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.

Alterations in male reproductive hormones in relation to environmental DDT exposure.

DDT [1, 1, 1-trichloro-2,2-bis (p-chlorophenyl)-ethane] compounds are used for indoor residual spraying (IRS) to control malaria mosquitoes. DDT is an endocrine disruptor chemical in experimental conditions, but little is known of adverse effects related to living conditions with continual uptake across a time span by all possible means of exposure. Based on estrogenic and/or anti-androgenic effects found in animal studies, we hypothesized that chronic DDT/DDE exposures in men may be associated with changes in male reproductive hormones. We tested this hypothesis by compared the magnitude and direction of associations between DDT and DDE (1,1-dichloro-2,2-bis(p-chlorophenyl) ethylene) concentrations and male reproductive hormones in samples collected from IRS and non-IRS areas. We sampled a cross-section of 535 men (aged 18-40 years). Men living in IRS villages had significantly higher DDT and DDE concentrations compared with men from non-IRS villages. Men with DDT or DDE uptake (as reflected in detectable plasma concentrations) had significantly higher total-, free and bio-available testosterone (T), and lower follicle stimulating hormone (FSH) concentrations; lower luteinizing hormone (LH) concentrations were only evident with DDT uptake. To establish a dose-dependent effect, four sub-categories were defined. Men with the highest DDT (74-519 µg/g) and DDE (173-997 µg/g) concentrations had significantly higher total-, free and bio-available T, and lower FSH concentrations compared with subjects with non-detectable isomer concentrations. Estradiol concentrations were significantly higher in men with DDT and DDE concentrations in both the third (DDE: 27-172 µg/g; DDT: 5-73 µg/g) and fourth (DDE: 173-997 µg/g; DDT: 74-519 µg/g) categories. Men from IRS villages were significantly more likely to have higher total and bioavailable T as well as higher estradiol concentrations OR = 2.5 (95% CI 1.2, 3.2); OR 2.5 (95% CI 1.6, 4.0) and OR = 2.3 (95% CI 1.3, 4.1) compared to men from non-IRS villages, after controlling for age, BMI, personal use of pesticides, and smoking. Men living in IRS villages with life-long exposure (17.6 (±6) years) at the current residence with multiple exposure modalities incurred the highest degree of physiological imbalance over and above circulating isomer concentrations. Further studies are needed to elucidate the health implications of these findings.

Estrogenic activity, chemical levels and health risk assessment of municipal distribution point water from Pretoria and Cape Town, South Africa.

Endocrine disrupting chemicals (EDCs) are ubiquitous in the environment and have been detected in drinking water from various countries. Although various water treatment processes can remove EDCs, chemicals can also migrate from pipes that transport water and contaminate drinking water. This study investigated the estrogenic activity in drinking water from various distribution points in Pretoria (City of Tshwane) (n = 40) and Cape Town (n = 40), South Africa, using the recombinant yeast estrogen screen (YES) and the T47D-KBluc reporter gene assay. The samples were collected seasonally over four sampling periods. The samples were also analysed for bisphenol A (BPA), nonylphenol (NP), di(2-ethylhexyl) adipate (DEHA), dibutyl phthalate (DBP), di(2-ethylhexyl) phthalate (DEHP), diisononylphthalate (DINP), 17ß-estradiol (E2), estrone (E1) and ethynylestradiol (EE2) using ultra-performance liquid chromatography-tandem mass spectrophotometry (UPLC-MS/MS). This was followed by a scenario based health risk assessment to assess the carcinogenic and toxic human health risks associated with the consumption of distribution point water. None of the water extracts from the distribution points were above the detection limit in the YES bioassay, but the EEq values ranged from 0.002 to 0.114 ng/L using the T47D-KBluc bioassay. BPA, DEHA, DBP, DEHP, DINP E1, E2, and EE2 were detected in distribution point water samples. NP was below the detection limit for all the samples. The estrogenic activity and levels of target chemicals were comparable to the levels found in other countries. Overall the health risk assessment revealed acceptable health and carcinogenic risks associated with the consumption of distribution point water.

Changing the policy for intermittent preventive treatment with sulfadoxine-pyrimethamine during pregnancy in Malawi.

BACKGROUND: The growing resistance of Plasmodium falciparum to sulfadoxine-pyrimethamine (SP) treatment for uncomplicated malaria led to a recommendation by the World Health Organization for the use of artemisinin-based combination therapy. Inevitably, concerns were also raised surrounding the use of SP for intermittent prevention treatment of malaria during pregnancy (IPTp) amidst the lack of alternative drugs. Malawi was the first country to adopt intermittent prevention treatment with SP in 1993, and updated in 2013. This case study examines the policy updating process and the contribution of research and key stakeholders to this process. The findings support the development of a malaria research-to-policy framework in Malawi. METHODS: Documents and evidence published from 1993 to 2012 were systematically reviewed in addition to key informant interviews. RESULTS: The online search identified 170 potential publications, of which eight from Malawi met the inclusion criteria. Two published studies from Malawi were instrumental in the WHO policy recommendation which in turn led to the updating of national policies. The updated policy indicates that more than two SP doses, as informed by research, overcome the challenges of the first policy of two SP doses only because of ineffectiveness by P. falciparum resistance and the global lack of replacement drugs to SP for IPTp. CONCLUSION: International WHO recommendations facilitated a smooth policy change driven by motivated local leadership with technical and financial support from development partners. Policy development and implementation should include key stakeholders and use local malaria research in a research-to-policy framework.

Pesticide residues and estrogenic activity in fruit and vegetables sampled from major fresh produce markets in South Africa.

Food is likely to be one of the major pathways through which people are exposed to endocrine-disrupting chemicals. With the exception of residual effects, there are concerns that a number of naturally occurring and synthetic chemicals exert adverse effects upon endocrine systems in wildlife and humans. The current study reports selected pesticide concentrations and the total estrogenic activity of fruit and vegetables using the recombinant yeast oestrogen screen (YES) and T47D-KBluc reporter gene assays. A total of 53 food samples (27 fruit and 26 vegetables) from Johannesburg and Tshwane fresh produce markets (in South Africa) were analysed. Of these, 17 contained one to three different pesticide residues with concentrations ranging between 0.01 and 0.68 mg kg(-1), whereas in the rest of the samples no residues were detected. All pesticides detected except in one sample were below the maximum residue level (MRL), but others were unauthorised for use in specified fruit and vegetables. Estrogenic activity was detected in 26.4% (14 samples) of the samples tested, and the estradiol equivalents ranged from 0.007 to 2 pg g(-1). Although the estrogenic activity was low, it may contribute to adverse health effects. Continuous monitoring for pesticides in fruit and vegetables is important in view of the unauthorised pesticides detected in produce from South Africa and the endocrine-disrupting chemical activity found.

Comparison of five in vitro bioassays to measure estrogenic activity in environmental waters.

Bioassays are well established in the pharmaceutical industry and single compound analysis, but there is still uncertainty about their usefulness in environmental monitoring. We compared the responses of five bioassays designed to measure estrogenic activity (the yeast estrogen screen, ER-CALUX, MELN, T47D-KBluc, and E-SCREEN assays) and chemical analysis on extracts from four different water sources (groundwater, raw sewage, treated sewage, and river water). All five bioassays displayed similar trends and there was good agreement with analytical chemistry results. The data from the ER-CALUX and E-SCREEN bioassays were robust and predictable, and well-correlated with predictions from chemical analysis. The T47D-KBluc appeared likewise promising, but with a more limited sample size it was less compelling. The YES assay was less sensitive than the other assays by an order of magnitude, which resulted in a larger number of nondetects. The MELN assay was less predictable, although the possibility that this was due to laboratory-specific difficulties cannot be discounted. With standardized bioassay data analysis and consistency of operating protocols, bioanalytical tools are a promising advance in the development of a tiered approach to environmental water quality monitoring.

The Pine River statement: human health consequences of DDT use.

OBJECTIVES: Dichlorodiphenyltrichloroethane (DDT) was used worldwide until the 1970s, when concerns about its toxic effects, its environmental persistence, and its concentration in the food supply led to use restrictions and prohibitions. In 2001, more than 100 countries signed the Stockholm Convention on Persistent Organic Pollutants (POPs), committing to eliminate the use of 12 POPs of greatest concern. However, DDT use was allowed for disease vector control. In 2006, the World Health Organization and the U.S. Agency for International Development endorsed indoor DDT spraying to control malaria. To better inform current policy, we reviewed epidemiologic studies published from 2003 to 2008 that investigated the human health consequences of DDT and/or DDE (dichlorodiphenyldichloroethylene) exposure. DATA SOURCES AND EXTRACTION: We conducted a PubMed search in October 2008 and retrieved 494 studies. DATA SYNTHESIS: Use restrictions have been successful in lowering human exposure to DDT, but blood concentrations of DDT and DDE are high in countries where DDT is currently being used or was more recently restricted. The recent literature shows a growing body of evidence that exposure to DDT and its breakdown product DDE may be associated with adverse health outcomes such as breast cancer, diabetes, decreased semen quality, spontaneous abortion, and impaired neurodevelopment in children. CONCLUSIONS: Although we provide evidence to suggest that DDT and DDE may pose a risk to human health, we also highlight the lack of knowledge about human exposure and health effects in communities where DDT is currently being sprayed for malaria control. We recommend research to address this gap and to develop safe and effective alternatives to DDT.