Reproductive toxicity of DDT in the Japanese medaka fish model: Revisiting the impacts of DDT+ on female reproductive health.

The organochlorine pesticide dichlorodiphenyltrichloroethane (DDT) is an endocrine-disrupting compound (EDC) that has been banned by most countries for decades. However, it continues to be detected in nearly all humans and wildlife due to its biological and environmental persistence. The ovarian dysgenesis syndrome hypothesis speculates that exposure to EDCs during sensitive developmental windows such as early gonadal differentiation lead to reproductive disorders later in life. Yet, mechanisms by which DDT affects developing gonads remain unclear due to the inherent challenge of getting developmental exposure data from adults presenting with reproductive disease. The Japanese medaka (Oryzias latipes) is a valuable fish model for sex-specific toxicological studies due to its chromosomal sex determination, external embryonic development, short generation time, and extensively mapped genome. It is well documented that medaka exposed to DDT and its metabolites and byproducts (herein referred to as DDT+) at different developmental time points experience permanent alterations in gonadal morphology, reproductive success, and molecular and hormonal signaling. However, the overwhelming majority of studies focus primarily on functional and morphological outcomes in males and females and have rarely investigated long-term transcriptional or molecular effects. This review summarizes previous experimental findings and the state of our knowledge concerning toxic effects DDT + on reproductive development, fertility, and health in the valuable medaka model. It also identifies gaps in knowledge, emphasizing a need for more focus on molecular mechanisms of ovarian endocrine disruption using enhanced molecular tools that have become increasingly available over the past few decades. Furthermore, DDT forms a myriad of over 45 metabolites and transformation products in biota and the environment, very few of which have been evaluated for environmental abundance or health effects. This reinforces the demand for high throughput and economical in vivo models for predictive toxicology screening, and the Japanese medaka is uniquely positioned to meet this need.

Paternal DDT exposure induces sex-specific programming of fetal growth, placenta development and offspring's health phenotypes in a mouse model.

Mounting evidence suggests that environmentally induced epigenetic inheritance occurs in mammals and that traits in the progeny can be shaped by parental environmental experiences. Epidemiological studies link parental exposure to environmental toxicants, such as the pesticide DDT, to health phenotypes in the progeny, including low birth and increased risk of chronic diseases later in life. Here, we show that the progeny of male mice exposed to DDT in the pre-conception period are born smaller and exhibit sexual dimorphism in metabolic function, with male, but not female, offspring developing severe glucose intolerance compared to controls. These phenotypes in DDT offspring were linked to reduced fetal growth and placenta size as well as placenta-specific reduction of glycogen levels and the nutrient sensor and epigenetic regulator OGT, with more pronounced phenotypes observed in male placentas. However, placenta-specific genetic reduction of OGT only partially replicates the metabolic phenotype observed in offspring of DDT-exposed males. Our findings reveal a role for paternal pre-conception environmental experiences in shaping placenta development and in fetal growth restriction. While many questions remain, our data raise the tantalizing possibility that placenta programming could be a mediator of environmentally induced intergenerational epigenetic inheritance of phenotypes and needs to be further evaluated.

Postnatal Exposure to the Endocrine Disruptor Dichlorodiphenyltrichloroethane Affects Adrenomedullary Chromaffin Cell Physiology and Alters the Balance of Mechanisms Underlying Cell Renewal.

Dichlorodiphenyltrichloroethane (DDT) is a wide-spread systemic pollutant with endocrine disrupting properties. Prenatal exposure to low doses of DDT has been shown to affect adrenal medulla growth and function. The role of postnatal exposure to DDT in developmental disorders remains unclear. The aim of the present investigation is to assess growth parameters and the expression of factors mediating the function and renewal of chromaffin cells in the adult adrenal medulla of male Wistar rats exposed to the endocrine disruptor o,p'-DDT since birth until sexual maturation. The DDT-exposed rats exhibited normal growth of the adrenal medulla but significantly decreased tyrosine hydroxylase production by chromaffin cells during postnatal period. Unlike the control, the exposed rats showed enhanced proliferation and reduced expression of nuclear ß-catenin, transcription factor Oct4, and ligand of Sonic hedgehog after termination of the adrenal growth period. No expression of pluripotency marker Sox2 and absence of Ascl 1-positive progenitors were found in the adrenal medulla during postnatal ontogeny of the exposed and the control rats. The present findings indicate that an increase in proliferative activity and inhibition of the formation of reserve for chromaffin cell renewal, two main mechanisms for cell maintenance in adrenal medulla, in the adult DDT-exposed rats may reflect a compensatory reaction aimed at the restoration of catecholamine production levels. The increased proliferation of chromaffin cells in adults suggests excessive growth of the adrenal medulla. Thus, postnatal exposure to DDT alters cell physiology and increases the risk of functional insufficiency and hyperplasia of the adrenal medulla.

DDT and titanium dioxide nanoparticle coexposure induced neurobehavioral deficits in zebrafish.

Both dichlorodiphenyltrichloroethane (DDT) and titanium dioxide nanoparticle (TiO2 NP) have worldwide-scale commercial applications, resulting in their co-pollution in the ecosystems and posing combined health risks. However, there is a lack of toxicity studies for the interactions of DDT and TiO2 NP in the environmental relevant concentrations. In this study, we characterized the coexposures using a zebrafish waterborne exposure approach and evaluated the neurotoxicity response of the treated embryos or adults. Our results showed that DDT/TiO2 NP coexposure enhanced the DDT accumulation in vivo and increased the larval locomotor. The chronic DDT/TiO2 NP coexposure did not affect the overall survival rate, sex ratio and growth. However, DDT/TiO2 NP coexposure severely affected the adult locomotor activity, social contact, shoaling and aggressive behaviors compared to single treatment groups or controls. These adult behavioral deficits were accompanied by changes in neurotransmitter acetylcholine (ACH) level in the brain and muscle tissues, as well as neural development genes expression activation of growth-associated protein 43 (gap43) and synaptic vesicle glycoprotein 2 (sv2) in the brain. The significantly increased ACH level and the activated neural genes expression in the DDT/TiO2 NP co-exposed fish may account for the observed hyperactivity and social deficits.

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.

Apparent Khat chewers exposure to DDT in Ethiopia and its potential toxic effects: A scoping review.

Dichlorodiphenyltrichloroethane (DDT) is an insecticide, a member of dirty dozen persistent organic pollutants, used widely in the world until it was banned in the 1970s.The banning of DDT was strengthened by the Stockholm Convention in 2001. DDT is allowed only for malaria control in Ethiopia. However, farmers are misusing DDT and applying it to Khat (Catha edulis) farming. So, this review analyzes available data in the literature on the current trend, application, occurrence, fate and effects of DDT and its metabolites, dichlorodiphenyldichloroethane (DDD), dichlorodiphenyldichloroethylene (DDE), in the chewable parts of Khat. Generally, the concentration level of DDT, DDD, and DDE, designated as DDTs, is detected in different farmlands of Ethiopia. Some of the DDTs concentrations detected are very high (141.2-973 µg/kg (Gelemso), 194.4-999 µg/kg (Aseno) and 6253-8413.3 µg/kg (Gurage), and these concentrations may indicate increasing recent unmonitored application of DDT on Khat leaves. Some of the detected concentrations of DDT in the literature were above the maximum residue limit (MRL) set by FAO/WHO (100 µg/kg) and the European Commission 10 µg/kg in vegetables and 50 µg/kg in cereals. DDT exposure of Khat chewers linked to the concentration of DDT on Khat leaves and the amount of Khat consumed. DDT might pose health risks to chewers due to chronic toxicity, bioaccumulation, persistent and endocrine disruption properties.

Features of Spleen Development in Newborn Rats Exposed to Endocrine Disrupter Dichlorodiphenyltrichloroethane during the Prenatal Period.

The development of the spleen in newborn male Wistar rats exposed to low-dose endocrine disruptor dichlorodiphenyltrichloroethane during the prenatal period was studied. Histological examination of the spleen revealed a more active development of periarterial lymphoid sheaths and lower granulocyte content in the organ. Cytofluorimetry showed a significantly lower content of B cells. Thus, low-dose exposure of the endocrine disruptor dichlorodiphenyltrichloroethane on the developing organism during the prenatal period induced changes in spleen morphogenesis resulting in extensive development of lymphoid formations and a lower intensity of lymphocyte and granulocyte differentiation.

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.

Comparative in vitro and in silico study on the estrogenic effects of 2,2-bis(4-chlorophenyl)ethanol, 4,4'-dichlorobenzophenone and DDT analogs.

DDT and its transformation products (DDTs) are frequently detected in environmental and biological media. Research suggests that DDT and its primary metabolites (DDD and DDE) could induce estrogenic effects by disturbing estrogen receptor (ER) pathways. However, the estrogenic effects of DDT high-order transformation products, and the exact mechanisms underlying the differences of responses in DDT and its metabolites (or transformation products) still remain unknown. Here, besides DDT, DDD and DDE, we selected two DDT high-order transformation products, 2,2-bis(4-chlorophenyl) ethanol (p,p'-DDOH) and 4,4'-dichlorobenzophenone (p,p'-DCBP). We aim to explore and reveal the relation between DDTs activity and their estrogenic effects by receptor binding, transcriptional activity, and ER-mediated pathways. Fluorescence assays showed that the tested 8 DDTs bound to the two isoforms (ERα and ERß) of ER directly. Among them, p,p'-DDOH exhibited the highest binding affinity, with IC50 values of 0.43 µM and 0.97 µM to ERα and ERß, respectively. Eight DDTs showed different agonistic activity toward ER pathways, with p,p'-DDOH exhibiting the strongest potency. In silico studies revealed that the eight DDTs bound to either ERα or ERß in a similar manner to 17ß-estradiol, in which specific polar and non-polar interactions and water-mediated hydrogen bonds were involved. Furthermore, we found that 8 DDTs (0.0008-5 µM) showed distinct pro-proliferative effects on MCF-7 cells in an ER-dependent manner. Overall, our results revealed not only for the first time the estrogenic effects of two DDT high-order transformation products by acting on ER-mediated pathways, but also the molecular basis for differential activity of 8 DDTs.

Developmental Exposure to DDT Disrupts Transcriptional Regulation of Postnatal Growth and Cell Renewal of Adrenal Medulla.

Dichlorodiphenyltrichloroethane (DDT) is the most widespread persistent pollutant with endocrine-disrupting properties. DDT has been shown to disrupt secretory and morphogenetic processes in the adrenal cortex. The present investigation aimed to evaluate transcriptional regulation of postnatal growth of the adrenal medulla and formation of the pools necessary for self-renewal of medullary cells in rats that developed under low-dose exposure to DDT. The study was performed using male Wistar rats exposed to low doses of o,p'-DDT during prenatal and postnatal development. Light microscopy and histomorphometry revealed diminished medulla growth in the DDT-exposed rats. Evaluation of Ki-67 expression in chromaffin cells found later activation of proliferation indicative of retarded growth of the adrenal medulla. All DDT-exposed rats exhibited a gradual decrease in tyrosine hydroxylase production by adrenal chromaffin cells. Immunohistochemical evaluation of nuclear ß-catenin, transcription factor Oct4, and ligand of sonic hedgehog revealed increased expression of all factors after termination of growth in the control rats. The DDT-exposed rats demonstrated diminished increases in Oct4 and sonic hedgehog expression and lower levels of canonical Wnt signaling activation. Thus, developmental exposure to the endocrine disruptor o,p'-DDT alters the transcriptional regulation of morphogenetic processes in the adrenal medulla and evokes a slowdown in its growth and in the formation of a reserve pool of cells capable of dedifferentiation and proliferation that maintain cellular homeostasis in adult adrenals.

Molecular forms of the Indian Anopheles subpictus complex differ in their susceptibility to insecticides and the presence of knockdown resistance (kdr) mutations in the voltage-gated sodium channel.

OBJECTIVES: To investigate the differential insecticide-susceptibility of two molecular forms of Anopheles subpictus complex (A and B) against DDT and pyrethroids, the occurrence of knockdown resistance (kdr) mutations in these forms, and the association of kdr mutations with insecticide resistance. METHODS: Insecticide susceptibility tests of An. subpictus s.l., collected from coastal and inland areas of mainland India, were performed against DDT, permethrin and deltamethrin using the WHO standard insecticide susceptibility test kit. The mosquitoes were characterized for molecular forms using a diagnostic PCR developed in this study. Representative samples of An. subpictus molecular forms A and B were sequenced for a genomic region encompassing the IIS4-5 linker to the IIS6 segments of the voltage-gated sodium channel to identify kdr mutations. A common PIRA-PCR was developed for identifying L1014F-kdr mutation and used for genotyping in both molecular forms of An. subpictus. RESULTS: Molecular form A of An. subpictus was resistant to all three insecticides, i.e., DDT, Permethrin and deltamethrin, whereas Form B was categorized as 'possibly resistant' to these insecticides. Significantly higher mortalities in WHO insecticide susceptibility tests were recorded in Form B compared to Form A in sympatric populations. Molecular characterization of the IIS4-5 linker to IIS-6 segments of the voltage-gated sodium channel revealed the presence of two alternative nucleotide transversions at L1014 residue in Form A, both leading to the same amino acid change, i.e., Leu-to-Phe; however, such mutations could not be observed in Form B. PIRA-PCR-based kdr-genotyping of field populations revealed high frequencies of L1014F-kdr mutations in Form A and the absence of this mutation in Form B. The proportion of L1014F mutation was significantly higher in resistant mosquitoes following insecticide-bioassay with DDT (p<0.0001), permethrin (p<0.001) and deltamethrin (p<0.01) as compared to their susceptible counterparts. CONCLUSIONS: Significant differences in insecticide susceptibility were found between two molecular forms of An. subpictus complex in sympatric populations. The L1014F-kdr mutation was observed in Form A only, which was found to be associated with DDT, permethrin and deltamethrin resistance.

Do good carefully: The long-term effects of low-dose DDT exposure in early childhood on education, marriage and employment.

It is well known that malaria has serious adverse effects on humans. Yet, little is known as to how dichlorodiphenyltrichloroethane (DDT), which is still used to control malaria, may affect human socioeconomic outcomes in the long run. Utilizing the large-scale indoor residual spraying of low-dose DDT in Taiwan in the 1950s, we estimated the long-term effects of low-dose DDT exposure in early childhood on education, marriage and employment in adulthood. Our identification hinges on the unexpected extension of DDT spraying after malaria had already been largely brought under control. We found that even at a very low dosage, DDT exposure still resulted in discernible negative effects on education and marriage. For employment, although no effect on the probability of working was detected, people exposed to more sprayings in childhood were more likely to work in the agricultural sector that typically requires less human capital.

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.

Xenobiotic responses of Drosophila melanogaster to insecticides with different modes of action and entry.

Depending on their chemical structure, insecticides enter the insect body either through the cuticle or by ingestion (mode of entry [MoE]), and, naturally, harm or even kill insects through different mechanisms (modes of action). In parallel, they trigger a systemic detoxification response, especially by activation of detoxification gene expression. We monitored the acute genetic alterations of known xenobiotic response target genes against five different insecticides with two most common MoEs (contact toxicity and stomach toxicity), found that: 1. only a few genes were detected responding to acute exposure to insecticides (LD90 ); 2. The expression of cyp12d1 was upregulated in all experiments, except for dichlorodiphenyltrichloroethane exposure, suggesting that cyp12d1 is a general first response gene of the xenobiotic response; 3. The contact and stomach entries did not show any notable difference, both MoEs induced the response of JNK signaling pathway, possibly serving as the driver of the response of cyp12d1 and a few other genes. In conclusion, the changes in gene expression levels were relatively modest and no significant differences were found between the two MoEs, so the insecticide entry route does not seem to have an impact on the detoxification response. However, the two MoEs of the same insecticide showed different efficiencies in our test. Thus, the study of these two MoEs will help to develop more efficient release and management methods for the use of such insecticides.

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 lentic microcosm approach to determine the toxicity of DDT and deltamethrin on diatom communities.

Worldwide the use of pesticides has increased, especially in the industry and agriculture sector even though they contain highly toxic substances. The use of pesticides has various negative effects on the aquatic ecosystem and organisms within these ecosystems. The paper aimed to assess the effects of increased concentrations of malaria vector control insecticides (Dichlorodiphenyltrichloroethane (DDT) and Deltamethrin (DTM)) on the freshwater diatom community structure using a microcosm approach as well as determine whether a mixture (DDT 1:1 Deltamethrin) exposure will have a greater influence on the diatom community when compared to single exposures of these insecticides. Diatoms were exposed to a high and low concentration (based on LC50 data for freshwater Xenopus laevis from the USEPA Ecotox database) of DDT, DTM and a mixture in lentic microcosms over a total period of 28 days. Results indicated that irrespective of exposure concentrations, DDT, DTM and a mixture had negative effects on the diatom community including functionality and vitality as these insecticides induced changes to their chloroplasts. There was an increased percentage dead cells for all exposures compared to the control, with the insecticides having a phototoxic effect on the diatom community. Exposure to the selected insecticides caused a significant decrease in some diatom metrics indicating the negative effects these insecticides have on the diatom metrics. Therefore, diatoms may prove to be useful as bio-indicators in ecotoxicology studies when assessing the effects of any insecticide exposures.

Maternal exposure to DDT, DDE, and pyrethroid insecticides for malaria vector control and hypospadias in the VHEMBE birth cohort study, Limpopo, South Africa.

Hypospadias is the ectopic opening of the urethra on the penis or scrotum. Exposure to estrogenic and/or anti-androgenic chemicals in utero may play an etiologic role. DDT and the pyrethroids cypermethrin and deltamethrin, are used to control malaria. DDT is estrogenic and its breakdown product DDE is anti-androgenic; cypermethrin and deltamethrin can also disrupt androgen pathways. We examined the relationship between maternal exposure to these insecticides during pregnancy and hypospadias among boys participating in the Venda Health Examination of Mothers, Babies and their Environment (VHEMBE) in Limpopo Province, South Africa. We measured peripartum levels of p,p'-DDT and p,p'-DDE in maternal serum and urinary pyrethroid metabolites. We conducted urogenital examination on 359 one-year-old boys. A total of 291 (81.0 %) had phimosis, which prevented full urogenital examination, leaving a final sample of 68 boys for determination of the presence of hypospadias. Diagnosis was based on concordance of two independent physicians. We identified hypospadias in 23 of the 68 boys (34 %). Maternal urinary concentrations of cis-DCCA and trans-DCCA metabolites of cypermethrin and other pyrethroids, were associated with an increased risk for hypospadias, but the other metabolite 3-PBA was not (adjusted relative risk per 10-fold increase = 1.58, 95 % CI 1.07-2.34; 1.61, 95 % CI 1.09-2.36; and 1.48, 95 % CI 0.78-2.78, respectively). No associations were found between p,p'-DDT, p,p'-DDE, 3-PBA or cis-DBCA and hypospadias. We observed a high prevalence of hypospadias among boys without phymosis. Boys with higher prenatal exposure to pyrethroid insecticides were at higher risk of hypospadias. Our findings may have global implications given that pyrethroid insecticides are widely used for malaria control, in agriculture and for home use.

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.

Developmental Exposure to Endocrine Disrupter DDT Interferes with Age-Related Involution of Thymus.

The impact of endocrine-disrupting chemicals on the development and involution of the immune system is a possible reason for the increased incidence of disorders associated with inappropriate immune function. The thymus is a lymphoid and also an endocrine organ, and, accordingly, its development and functioning may be impaired by endocrine disruptors. The aim was to evaluate age-related thymus involution in mature rats exposed to the endocrine disruptor DDT during prenatal and postnatal ontogeny. Methodology included in vivo experiment on male Wistar rats exposed to low doses of DDT during prenatal and postnatal development and morphological assessment of thymic involution, including the immunohistochemical detection of proliferating thymocytes. The study was carried out at the early stage of involution. Results: DDT-exposed rats exhibited a normal anatomy, and the relative weight of the thymus was within the control ranges. Histological and immunohistochemical examinations revealed increased cellularity of the cortex and the medulla, higher content of lymphoblasts, and more intensive proliferation rate of thymocytes compared to the control. Evaluation of thymic epithelial cells revealed a higher rate of thymic corpuscles formation. Conclusion: The data obtained indicate that endocrine disrupter DDT disturbs postnatal development of the thymus. Low-dose exposure to DDT during ontogeny does not suppress growth rate but violates the developmental program of the thymus by slowing down the onset of age-related involution and maintaining high cell proliferation rate. It may result in excessive formation of thymus-dependent areas in peripheral lymphoid organs and altered immune response.

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.