The Association between Long-Term DDT or DDE Exposures and an Altered Sperm Epigenome-a Cross-Sectional Study of Greenlandic Inuit and South African VhaVenda Men.

BACKGROUND: The organochlorine dichlorodiphenyltrichloroethane (DDT) is banned worldwide owing to its negative health effects. It is exceptionally used as an insecticide for malaria control. Exposure occurs in regions where DDT is applied, as well as in the Arctic, where its endocrine disrupting metabolite, p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE) accumulates in marine mammals and fish. DDT and p,p'-DDE exposures are linked to birth defects, infertility, cancer, and neurodevelopmental delays. Of particular concern is the potential of DDT use to impact the health of generations to come via the heritable sperm epigenome. OBJECTIVES: The objective of this study was to assess the sperm epigenome in relation to p,p'-DDE serum levels between geographically diverse populations. METHODS: In the Limpopo Province of South Africa, we recruited 247 VhaVenda South African men and selected 50 paired blood serum and semen samples, and 47 Greenlandic Inuit blood and semen paired samples were selected from a total of 193 samples from the biobank of the INUENDO cohort, an EU Fifth Framework Programme Research and Development project. Sample selection was based on obtaining a range of p,p'-DDE serum levels (mean=870.734±134.030 ng/mL). We assessed the sperm epigenome in relation to serum p,p'-DDE levels using MethylC-Capture-sequencing (MCC-seq) and chromatin immunoprecipitation followed by sequencing (ChIP-seq). We identified genomic regions with altered DNA methylation (DNAme) and differential enrichment of histone H3 lysine 4 trimethylation (H3K4me3) in sperm. RESULTS: Differences in DNAme and H3K4me3 enrichment were identified at transposable elements and regulatory regions involved in fertility, disease, development, and neurofunction. A subset of regions with sperm DNAme and H3K4me3 that differed between exposure groups was predicted to persist in the preimplantation embryo and to be associated with embryonic gene expression. DISCUSSION: These findings suggest that DDT and p,p'-DDE exposure impacts the sperm epigenome in a dose-response-like manner and may negatively impact the health of future generations through epigenetic mechanisms. Confounding factors, such as other environmental exposures, genetic diversity, and selection bias, cannot be ruled out. https://doi.org/10.1289/EHP12013.

The p,p'-DDE disturbs the M1 function without affecting the M2 phenotype nor unstimulated bone marrow-derived macrophages from BALB/c mice.

DDT, a persistent organic pollutant, remains affecting human health worldwide. DDT and its most persistent metabolite (p,p'-DDE) negatively affect the immune response regulation and mechanisms involved in protecting against pathogens Such metabolite decreases the capability to limit intracellular growth of Mycobacterium microti and yeast. However, the effect on unstimulated (M0) and anti-inflammatory macrophages (M2) has been evaluated scanty. Herein, we evaluated the impact of p,p'-DDE at environmentally relevant concentrations (0.125, 1.25, 2.5, and 5 µg/mL) on bone marrow-derived macrophages stimulated with IFNγ+LPS to M1 or with IL-4 +IL-13 to M2. Thus we study whether the p,p'-DDE induces M0 to a specific phenotype or modulates activation of the macrophage phenotypes and explains, at least partly, the reported effects of p,p'-DDE on the M1 function. The p,p'-DDE did not affect the cell viability of M0 or the macrophage phenotypes. In M1, the p,p'-DDE decreased NO•- production and IL-1ß secretion, but increasing cellular ROS and mitochondrial O2•-, but did not alter iNOS, TNF-α, MHCII, and CD86 protein expression nor affect M2 markers arginase activity, TGF-ß1, and CD206; p,p'-DDE, did not affect marker expression in M0 or M2, supporting that its effects on M1 parameters are not dependent on M0 nor M2 modulation. The decreasing of NO•- production by the p,p'-DDE without altering iNOS levels, Arginase activity, or TNF-α, but increasing cellular ROS and mitochondrial O2 suggests that p,p'-DDE interferes with the iNOS function but not with its transcription. The p,p'-DDE decreasing of IL-1ß secretion, without any effect on TNF-α, suggest that an alteration of specific targets involved in IL-1ß secretion may be affected and related to ROS induction. The p,p'-DDE effect on iNOS function and the IL-1ß secretion process, as the NLRP3 activation, deserves further study.

Induction of cardiotoxicity in zebrafish embryos by 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene through the JAK-STAT and NOTCH signaling pathways.

1,1-Dichloro-2,2-bis(p-chlorophenyl)ethylene (p,p'-DDE) is the primary molecular metabolite of 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane (DDT), a pesticide used to control the spread of dengue and Zika viruses, and can be detected in the majority of human blood samples. However, whether p,p'-DDE affects embryonic cardiac development remains unknown. This study aimed to explore the cardiotoxicity of p,p'-DDE and its potential mechanisms of action in zebrafish embryos. We demonstrated for the first time that zebrafish embryos exposed to p,p'-DDE exhibited cardiac development abnormalities, including morphological and functional abnormalities, such as pericardial edema, thinning of the ventricular wall, reduced erythrocyte intensity, and increased heart rate. The results of Kyoto Encyclopedia of Genes and Genomes analysis of differentially expressed genes and qRT-PCR showed that JAK-STAT-related genes (il17d, socs3a, and bcl2b) and Notch-related genes (notch1a, notch1b, bmp10, efnb2a, tbx2b, and tbx5a) were altered after p,p'-DDE treatment, leading to reduced proliferation and increased apoptosis of cardiomyocytes and irregular formation of ventricular and abnormal atrioventricular junctions. These results were verified using acridine orange staining, 5-ethynyl-2'-deoxyuridine assays, and whole-mount in situ hybridization. Our research suggests that p,p'-DDE affects cardiac development in zebrafish embryos and that its cardiotoxicity may be associated with the JAK-STAT and Notch signaling pathways. Our findings may provide the basis for future population-based cohort studies.

Effects of DDT on Amyloid Precursor Protein Levels and Amyloid Beta Pathology: Mechanistic Links to Alzheimer's Disease Risk.

BACKGROUND: The interaction of aging-related, genetic, and environmental factors is thought to contribute to the etiology of late-onset, sporadic Alzheimer's disease (AD). We previously reported that serum levels of p,p'-dichlorodiphenyldichloroethylene (DDE), a long-lasting metabolite of the organochlorine pesticide dichlorodiphenyltrichloroethane (DDT), were significantly elevated in patients with AD and associated with the risk of AD diagnosis. However, the mechanism by which DDT may contribute to AD pathogenesis is unknown. OBJECTIVES: This study sought to assess effects of DDT exposure on the amyloid pathway in multiple in vitro and in vivo models. METHODS: Cultured cells (SH-SY5Y and primary neurons), transgenic flies overexpressing amyloid beta (Aß), and C57BL/6J and 3xTG-AD mice were treated with DDT to assess impacts on the amyloid pathway. Real time quantitative polymerase chain reaction, multiplex assay, western immunoblotting and immunohistochemical methods were used to assess the effects of DDT on amyloid precursor protein (APP) and other contributors to amyloid processing and deposition. RESULTS: Exposure to DDT revealed significantly higher APP mRNA and protein levels in immortalized and primary neurons, as well as in wild-type and AD-models. This was accompanied by higher levels of secreted Aß in SH-SY5Y cells, an effect abolished by the sodium channel antagonist tetrodotoxin. Transgenic flies and 3xTG-AD mice had more Aß pathology following DDT exposure. Furthermore, loss of the synaptic markers synaptophysin and PSD95 were observed in the cortex of the brains of 3xTG-AD mice. DISCUSSION: Sporadic Alzheimer's disease risk involves contributions from genetic and environmental factors. Here, we used multiple model systems, including primary neurons, transgenic flies, and mice to demonstrate the effects of DDT on APP and its pathological product Aß. These data, combined with our previous epidemiological findings, provide a mechanistic framework by which DDT exposure may contribute to increased risk of AD by impacting the amyloid pathway. https://doi.org/10.1289/EHP10576.

Organochlorine pesticides, oxidative stress biomarkers, and leukemia: a case-control study.

Exposure to pesticides has been linked to an elevated risk of leukemia. The present research aimed to evaluate the relationship between organochlorine (OC) pesticides and biomarkers of oxidative stress in patients with leukemia. This work was conducted on 109 patients with leukemia and 109 healthy controls. The serum concentrations of seven derivatives of OCs including alpha-hexachlorocyclohexane (HCH), beta-HCH, gamma-HCH, 2,4-dichlorodiphenyltrichloroethane (DDT), 4,4-DDT, 2,4-dichlorodiphenyldichloroethylene (DDE), and 4,4-DDE along with acetylcholinesterase (AChE), glutathione peroxidase (GPx), superoxide dismutase (SOD), paraoxonase-1 (PON1), and catalase (CAT) activities as well as total antioxidant capacity (TAC), nitric oxide (NO), protein carbonyl (PC), and malondialdehyde (MDA) levels were measured in all the subjects. Levels of OCs were remarkably higher in patients with leukemia compared with the controls (p<0.05). In addition, levels of SOD, AChE, GPx, PON1, and TAC were remarkably lower in patients with leukemia compared with controls (p<0.05). In contrast, MDA, NO, and PC concentrations were higher in patients with leukemia than in the controls (p<0.05). Moreover, the serum level of 4,4-DDE was negatively associated with GPx activity (p=0.038). Our findings suggest that OCs may play a role in the development of leukemia by disrupting the oxidant/antioxidant balance.

Chronic DDE Exposure Modifies Mitochondrial Respiration during Differentiation of Human Adipose-Derived Mesenchymal Stem Cells into Mature Adipocytes.

The contribution of environmental pollutants to the obesity pandemic is still not yet fully recognized. Elucidating possible cellular and molecular mechanisms of their effects is of high importance. Our study aimed to evaluate the effect of chronic, 21-day-long, 2,2-bis (4-chlorophenyl)-1,1-dichlorethylenedichlorodiphenyldichloroethylene (p,p'-DDE) exposure of human adipose-derived mesenchymal stem cells committed to adipogenesis on mitochondrial oxygen consumption on days 4, 10, and 21. In addition, the mitochondrial membrane potential (MMP), the quality of the mitochondrial network, and lipid accumulation in maturing cells were evaluated. Compared to control differentiating adipocytes, exposure to p,p'-DDE at 1 µM concentration significantly increased basal (routine) mitochondrial respiration, ATP-linked oxygen consumption and MMP of intact cells on day 21 of adipogenesis. In contrast, higher pollutant concentration seemed to slow down the gradual increase in ATP-linked oxygen consumption typical for normal adipogenesis. Organochlorine p,p'-DDE did not alter citrate synthase activity. In conclusion, in vitro 1 µM p,p'-DDE corresponding to human exposure is able to increase the mitochondrial respiration per individual mitochondrion at the end of adipocyte maturation. Our data reveal that long-lasting exposure to p,p'-DDE could interfere with the metabolic programming of mature adipocytes.

In vitro effect of DDE exposure on the regulation of B-TC-6 pancreatic beta cell insulin secretion: a potential role in beta cell dysfunction and type 2 diabetes mellitus.

Organochlorine compounds (OC) include synthetic insecticides previously used throughout the world before being banned for their adverse effects and environmental persistence; DDT (dichlorodiphenyltrichloroethane) was one of the most widely used. Epidemiological evidence suggests that higher levels of some OC, including metabolites of DDT, such as dichlorodiphenyldichloroethylene (DDE), are associated with type 2 diabetes mellitus (T2D). DDE exposure may affect pancreatic cellular functions associated with glucose control and possibly cause beta cell dysfunction. The in vitro effect of DDE exposure on pancreatic beta cell insulin secretion was investigated using Beta-Tumor Cell-6 (B-TC-6) murine pancreatic beta cells. DDE exposure significantly increased insulin secretion suggesting a role for DDE in altering insulin synthesis and secretion. Reactive oxygen species (ROS) levels were not significantly increased indicating that oxidative stress is not responsible for the DDE-induced insulin secretion. Pancreatic and duodenal homeobox factor-1 (PDX-1) levels were not significantly increased suggesting that DDE exposure does not alter insulin transcription, but prohormone convertase (PC) levels were increased suggesting a role for DDE in altering insulin translation. Based on these in vitro results, DDE may play a role in beta cell dysfunction by affecting mechanisms that regulate insulin secretion but it is not likely to be the major mechanism behind the DDE/T2D epidemiological association.

1,1,1-trichloro-2,2-bis (p-chlorophenyl)-ethane (DDT) and 1,1-Dichloro-2,2-bis (p, p'-chlorophenyl) ethylene (DDE) as endocrine disruptors in human and wildlife: A possible implication of mitochondria.

1,1,1-trichloro-2,2-bis (p-chlorophenyl)-ethane (DDT) and its main metabolite 1,1-Dichloro-2,2-bis (p, p'-chlorophenyl) ethylene (DDE) act as endocrine disruptors in humans and wildlife. Immunomodulatory functions have also been attributed to both xenobiotics. DDT was banned in the 1970s due to its toxicity, but it is still produced and used for indoor residual spraying with disease vector control purposes. Due to their persistence and lipophilic properties, DDT and DDE can bioaccumulate through the food chain, being stored in organisms' adipose depots. Their endocrine disruptor function is mediated by agonist or antagonist interaction with nuclear receptors. Present review aimed to provide an overview of how DDT and DDE exposure impacts reproductive and immune systems with estrogen-disrupting action in humans and wildlife. Studies showing DDT and DDE impact on mitochondrial function and apoptosis pathway will also be reviewed, suggesting the hypothesis of direct action on mitochondrial steroid receptors.

The effect of DDE and dieldrin and their parental substances (DDT and aldrin) on PGE2 and PGF2α release from bovine endometrial explants collected during 120 to 180 days of the gestational period.

Dieldrin and DDE are environmental metabolites of the organochlorine pesticides aldrin and DDT, respectively. During pregnancy, these chemicals can quickly infiltrate through the placental barrier, accumulate in amniotic fluid and fetus, and act as endocrine disruptors (EDs). The aim of this study was to investigate the effect of DDE and dieldrin and their parental substances at concentrations of 1 and 10 ng/ml on secretion of PGE2 and PGF2α from bovine endometrial explants (120-150 and 151-180 days of pregnancy) after 24 hr of incubation with EDs. The mRNA expression of COX2, PGES and PGFS and the concentrations of PGE2 and PGF2α were measured. EDs did not affect (p>0.05) COX2 gene expression, but DDT and DDE decreased (p⟨0.05) PGES expression and PGE2 secretion in the explants from 120-150 days of pregnancy. Depending on the dose, DDT and DDE increased (p⟨0.05) PGFS expression and PGF2α secretion from the explants from 120-150 days and decreased PGF2α secretion (p⟨0.05) from the explants from 151-180 days of pregnancy. Aldrin and dieldrin decreased (p⟨0.05) PGFS expression and PGF2α secretion from all explants. In summary, EDs disrupt the secretion of PGE2 and PGF2α by influencing the gene expression of PGES and PGFS.

[Thyroid disruptor p, p'-DDE inhibited the expression of LHX4 and DIS3L protein in Nthy-ori-3-1 cells].

Objective: To observe the changes of LHX4 and DIS3L mRNA and protein expression in Nthy-ori-3-1 cells after the treatment of thyroid disruptor p, p'-DDE. Methods: Nthy-ori-3-1 cells in logarithmic growth phase were treated with 0, 0.5, 1.0, 2.0 and 5.0 µg/ml p, p'-DDE solution. The growth state and morphology of the cells were observed by microscope. The mRNA levels of LHX4 and DIS3L were detected by real-time fluorescent quantitative PCR, and the protein expression levels of LHX4 and DIS3L were detected by Western blot. Results: when the concentrations of p, p'-DDE were 0, 0.5, 1.0 and 2.0 µg/ml, Nthy-ori-3-1 cells grew normally. There were 33 differential genes in 2.0 µg/ml group, among which 13 genes were down regulated and 20 genes were up-regulated. Compared with the control group, the protein expression levels of LHX4 and DIS3L in 1.0 and 2.0 µg/ml groups were significantly decreased (P<0.05) , and the relative expression levels of LHX4 and DIS3L protein mRNA in 1.0 µg/ml group were significantly decreased (P<0.05) . Conclusion: p, p'-DDE can affect the protein expression of LHX4 and dis3l in nthy-ori-3-1 cells.

Exposure to DDT from indoor residual spraying and biomarkers of inflammation among reproductive-aged women from South Africa.

BACKGROUND: Evidence from animal studies suggests that DDT and DDE can adversely affect immuno-competence while human data are less conclusive. We aimed to assess the association of plasma concentrations of DDT and DDE with biomarkers of inflammation among reproductive-aged women residing in homes sprayed with DDT through Indoor Residual Spraying (IRS). METHODS: This study included 416 women from the Study of Women and Babies, South Africa (2010-2011). DDT, DDE, and biomarkers of inflammation (immunoglobulins A, G and M, interleukins 1ß, 6, and 8, tumor necrosis factor-α, C-reactive protein, serum amyloid-A, intercellular adhesion molecule-1, vascular cell adhesion molecule-1) were quantified in plasma. Linear regression was used to assess associations of DDT and DDE with each natural log-transformed biomarker. Models were adjusted for age, body mass index, parity, income, and season; beta estimates were expressed as percent differences. RESULTS: Compared to women with the lowest plasma concentrations of DDT and DDE, those with the highest concentrations of both compounds had higher levels IL-1ß, IL6, and TNF- α. While associations were statistically significant for both DDT and DDE, the magnitude of the associations was slightly stronger for DDT. Compared to women in the lowest quintile of DDT, women in the highest quintile were estimated to have 53.0% (95%CI: 21.7%, 84.4%), 28.1% (95%CI: 6.4%, 49.8%), and 26.6% (95%CI: 12.0%, 41.1%) higher levels of IL-1ß, IL6, and TNF- α, respectively. CONCLUSIONS: Our results suggest that increased plasma concentrations of DDT and DDE resulting from exposure to IRS may increase concentrations of pro-inflammatory biomarkers among reproductive-aged women in South Africa.

Exposure to polychlorinated compounds and cryptorchidism; A nested case-control study.

BACKGROUND: Maldescended testes or cryptorchidism is a genital birth defect that affects 2-9% of all male new-borns. Over the last 40 years there have been reports of increased prevalence in countries like the US, the UK and the Scandinavian countries. This possible increase has in some studies been linked to a foetal exposure to chemical pollutants. In this matched case-control study, we analysed maternal serum samples in early pregnancy for three different organochlorine compounds, to investigate whether the levels were associated with the risk of cryptorchidism. METHOD: Maternal serum samples taken during the first trimester of pregnancy from 165 cases (boys born with cryptorchidism) and 165 controls, matched for birth year and maternal age, parity and smoking habits during the pregnancy, were retrieved from the Southern Sweden Maternity Biobank. The samples were analysed for 2,2',4,4',5,5'-hexachlorobiphenyl (PCB-153), dichlorodiphenyltrichloroethane (p,p'-DDE) and hexachlorobenzene (HCB), using gas chromatography mass spectrometry. Associations between exposure and cryptorchidism were evaluated by conditional logistic regression. RESULTS: We found no statistically significantly associations between exposure to these compounds and cryptorchidism, either when the exposure variables were used as a continuous variable, or when the exposure levels were divided in quartiles. CONCLUSION: We found no evidence of an association between maternal levels of PCB-153, p,p'-DDE or HCB during the pregnancy and the risk of having cryptorchidism in the sons.

Protective effect of Pedro-Ximénez must against p,p'-DDE-induced liver damages in aged Mus spretus mice.

Aging is characterized by deterioration of biomolecules and impaired stress responses that make the elderly especially vulnerable to environmental pollutants. The pesticide p,p'-DDE is a DDT derivative that generates great concern because of its wide distribution and its harmful effects on both human health and the environment. We analyzed here the biological responses elicited by p,p'-DDE exposure in the liver of aged Mus spretus mice. Data demonstrate that the elderly constitute a population especially sensitive to this noxious environmental pollutant. We also demonstrated here that the daily consumption of sun-dried Pedro Ximénez (PX) white-grape must (PXM) protects the liver of aged mice from both the age and the damages caused by p,p'-DDE exposure. The PXM activity was exerted through the restoration of the hepatic metabolisms of lipids and carbohydrates and, probably, is a consequence of the ability of this polyphenol-rich mixture to avoid oxidative stress. Nutritional interventions including PXM, which ameliorates the effects of unavoidable exposure to pesticides in our food, are helpful tools that can help elderly populations to enjoy a healthy and expanded lifetime.

Metabolic Impairments Caused by a "Chemical Cocktail" of DDE and Selenium in Mice Using Direct Infusion Triple Quadrupole Time-of-Flight and Gas Chromatography-Mass Spectrometry.

Among organic contaminants, pesticides are one of the most important groups of chemicals due to their persistent character and toxicity. However, the biological systems are exposed to a complex environment in which the contaminants can interact in a synergistic/antagonistic fashion, and for this reason, the study of "chemical cocktails" is of great interest to fully understand the final biological effect. In this way, selenium is known for its antagonistic action against several toxicants. In this paper, metabolic impairments caused by the joint exposure of p,p'-dichloro diphenyl trichloroethane (DDE) and selenium (Se) have been issued for the first time. A metabolomic workflow was applied to mice fed DDE and DDE with Se diet, on the basis of the complementary use of two organic mass spectrometric techniques, combining direct infusion mass spectrometry (DI-ESI-QqQ-TOF MS) and gas chromatography-mass spectrometry (GC-MS). The results show a good classification between the studied groups caused by about 70 altered metabolites in the liver, kidney, or brain, including the pathways of energy metabolism, degradation of phospholipidic membrane, ß-oxidation, and oxidative stress, which confirm the potential of combined metabolomic platforms in environmental studies.

Serum levels of Organochlorine Pesticides and Breast Cancer Risk in Iranian Women.

Breast cancer is a multifactorial disease and its etiology is linked to multiple risk factors. There are shreds of controversial evidence that exposure to organochlorine pesticides (OCPs) are important in the etiology of breast cancer. The present study aimed to determine the circulating levels of OCPs in patients with breast tumors in Southeastern of Iran. This case-control study included 27 patients with malignant breast tumors (MBT), 31 patients with benign breast tumors (BBT), and 27 healthy women as a control group. Serum OCPs levels, including α-hexachlorocyclohexane (α-HCH), ß-HCH, γ-HCH, 2,4-dichlorodiphenyltrichloroethane (2,4-DDT), 4,4-DDT, 2,4-dichlorodiphenyldichloroethylene (2,4-DDE), and 4,4-DDE, were measured using gas chromatography. Our data revealed significantly higher concentrations of 2,4-DDT in MBT and BBT groups compared with control ones (P < 0.001 for both comparisons). Patients with breast cancer suffered significantly higher accumulation levels of 4,4-DDE compared with control subjects (P = 0.04). Significant correlations were found among organochlorine compounds with each other in both patients' groups. There was a significant positive correlation between body mass index and serum levels of 2,4-DDT in BBT group (r = 0.407, P = 0.02). The present findings suggest that the serum levels of 4,4-DDE and 2,4-DDT are associated with an increase in the risk of breast cancer in Southeastern women of Iran.

Cytokine expression and lymphocyte proliferative capacity in diseased harbor porpoises (Phocoena phocoena) - Biomarkers for health assessment in wildlife cetaceans.

Harbor porpoises (Phocoena phocoena) in the North and Baltic Seas are exposed to anthropogenic influences including acoustic stress and environmental contaminants. In order to evaluate immune responses in healthy and diseased harbor porpoise cells, cytokine expression analyses and lymphocyte proliferation assays, together with toxicological analyses were performed in stranded and bycaught animals as well as in animals kept in permanent human care. Severely diseased harbor porpoises showed a reduced proliferative capacity of peripheral blood lymphocytes together with diminished transcription of transforming growth factor-ß and tumor necrosis factor-α compared to healthy controls. Toxicological analyses revealed accumulation of polychlorinated biphenyls (PCBs), dichlorodiphenyldichloroethylene (DDE), and dichlorodiphenyltrichloroethane (DDT) in harbor porpoise blood samples. Correlation analyses between blood organochlorine levels and immune parameters revealed no direct effects of xenobiotics upon lymphocyte proliferation or cytokine transcription, respectively. Results reveal an impaired function of peripheral blood leukocytes in severely diseased harbor porpoises, indicating immune exhaustion and increased disease susceptibility.

Plasma levels of dichlorodiphenyldichloroethene (DDE) and dichlorodiphenyltrichloroethane (DDT) and survival following breast cancer in the Carolina Breast Cancer Study.

OBJECTIVES: To examine plasma levels of dichlorodiphenyldichloroethene (DDE) and dichlorodiphenyltrichloroethane (DDT) in association with survival among women with breast cancer who participated in a population-based case-control study. METHODS: Participants included 456 white and 292 black women from the Carolina Breast Cancer Study Phase I who were diagnosed with primary invasive breast cancer from 1993 to 1996, and who had available DDE/DDT and lipid measurements from blood samples obtained on average 4.1 months after diagnosis. Using the National Death Index, we identified 392 deaths (210 from breast cancer) over a median follow-up of 20.6 years. We used Cox regression to estimate covariate-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause and breast cancer-specific 5-year mortality, and 20-year mortality conditional on 5-year survival, for lipid-standardized DDE and DDT levels. Associations stratified by race and estrogen receptor (ER) status were also examined. RESULTS: The highest versus lowest DDE tertile and the highest vs non-detectable DDT quantile were associated with HRs of 1.95 (95% CI = 1.31-2.92) and 1.64 (95% CI = 1.10-2.44), respectively, for 20-year conditional all-cause mortality. DDE levels above versus below the median were associated with a HR of 1.69 (95% CI = 1.06-2.68) for 20-year conditional breast cancer-specific mortality among women overall, and HRs were 2.36 (95% CI = 1.03-5.42) among black women and 1.57 (95% CI = 0.86-2.89) among white women (PInteraction = 0.42), and 3.24 (95% CI = 1.38-7.58) among women with ER- tumors and 1.29 (95% CI = 0.73-2.28) among women with ER+ tumors (PInteraction = 0.03). CONCLUSION: Exposure to DDE/DDT may adversely impact overall and breast cancer-specific survival. DDE exposure may contribute to the racial disparities in breast cancer survival.

Dietary Se supplementation partially restores the REDOX proteomic map of M. spretus liver exposed to p,p'-DDE.

The toxicity of p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE), a contaminant and metabolite derivative of DDT [1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane] is partially mediated by reactive oxygen species. Protein cysteine-based regulatory switches and subsequent alterations of the overall hepatic metabolism are triggered by p,p'-DDE through the disruption of the cellular redox status. The consequences are reproductive impairment, metabolic disorders, diabetes, neurotoxicity and cancer. In recent years, the risk of p,p'-DDE exposure has increased worldwide, reflecting the rise of mosquito-borne diseases in tropical countries that produce and export contaminated foods. Selenium (Se) is an essential trace element in animal nutrition with antioxidant properties that protects against the toxicity of some xenobiotics. We analyzed the ability of diet Se-supplementation to prevent damages induced by p,p'-DDE in the liver of M. spretus mice, by using redox proteomics based on the determination of the redox status of protein Cys residues. Se selectively acted on specific target, restoring the redox status and functionality of some membrane proteins involved in mitochondrial functionality, protein transport, cell signaling and protein metabolism. However, the Se-enriched diet did not completely prevent the metabolic shift caused by p,p'-DDE exposure that leads to disturbed lipogenesis, hepatic steatosis and alterations in the synthesis of hormones and other cell signals.

The scaffold protein RACK1 is a target of endocrine disrupting chemicals (EDCs) with important implication in immunity.

We recently demonstrated the existence of a complex hormonal balance between steroid hormones in the control of RACK1 (Receptor for Activated C Kinase 1) expression and immune activation, suggesting that this scaffold protein may also be targeted by endocrine disrupting chemicals (EDCs). As a proof of concept, we investigated the effect of the doping agent nandrolone, an androgen receptor (AR) agonist, and of p,p'DDT (dichlorodiphenyltrichloroethane) and its main metabolite p,p'DDE (dichlorodiphenyldichloroethylene), a weak and strong AR antagonist, respectively, on RACK1 expression and innate immune response. In analogy to endogenous androgens, nandrolone induced a dose-related increase in RACK1 transcriptional activity and protein expression, resulting in increased LPS-induced IL-8 and TNF-α production and proliferation in THP-1 cells. Conversely, p,p'DDT and p,p'DDE significantly decrease RACK1 expression, LPS-induced cytokine production and CD86 expression; with p,p'DDE exerting a stronger repressor effect than p,p'DDT, consistent with its stronger AR antagonistic effect. These results indicate that RACK1 could be a relevant target of EDCs, responding in opposite ways to agonist or antagonist of AR, representing a bridge between the endocrine system and the innate immune system.

Persistent organic pollutants (POPs) in human follicular fluid and in vitro fertilization outcomes, a pilot study.

Persistent organic pollutants (POPs) are ubiquitously distributed among the U.S. population and adversely impact human reproduction. These compounds have been detected in human ovarian follicular fluid (FF), where they directly contact a developing oocyte. As a pilot investigation, we measured 43 polychlorinated biphenyl (PCB) congeners, p,p'-dichlorodiphenyltrichloroethane (DDT), and its persistent metabolite p,p'-dichlorodiphenyldichloroethylene (DDE) in residual FF collected from 32 women undergoing in vitro fertilization (IVF). We identified significant inverse associations between higher levels of PCB congeners and indicators of ovarian reserve (e.g., antral follicle count), follicular response to administered gonadotropins (e.g., peak estradiol, number of oocytes retrieved, endometrial thickness), intermediate IVF endpoints (e.g., oocyte fertilization and embryo quality), and clinical IVF outcomes (e.g., embryo implantation and live birth), after adjusting for body mass index, cigarette smoking, race, and age. Our results suggest that ongoing exposure to POPs impacts IVF and merit confirmation in a larger and more definitive future study.