Persistent organic pollutants dysregulate energy homeostasis in human ovaries in vitro.

Exposure to persistent organic pollutants (POPs), such as dichlorodiphenyltrichloroethane (DDT) and polychlorinated biphenyls (PCBs), has historically been linked to population collapses in wildlife. Despite international regulations, these legacy chemicals are still currently detected in women of reproductive age, and their levels correlate with reduced ovarian reserve, longer time-to-pregnancy, and higher risk of infertility. However, the specific modes of action underlying these associations remain unclear. Here, we examined the effects of five commonly occurring POPs - hexachlorobenzene (HCB), p,p'-dichlorodiphenyldichloroethylene (DDE), 2,3,3',4,4',5-hexachlorobiphenyl (PCB156), 2,2',3,4,4',5,5'-heptachlorobiphenyl (PCB180), perfluorooctane sulfonate (PFOS) - and their mixture on human ovaries in vitro. We exposed human ovarian cancer cell lines COV434, KGN, and PA1 as well as primary ovarian cells for 24 h, and ovarian tissue containing unilaminar follicles for 6 days. RNA-sequencing of samples exposed to concentrations covering epidemiologically relevant levels revealed significant gene expression changes related to central energy metabolism in the exposed cells, indicating glycolysis, oxidative phosphorylation, fatty acid metabolism, and reactive oxygen species as potential shared targets of POP exposures in ovarian cells. Alpha-enolase (ENO1), lactate dehydrogenase A (LDHA), cytochrome C oxidase subunit 4I1 (COX4I1), ATP synthase F1 subunit alpha (ATP5A), and glutathione peroxidase 4 (GPX4) were validated as targets through qPCR in additional cell culture experiments in KGN. In ovarian tissue cultures, we observed significant effects of exposure on follicle growth and atresia as well as protein expression. All POP exposures, except PCB180, decreased unilaminar follicle proportion and increased follicle atresia. Immunostaining confirmed altered expression of LDHA, ATP5A, and GPX4 in the exposed tissues. Moreover, POP exposures modified ATP production in KGN and tissue culture. In conclusion, our results demonstrate the disruption of cellular energy metabolism as a novel mode of action underlying POP-mediated interference of follicle growth in human ovaries.

Effects of DDT and DDE on placental cholinergic receptors.

The placental cholinergic system; known as an important factor in intracellular metabolic activities, regulation of placental vascular tone, placental development, and neurotransmission; can be affected by persistent organic pesticides, particularly organochlorine pesticides(OCPs), which can influence various epigenetic regulations and molecular pathways. Although OCPs are legally prohibited, trace amounts of the persistent dichlorodiphenyltrichloroethane(DDT) are still found in the environment, making prenatal exposure inevitable. In this study, the effects of 2,4'-DDT and 4,4'-DDT; and its breakdown product 4,4'-DDE in the environment on placental cholinergic system were evaluated with regards to cholinergic genes. 40 human placentas were screened, where 42,50% (17 samples) were found to be positive for the tested compounds. Average concentrations were 10.44 µg/kg; 15.07 µg/kg and 189,42 µg/kg for 4,4'-DDE; 2,4'-DDT and 4,4'-DDT respectively. RNA-Seq results revealed 2396 differentially expressed genes in positive samples; while an increase in CHRM1,CHRNA1,CHRNG and CHRNA2 genes at 1.28, 1.49, 1.59 and 0.4 fold change were found(p<0028). The increase for CHRM1 was also confirmed in tissue samples with immunohistochemistry. In vitro assays using HTR8/SVneo cells; revealed an increase in mRNA expression of CHRM1, CHRM3 and CHRN1 in DDT and DDE treated groups; which was also confirmed through western blot assays. An increase in the expression of CHRM1,CHRNA1, CHRNG(p<0001) and CHRNA2(p<0,05) were found from the OCPs exposed and non exposed groups.The present study reveals that intrauterine exposure to DDT affects the placental cholinergic system mainly through increased expression of muscarinic receptors. This increase in receptor expression is expected to enhance the sensitivity of the placental cholinergic system to acetylcholine.

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.

Paternal p,p'-DDE exposure and pre-pubertal high-fat diet increases the susceptibility to fertility impairment and sperm Igf2 DMR2 hypo-methylation in male offspring.

The hypothesis of paternal origins of health and disease (POHaD) indicates that paternal exposure to adverse environment could alter the epigenetic modification in germ line, increasing the disease susceptibility in offspring or even in subsequent generations. p,p'-Dichlorodiphenyldichloroethylene (p,p'-DDE) is an anti-androgenic chemical and male reproductive toxicant. Gestational p,p'-DDE exposure could impair reproductive development and fertility in male offspring. However, the effect of paternal p,p'-DDE exposure on fertility in male offspring remains uncovered. From postnatal day (PND) 35 to 119, male rats (F0) were given 10 mg/body weight (b.w.) p,p'-DDE or corn oil by gavage. Male rats were then mated with the control females to generate male offspring. On PND35, the male offspring were divided into 4 groups according whether to be given the high-fat diet (HF): corn oil treatment with control diet (C-C), p,p'-DDE treatment with control diet (DDE-C), corn oil treatment with high-fat diet (C-HF) or p,p'-DDE treatment with high-fat diet (DDE-HF) for 35 days. Our results indicated that paternal p,p'-DDE exposure did not affect the male fertility of male offspring directly, but decreased sperm quality and induced testicular apoptosis after the high-fat diet treatment. Further analysis demonstrated that paternal exposure to p,p'-DDE and pre-pubertal high-fat diet decreased sperm Igf2 DMR2 methylation and gene expression in male offspring. Hence, paternal exposure to p,p'-DDE and pre-pubertal high-fat diet increases the susceptibility to male fertility impairment and sperm Igf2 DMR2 hypo-methylation in male offspring, posing a significant implication in the disease etiology.

Review of DDT, DDE, DDD, DDMU and DDMS Toxicity Data for Organisms Used in Estuarine and Marine Sediment Toxicity Tests.

The open literature was searched for laboratory toxicity data for marine/estuarine organisms exposed to dichlorodiphenyltrichloroethane (DDT) and its degradation products of dichlorodiphenyldichloroethylene (DDE), dichlorodiphenyldichloroethane (DDD), dichlorodiphenylchloroethylene (DDMU), and dichlorodiphenylchloroethane (DDMS). The goal of the review was to determine water-column toxicity values that could be used for porewater-based assessment of sediment toxicity. Data for individual compounds (and isomers thereof) in this group were very limited; most available data were for mixtures of multiple compounds, some defined and others undefined. Further, the majority of relevant studies involved exposure to spiked or field-contaminated sediment (rather than waterborne exposure), which requires inferring concentration in porewater from bulk sediment. Comparing data on the basis of effect concentrations for water or inferred concentration in sediment pore water, the lower reported effect concentrations were in the range of 0.05 to 0.1 µg/L, generally in studies of longer duration and/or evaluating sub-lethal effects. Because field exposures are generally to mixtures of these compounds in varied proportions, additional data on chemical-specific toxicity would aid in pore-water based toxicity assessment for marine/estuarine sediments contaminated with DDT-related chemicals.

Age at menarche and chemical exposure: per- and polyfluoroalkyl substances (PFAS), dichloro-diphenyl-trichloroethane (DDT), dichloro-diphenyl-dichloroethylene (DDE), and polychlorinated biphenyls (PCBs).

CONTEXT: Humans are now exposed to a multitude of chemicals throughout the life course, some of which may affect growth and development owing to their endocrine-like activity. OBJECTIVE: To assess the relationship of suspect toxicants to maturation, specifically to age at menarche. METHODS: We conducted two systematic reviews of age at menarche and PFOA, PFOS, PCBs and DDE/DDT based on publications indexed by pubmed. RESULTS: 16 unique reports were identified. Most studies of PFOA and PFOS reported either no association or delays in the age at menarche; only one reported an earlier age. Studies of DDT and DDE were more mixed. Reports on PCBs varied by PCB congener group with an equal number of them reporting delays and no association but one an acceleration. Sources of variation in results include the timing of exposure assessment (prenatal vs. postnatal), level of the toxicant, and sample size. No obvious pattern to the variation in results could be tied to those sources of variation. CONCLUSION: The absence of consistent evidence from multiple reports of earlier age at menarche suggests that these toxicants may not be responsible for accelerated sexual maturation in girls. However, human populations naturally vary in the variety and levels of exposure, making the comparison of studies difficult. Further, studies vary in methodology, complicating aggregation of results and generalisations.

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.

A New In Vivo Zebrafish Bioassay Evaluating Liver Steatosis Identifies DDE as a Steatogenic Endocrine Disruptor, Partly through SCD1 Regulation.

Non-alcoholic fatty liver disease (NAFLD), which starts with liver steatosis, is a growing worldwide epidemic responsible for chronic liver diseases. Among its risk factors, exposure to environmental contaminants, such as endocrine disrupting compounds (EDC), has been recently emphasized. Given this important public health concern, regulation agencies need novel simple and fast biological tests to evaluate chemical risks. In this context, we developed a new in vivo bioassay called StAZ (Steatogenic Assay on Zebrafish) using an alternative model to animal experimentation, the zebrafish larva, to screen EDCs for their steatogenic properties. Taking advantage of the transparency of zebrafish larvae, we established a method based on fluorescent staining with Nile red to estimate liver lipid content. Following testing of known steatogenic molecules, 10 EDCs suspected to induce metabolic disorders were screened and DDE, the main metabolite of the insecticide DDT, was identified as a potent inducer of steatosis. To confirm this and optimize the assay, we used it in a transgenic zebrafish line expressing a blue fluorescent liver protein reporter. To obtain insight into DDE's effect, the expression of several genes related to steatosis was analyzed; an up-regulation of scd1 expression, probably relying on PXR activation, was found, partly responsible for both membrane remodeling and steatosis.

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.

Metallothionein gene expression in rat tissues: response to dietary restriction after orally dichlorodiphenyldichloroethylene (DDE) exposure and high-fat feeding.

Dichlorodiphenyldichloroethylene (DDE) is an environmental pollutant that accumulates in adipose tissue through the food chain. Hypercaloric, high-fat diet is considered to promote the accumulation of toxic lipophilic substances in tissues, whereas the loss of body fat through caloric restriction results in a recirculation of these substances. In rats, oral administration of DDE causes the onset of tissues damage; the concomitant intake of a high-fat diet ameliorates tissues status, probably because of the entrapment of the lipophilic substance in fat depots. Recent evidence demonstrates that DDE alters the expression of metallothioneins, proteins involved in cellular defense from oxidative stress, in a diet- and tissue-specific manner. This study is aimed to verify if 2 weeks of caloric restriction after the oral DDE treatment can modify metallothionein gene expression in tissues of high-fat fed rats. Real-time PCR analysis demonstrates that metallothionein gene expression after calorie restriction is tissue-specific and strongly influenced by both previous dietary conditions and DDE exposure. To avoid misleading conclusions on the interference of toxic xenobiotics on metallothionein gene expression is particularly important to consider the tissue, the cellular conditions, and the nutritional status of the animals, especially when the protein is used as an index of cells health.

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.

A multipollutant low-grade exposure regulates the expression of miR-30b, Let-7a and miR-223 in maternal sera: Evidence from the NEHO cohort.

There is growing evidence that environmental pollutants can induce epigenetic modifications altering the balance of miRNAs and inducing the onset of pathological conditions in animals. In this study, we measured the serum concentration of a suite of inorganic and organic pollutants (Cu, Zn, Se, Hg, HCB, p,p'-DDE, PCBs) and their association to serum miR-30b, miR-223 and Let-7a microRNA expression in 68 healthy pregnant women from the NEHO birth cohort sited in a highly industrialized area. The effects of the pollutants on the modulation of circulating miRNAs' expression were first investigated using linear continuous regression models with a single-compound approach showing that miR-223 expression was significantly associated with serum concentration of Se and Zn (pSe = 0.0336; pZn = 0.0225) and miR-30b was associated with Hg levels (pHg = 0.019). Furthermore, when contaminants were categorized into tertiles, miR-223 and miR-30b showed a positive association with higher tertiles of Zn, p,p'-DDE (pZn = 0.023; pDDE = 0.041) and Hg (pHg = 0.008), respectively. Moreover, Let-7a expression was exclusively influenced by medium tertiles levels of Se (low vs medium tertiles, p = 0.001). Simultaneous exposure to multi-pollutant mixture was approached by WQS regression model. Statistical analysis shows a driving effect of Zn, Se, Cu, Hg and HCB on significant increased expression of Let-7a (p = 0.045). Mercury and Se significantly amplified the expression for miR-30b (p = 0.038). Differently, the combined effect of p,p'-DDE, Zn and Se decreased miR-223 expression (p = 0.0001). The documented modified expression of circulating miRNAs in the serum of pregnant women, exposed to low-medium dose contaminants mixtures offers innovative early-warning approaches to human health risk assessment.

Investigation of obesogenic effects of hexachlorobenzene, DDT and DDE in male rats.

Obesity has become a very important public health problem and is increasing globally. Genetics, individual and environmental factors play roles in the etiology of this complex disorder. Recently, several environmental pollutants have been suggested to have obesogenic activities. Peroxisome proliferator activating receptor gamma (PPARγ), uncoupling protein-1 (UCP1) and their expression in white adipose tissue (WAT) and brown adipose tissue (BAT) play key roles in adipogenesis. UCP3 and irisin were reported to play roles in non-shivering thermogenesis. Our primary aim was to investigate obesogenic effects of hexachlorobenzene (HCB), dichlorodiphenyltrichloroethane (DDT) and dichlorodiphenyldichloroethylene (DDE) in rats. In addition, thermoregulatory effects of HCB, DDT and DDE were also investigated by analyzing the levels of Ucp3 and irisin. Thirty-two adult male Sprague-Dawley rats were randomly divided into four groups as control, HCB, DDT and DDE. Animals were administered with organochlorine pesticides (OCPs; 5 mg/kg bw) by oral gavage every other day for five weeks. At the end of the experimental period, the animals were sacrificed, BAT and WAT samples were collected to analyze Pparγ, Ucp1 and Ucp3 levels. Moreover, skeletal muscle samples were collected to examine Ucp3 and irisin levels. Serum glucose, cholesterol and triglyceride levels were also determined. Body weight and core temperature of the animals were not significantly affected by any of the OCP administration. Serum glucose, cholesterol and triglyceride levels were similar among the experimental groups. Pparγ expression was significantly elevated by HCB administration only in WAT (p < 0.05). On the other hand, both Pparγ and Ucp1 expressions were diminished in WAT and BAT (p < 0.01) by DDT treatment, while in WAT, DDE significantly decreased Pparγ expression without altering its expression in BAT (p < 0.001). Ucp3 and irisin levels in skeletal muscle were not altered. Our findings show that both DDT and DDE reduce the browning of WAT by suppressing white adipocytes and thus may have obesogenic activity in male rats without altering thermoregulation. In addition, HCB, DDT and DDE-induced alterations in expression of Pparγ and Ucp1 in WAT implicates differential regulation of adipogenic processes.

Associations between autoimmune dysfunction and pollutants in Akwesasne Mohawk women: Dichlorodiphenyltrichloroethane and polychlorinated biphenyl exposure.

BACKGROUND: Pollutant exposures, including polychlorinated biphenyls (PCBs) and dichlorodiphenyltrichloroethane (DDT), have been found to disrupt normal immune function. Native American communities are disproportionately affected by autoimmune dysfunction and are more likely to be exposed to harmful pollutants than the general population. OBJECTIVE: To determine the association between autoimmune dysfunction and pollutant exposure levels, this study evaluates the statistical relationship between the presence of autoimmune dysfunction and pollutant exposure. METHODS: Information was collected from Akwesasne Mohawk women (n = 182), 21-39 years of age, between 2009 and 2013. Data collection included anthropometric measurements, medical diagnoses of autoimmune disease and symptoms of autoimmune dysfunction in the medical record, and blood draws for measurement of pollutants. Multivariate analyses determined the association between toxicant exposure and autoimmune dysfunction. RESULTS: Toxicant p,p'-DDE was positively associated with an almost two-fold risk of autoimmune dysfunction. p,p'-DDE and PCB congeners 32, 136, and 138 were positively associated in a multivariate analysis with an autoimmune diagnosis. CONCLUSIONS: Pollutant exposures, specifically to p,p'-DDE and some PCB congeners, are common exposures that are associated with autoimmune dysfunction and autoimmune disease, although there are other factors and causes related to autoimmune dysfunction incidence.

Exposure to DDT and DDE and functional neuroimaging in adolescents from the CHAMACOS cohort.

BACKGROUND: Epidemiological studies suggest that exposure to p,p'-dichloro-diphenyl-trichloroethane (p,p'-DDT) is associated with poorer cognitive function in children and adolescents, but the neural mechanisms underlying this association remain unclear. OBJECTIVE: We investigated associations of prenatal and childhood exposure to p,p'-DDT and its metabolite p,p'-dichloro-diphenyl-dichloroethylene (p,p'-DDE) with cortical activation in adolescents using functional near-infrared spectroscopy (fNIRS). METHODS: We administered fNIRS to 95 adolescents from the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS) aged 15-17 years. We assessed cortical activity in the frontal, temporal, and parietal brain regions while participants completed tasks of executive function, language comprehension, and social cognition. We measured serum p,p'-DDT and -DDE concentrations at age 9 years and then estimated exposure-outcome associations using linear regression models adjusted for sociodemographic characteristics. In secondary analyses, we back-extrapolated prenatal concentrations using prediction models and examined their association with cortical activation. RESULTS: Median (P25-P75) p,p'-DDT and -DDE concentrations in childhood were 1.4 (1-2.3) and 141.5 (75.0-281.3) ng/g lipid, respectively. We found that childhood exposure to p,p'-DDT and -DDE was associated with altered patterns of brain activation during tasks of cognition and executive functions. For example, we observed increased activity in the left frontal lobe during a language comprehension task (ß per 10 ng/g lipid increase of serum p,p'-DDE at age 9 years = 3.4; 95% CI: 0.0, 6.9 in the left inferior frontal lobe; and ß = 4.2; 95% CI: 0.9, 7.5 in the left superior frontal lobe). We found no sex differences in the associations of childhood p,p'-DDT and -DDE concentrations with neural activity. Associations between prenatal p,p'-DDT and p,p'-DDE concentrations and brain activity were similar to those observed for child p,p'-DDT and -DDE concentrations. CONCLUSIONS: Childhood p,p'-DDT and -DDE exposure may impact cortical brain activation, which could be an underlying mechanism for its previously reported associations with poorer cognitive function.

The toxic effects of combined exposure of chlorpyrifos and p, p'-DDE to zebrafish (Danio rerio) and tissue bioaccumulation.

Pesticides are widely used and frequently detected in the environment. The evaluation on the toxic effects of the co-exposure of two or more pesticides or related metabolites could reflect the real situation of the exposing risks. In this study, zebrafish was used as a model to investigate the potential toxic interactions of chlorpyrifos and 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (p,p'-DDE) on the survival rate, oxidative stress response and neurotoxicity, as well as their bioaccumulation and distribution in tissues. Co-exposure of chlorpyrifos and p,p'-DDE resulted in significant additive acute toxic effects on adult zebrafish with model deviation ratio (MDR) = 1.64. Both 7-day short-term at 1% LC50 and 35-day long-term at 0.5% LC50 co-exposure of chlorpyrifos with p,p'-DDE (50 and 100 µg/L) significantly reduced the survival rate of zebrafish colony to 75 and 82.5%. Co-exposure of chlorpyrifos and p,p'-DDE contributed to increased activity of antioxidant enzyme CAT, SOD and GST and excessive MDA generation, and decreased activity of CarE, CYP450 and AChE, compared with either single exposure of them. In co-exposure, the bioaccumulation of chlorpyrifos and p,p'-DDE was significantly different from the single exposure group. Overall, this study unraveled the potential toxic interaction of chlorpyrifos and p,p'-DDE on zebrafish and provided reference for environmental risk assessment of pesticide mixture.

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.

Assessing the risk of diabetes in participants with DDT DDE exposure- A systematic review and meta-analysis.

We have performed a systematic review and meta-analysis of the association between DDT/DDE and diabetes, searching PubMed, Embase, and Cochrane for relevant articles published up to August 30, 2021, and eventually including 43 publications. Our researchers evaluate included studies' quality and risk of bias via the recommended tool. This study uses meta-analyses of random effects of each exposure and outcome to estimate combined odds ratios (ORs) and 95% confidence intervals (CIs). Our research identified 43 cross-sectional, case-control, and cohort studies, including 40,141 individuals in America, Europe, Asia, and Africa. The summary ORs (95% CIs) of incident diabetes were 1.61 (1.10-2.39) for DDT, 1.67 (1.41-1.98) for DDE. The subgroup analysis indicated that the association is significantly higher in the region of Asia for both DDT (OR = 2.73) and DDE (OR = 2.62). Besides, we also tried various types of stratification to identify the more influential confounding factors, among which regional factors have a significant influence. Study evidence suggests that exposure to DDT and its breakdown product, DDE, might be associated with the risk of incident diabetes. Among Asian patients, DDT/DDE concentrations are more closely associated with diabetes. Further studies in specific regions will be considered in the future.

Effects of different DDE exposure paradigms on testicular steroid hormone secretion and hepatic oxidative stress in male Long-Evans rats.

Chronic exposure to low doses of anthropogenic chemicals in the environment continues to be a major health issue. Due to concerns about the effects in humans and wildlife, use of persistent organic pollutants, such as dichlorodiphenyltrichloroethane (DDT), is prohibited. However, their ubiquitous nature and persistence allows them to remain in the environment at low levels for decades. Dichlorodiphenyldichloroethylene (DDE) is the most persistent metabolite of DDT and has been shown to cause hepatotoxicity, nephrotoxicity, hormonal disorders, and induce oxidative stress in many organisms. Although the effects of acute exposure to DDT and its metabolite DDE have been extensively studied, the chronic effects of sub-lethal DDE exposure at levels comparable to those found in the environment have not been well documented. Long-Evans male rats were used to determine the effect of relatively chronic and short term DDE (doses ranged from 0.001 to 100 µg/L) exposure on endocrine function and oxidative stress at different developmental time points. We found that circulating serum testosterone (T) levels were significantly decreased and T secretion in testicular explants were significantly influenced in a dose dependent manner in both pre-pubertal and pubertal male rats after DDE exposure, with pubertal rats being the most affected contrary to our original prediction. Additionally, exposure to DDE increased expression of protein oxidation indicating a possible increase in cellular damage caused by oxidative stress. This study suggests that chronic exposures to environmentally relevant levels of DDE affected testicular function and decreased T secretion with implications for reproductive capacity.

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.