Roundup® (equivalent to GLP concentrations of 0, 10, 20, and 40 mg/kg) for a 35-day feeding trial. The results showed that the kidneys in the 40-mg/kg GLP group suffered slight damage. Roundup® significantly decreased the activity of catalase (CAT) (P=0.005) and increased the activity of superoxide dismutase (SOD) (P=0.029). Roundup® increased the level of cystatin-C (Cys-C) in the plasma (linear, P=0.002 and quadratic, P=0.015). The levels of neutrophil gelatinase-associated lipocalin (NGAL) in plasma increased linearly (P=0.007) and quadratically (P=0.003) as the dose of GLP increased. The mRNA expression of intercellular cell adhesion molecule-1 (ICAM-1) in the 20-mg/kg GLP group was increased significantly (P<0.05). There was a significant increase in the mRNA levels of pregnenolone X receptor (PXR), constitutive androstane receptor (CAR), and uridine diphosphate glucuronosyltransferase 1A3 (UGT1A3) (P<0.05). Our findings found that kidney nuclear xenobiotic receptors (NXRs) may play an important role in defense against GBHs.

Disruption of developmental programming with long-term consequences after exposure to a glyphosate-based herbicide in a rat model.

Glyphosate-based herbicides (GBHs) have been associated with endocrine disrupting effects on reproductive organs. We examined whether postnatal exposure to GBH affects developmental programming of the uterus with long-term consequences. Female Wistar pups received vehicle (control) or GBH (2 mg of glyphosate/kg/day) from postnatal day (PND) 1 to PND7, where the developing uterus is highly sensitive to endocrine disruption. Short-, mid- and long-term effects were evaluated on PND8, PND120 and PND600, respectively. GBH induced hyperplasia and epigenetic alterations in the uterus of neonatal females (PND8). DNA hypermethylation, enrichment of H3K9me3 and reductions of H3K27me3 at regulatory regions of the morphoregulatory gene Hoxa10 resulted in gene downregulation. In young adult females (PND120), GBH increased 17ß-estradiol (E2) and decreased progesterone (P4) serum levels, altering estrous cyclicity. Aged females (PND600) exposed to GBH developed leiomyoma and pre-neoplastic glandular lesions in the uterus. Vaginal rhabdomyosarcoma and intrahepatic bile duct adenoma were also observed. In conclusion, neonatal exposure to GBH altered the expression and induced hypermethylation of the Hoxa10 gene in uterine tissue at early life, and increased E2/P4 ratio serum level at middle-age. We propose that epigenetic reprogramming of Hoxa10 in association with hormonal imbalance could be among the possible mechanisms underlying the long-term adverse effects detected in GBH-exposed rats.

Low concentrations of glyphosate alone affect the pubertal male rat meiotic step: An in vitro study.

Glyphosate is the most used herbicide in the world. Controversial studies exist on its effect on the male reproductive system. We used the validated BioAlter® model to test the effects of low concentrations of Glyphosate. Pubertal rat seminiferous tubules were treated with Glyphosate 50 nM, 500 nM, 5 µM or 50 µM over a 3-week culture period. The Trans-Epithelial Electrical Resistance was not modified by any of the concentrations. The decrease of Clusterin mRNAs suggested that glyphosate would target the integrity of Sertoli cells. The decrease of the numbers of germ cells from day 14 onward highlighted the chronic effect of glyphosate at 50 nM, 500 nM or 5 µM. No consistent effect of glyphosate was observed on the numbers of spermatogonia or on their specific mRNA levels. However, those low concentrations of glyphosate targeted young spermatocytes and middle to late pachytene spermatocytes resulting in a decrease of the numbers of round spermatids, the direct precursors of spermatozoa. This study underlines that the effect of a toxicant should be also studied at low doses and during the establishment of the blood-testis barrier.