African-specific molecular taxonomy of prostate cancer.

Prostate cancer is characterized by considerable geo-ethnic disparity. African ancestry is a significant risk factor, with mortality rates across sub-Saharan Africa of 2.7-fold higher than global averages1. The contributing genetic and non-genetic factors, and associated mutational processes, are unknown2,3. Here, through whole-genome sequencing of treatment-naive prostate cancer samples from 183 ancestrally (African versus European) and globally distinct patients, we generate a large cancer genomics resource for sub-Saharan Africa, identifying around 2 million somatic variants. Significant African-ancestry-specific findings include an elevated tumour mutational burden, increased percentage of genome alteration, a greater number of predicted damaging mutations and a higher total of mutational signatures, and the driver genes NCOA2, STK19, DDX11L1, PCAT1 and SETBP1. Examining all somatic mutational types, we describe a molecular taxonomy for prostate cancer differentiated by ancestry and defined as global mutational subtypes (GMS). By further including Chinese Asian data, we confirm that GMS-B (copy-number gain) and GMS-D (mutationally noisy) are specific to African populations, GMS-A (mutationally quiet) is universal (all ethnicities) and the African-European-restricted subtype GMS-C (copy-number losses) predicts poor clinical outcomes. In addition to the clinical benefit of including individuals of African ancestry, our GMS subtypes reveal different evolutionary trajectories and mutational processes suggesting that both common genetic and environmental factors contribute to the disparity between ethnicities. Analogous to gene-environment interaction-defined here as a different effect of an environmental surrounding in people with different ancestries or vice versa-we anticipate that GMS subtypes act as a proxy for intrinsic and extrinsic mutational processes in cancers, promoting global inclusion in landmark studies.

Human origins in a southern African palaeo-wetland and first migrations.

Anatomically modern humans originated in Africa around 200 thousand years ago (ka)1-4. Although some of the oldest skeletal remains suggest an eastern African origin2, southern Africa is home to contemporary populations that represent the earliest branch of human genetic phylogeny5,6. Here we generate, to our knowledge, the largest resource for the poorly represented and deepest-rooting maternal L0 mitochondrial DNA branch (198 new mitogenomes for a total of 1,217 mitogenomes) from contemporary southern Africans and show the geographical isolation of L0d1'2, L0k and L0g KhoeSan descendants south of the Zambezi river in Africa. By establishing mitogenomic timelines, frequencies and dispersals, we show that the L0 lineage emerged within the residual Makgadikgadi-Okavango palaeo-wetland of southern Africa7, approximately 200 ka (95% confidence interval, 240-165 ka). Genetic divergence points to a sustained 70,000-year-long existence of the L0 lineage before an out-of-homeland northeast-southwest dispersal between 130 and 110 ka. Palaeo-climate proxy and model data suggest that increased humidity opened green corridors, first to the northeast then to the southwest. Subsequent drying of the homeland corresponds to a sustained effective population size (L0k), whereas wet-dry cycles and probable adaptation to marine foraging allowed the southwestern migrants to achieve population growth (L0d1'2), as supported by extensive south-coastal archaeological evidence8-10. Taken together, we propose a southern African origin of anatomically modern humans with sustained homeland occupation before the first migrations of people that appear to have been driven by regional climate changes.

Evaluating Germline Testing Panels in Southern African Males With Advanced Prostate Cancer.

BACKGROUND: Germline testing for prostate cancer is on the increase, with clinical implications for risk assessment, treatment, and management. Regardless of family history, NCCN recommends germline testing for patients with metastatic, regional, very-high-risk localized, and high-risk localized prostate cancer. Although African ancestry is a significant risk factor for aggressive prostate cancer, due to a lack of available data no testing criteria have been established for ethnic minorities. PATIENTS AND METHODS: Through deep sequencing, we interrogated the 20 most common germline testing panel genes in 113 Black South African males presenting with largely advanced prostate cancer. Bioinformatic tools were then used to identify the pathogenicity of the variants. RESULTS: After we identified 39 predicted deleterious variants (16 genes), further computational annotation classified 17 variants as potentially oncogenic (12 genes; 17.7% of patients). Rare pathogenic variants included CHEK2 Arg95Ter, BRCA2 Trp31Arg, ATM Arg3047Ter (2 patients), and TP53 Arg282Trp. Notable oncogenic variants of unknown pathogenicity included novel BRCA2 Leu3038Ile in a patient with early-onset disease, whereas patients with FANCA Arg504Cys and RAD51C Arg260Gln reported a family history of prostate cancer. Overall, rare pathogenic and early-onset or familial-associated oncogenic variants were identified in 6.9% (5/72) and 9.2% (8/87) of patients presenting with a Gleason score ≥8 or ≥4 + 3 prostate cancer, respectively. CONCLUSIONS: In this first-of-its-kind study of southern African males, we provide support of African inclusion for advanced, early-onset, and familial prostate cancer genetic testing, indicating clinical value for 30% of current gene panels. Recognizing current panel limitations highlights an urgent need to establish testing guidelines for men of African ancestry. We provide a rationale for considering lowering the pathologic diagnostic inclusion criteria and call for further genome-wide interrogation to ensure the best possible African-relevant prostate cancer gene panel.

Metagenomic analysis reveals a rich bacterial content in high-risk prostate tumors from African men.

BACKGROUND: Inflammation is a hallmark of prostate cancer (PCa), yet no pathogenic agent has been identified. Men from Africa are at increased risk for both aggressive prostate disease and infection. We hypothesize that pathogenic microbes may be contributing, at least in part, to high-risk PCa presentation within Africa and in turn the observed ethnic disparity. METHODS: Here we reveal through metagenomic analysis of host-derived whole-genome sequencing data, the microbial content within prostate tumor tissue from 22 men. What is unique about this study is that patients were separated by ethnicity, African vs European, and environments, Africa vs Australia. RESULTS: We identified 23 common bacterial genera between the African, Australian, and Chinese prostate tumor samples, while nonbacterial microbes were notably absent. While the most abundant genera across all samples included: Escherichia, Propionibacterium, and Pseudomonas, the core prostate tumor microbiota was enriched for Proteobacteria. We observed a significant increase in the richness of the bacterial communities within the African vs Australian samples (t = 4.6-5.5; P = .0004-.001), largely driven by eight predominant genera. Considering core human gut microbiota, African prostate tissue samples appear enriched for Escherichia and Acidovorax, with an abundance of Eubacterium associated with host tumor hypermutation. CONCLUSIONS: Our study provides suggestive evidence for the presence of a core, bacteria-rich, prostate microbiome. While unable to exclude for fecal contamination, the observed increased bacterial content and richness within the African vs non-African samples, together with elevated tumor mutational burden, suggests the possibility that bacterially-driven oncogenic transformation within the prostate microenvironment may be contributing to aggressive disease presentation in Africa.

TMPRSS2-ERG fusions linked to prostate cancer racial health disparities: A focus on Africa.

BACKGROUND: The androgen-regulated gene TMPRSS2 to the ETS transcription factor gene ERG fusion is the most common genomic alteration acquired during prostate tumorigenesis and biased toward men of European ancestry. In contrast, African American men present with more advanced disease, yet their tumors are less likely to acquire TMPRSS2-ERG. Data for Africa is scarce. METHODS: RNA was made available for genomic analyses from 181 prostate tissue biopsy cores from Black South African men, 94 with and 87 without pathological evidence for prostate cancer. Reverse transcription polymerase chain reaction was used to screen for the TMPRSS2-ERG fusion, while transcript junction coordinates and isoform frequencies, including novel gene fusions, were determined using targeted RNA sequencing. RESULTS: Here we report a frequency of 13% for TMPRSS2-ERG in tumors from Black South Africans. Present in 12/94 positive versus 1/87 cancer negative prostate tissue cores, this suggests a 92.62% predictivity for a positive cancer diagnosis (P = 0.0031). At a frequency of almost half that reported for African Americans and roughly a quarter of that reported for men of European ancestry, acquisition of TMPRSS2-ERG appears to be inversely associated with aggressive prostate cancer. Further support was provided by linking the presence of TMPRSS2-ERG to low-grade disease in younger patients (P = 0.0466), with higher expressing distal ERG fusion junction coordinates. CONCLUSIONS: Only the second study of its kind for the African continent, we support a link between TMPRSS2-ERG status and prostate cancer racial health disparity beyond the borders of the United States. We call for urgent evaluation of androgen deprivation therapy within Africa.

Spectrum of mitochondrial genomic variation and associated clinical presentation of prostate cancer in South African men.

BACKGROUND: Prostate cancer incidence and mortality rates are significantly increased in African-American men, but limited studies have been performed within Sub-Saharan African populations. As mitochondria control energy metabolism and apoptosis we speculate that somatic mutations within mitochondrial genomes are candidate drivers of aggressive prostate carcinogenesis. METHODS: We used matched blood and prostate tissue samples from 87 South African men (77 with African ancestry) to perform deep sequencing of complete mitochondrial genomes. Clinical presentation was biased toward aggressive disease (Gleason score >7, 64%), and compared with men without prostate cancer either with or without benign prostatic hyperplasia. RESULTS: We identified 144 somatic mtDNA single nucleotide variants (SNVs), of which 80 were observed in 39 men presenting with aggressive disease. Both the number and frequency of somatic mtDNA SNVs were associated with higher pathological stage. CONCLUSIONS: Besides doubling the total number of somatic PCa-associated mitochondrial genome mutations identified to date, we associate mutational load with aggressive prostate cancer status in men of African ancestry.

Clinical presentation of prostate cancer in black South Africans.

BACKGROUND: Compared with White Americans, Black American men are at a significant increased risk of presenting with prostate cancer (PCa) and associated mortality, suggesting a link to African-ancestry. However, PCa status within Africa is largely unknown. We address the clinical presentation of PCa within Black South African men. METHODS: Over 1,000 participants with or without PCa have enrolled in the Southern African Prostate Cancer Study (SAPCS). Using genome-wide profiling we establish a unique within Africa population substructure. Adjusting for age, clinical variables were assessed, compared against Black Americans and between rural and urban localities while addressing potential socio-demographic confounders. RESULTS: We report a significant difference in the distribution of prostate specific antigen (PSA) levels skewed towards higher PSA levels in the PCa cases (83.0% present with a PSA ≥ 20 µg/L; median PSA = 98.8 µg/L) relative to men with no detectable PCa (18.5% present with a PSA ≥ 20 µg/L; median PSA = 9.1 µg/L). Compared with Black Americans, Black South Africans presented with significantly more aggressive disease defined by Gleason score >7 (17% and 36%, respectively) and PSA ≥ 20 µg/L (17.2% and 83.2%, respectively). We report exasperated disease aggression defined by Gleason score >7 (P = 0.0042) and poorly differentiated tumor grade (P < 0.0001) within rural versus urban localities. CONCLUSION: Black South African men present with higher PSA levels and histopathological tumor grade compared with Black Americans, which is further escalated in men from rural localities. Our data suggests that lack of PSA testing may be contributing to an aggressive PCa disease phenotype within South African men.

The impact of telomere length on prostate cancer aggressiveness, genomic instability and health disparities.

The telomere repetitive TTAGGG motif at the ends of chromosomes, serves to preserve genomic integrity and chromosomal stability. In turn, genomic instability is a hallmark of cancer-implicating telomere disturbance. Prostate cancer (PCa) shows significant ancestral disparities, with men of African ancestry at the greatest risk for aggressive disease and associated genomic instability. Yet, no study has explored the role of telomere length (TL) with respect to ancestrally driven PCa health disparities. Patient- and technically-matched tumour-blood whole genome sequencing data for 179 ancestrally defined treatment naïve PCa patients (117 African, 62 European), we assessed for TL (blood and tumour) associations. We found shortened tumour TL to be associated with aggressive PCa presentation and elevated genomic instabilities, including percentage of genome alteration and copy number gains, in men of African ancestry. For European patients, tumour TL showed significant associations with PCa driver genes PTEN, TP53, MSH2, SETBP1 and DDX11L1, while shorter blood TL (< 3200 base pairs) and tumour TL (< 2861 base pairs) were correlated with higher risk for biochemical recurrence. Concurring with previous studies linking TL to PCa diagnosis and/or prognosis, for the first time we correlated TL differences with patient ancestry with important implications for future treatments targeting telomere dysfunction.

Addressing the contribution of previously described genetic and epidemiological risk factors associated with increased prostate cancer risk and aggressive disease within men from South Africa.

BACKGROUND: Although African ancestry represents a significant risk factor for prostate cancer, few studies have investigated the significance of prostate cancer and relevance of previously defined genetic and epidemiological prostate cancer risk factors within Africa. We recently established the Southern African Prostate Cancer Study (SAPCS), a resource for epidemiological and genetic analysis of prostate cancer risk and outcomes in Black men from South Africa. Biased towards highly aggressive prostate cancer disease, this is the first reported data analysis. METHODS: The SAPCS is an ongoing population-based study of Black men with or without prostate cancer. Pilot analysis was performed for the first 837 participants, 522 cases and 315 controls. We investigate 46 pre-defined prostate cancer risk alleles and up to 24 epidemiological measures including demographic, lifestyle and environmental factors, for power to predict disease status and to drive on-going SAPCS recruitment, sampling procedures and research direction. RESULTS: Preliminary results suggest that no previously defined risk alleles significantly predict prostate cancer occurrence within the SAPCS. Furthermore, genetic risk profiles did not enhance the predictive power of prostate specific antigen (PSA) testing. Our study supports several lifestyle/environmental factors contributing to prostate cancer risk including a family history of cancer, diabetes, current sexual activity and erectile dysfunction, balding pattern, frequent aspirin usage and high PSA levels. CONCLUSIONS: Despite a clear increased prostate cancer risk associated with an African ancestry, experimental data is lacking within Africa. This pilot study is therefore a significant contribution to the field. While genetic risk factors (largely European-defined) show no evidence for disease prediction in the SAPCS, several epidemiological factors were associated with prostate cancer status. We call for improved study power by building on the SAPCS resource, further validation of associated factors in independent African-based resources, and genome-wide approaches to define African-specific risk alleles.

ANO7 African-ancestral genomic diversity and advanced prostate cancer.

BACKGROUND: Prostate cancer (PCa) is a significant health burden for African men, with mortality rates more than double global averages. The prostate specific Anoctamin 7 (ANO7) gene linked with poor patient outcomes has recently been identified as the target for an African-specific protein-truncating PCa-risk allele. METHODS: Here we determined the role of ANO7 in a study of 889 men from southern Africa, leveraging exomic genotyping array PCa case-control data (n = 780, 17 ANO7 alleles) and deep sequenced whole genome data for germline and tumour ANO7 interrogation (n = 109), while providing clinicopathologically matched European-derived sequence data comparative analyses (n = 57). Associated predicted deleterious variants (PDVs) were further assessed for impact using computational protein structure analysis. RESULTS: Notably rare in European patients, we found the common African PDV p.Ile740Leu (rs74804606) to be associated with PCa risk in our case-control analysis (Wilcoxon rank-sum test, false discovery rate/FDR = 0.03), while sequencing revealed co-occurrence with the recently reported African-specific deleterious risk variant p.Ser914* (rs60985508). Additional findings included a novel protein-truncating African-specific frameshift variant p.Asp789Leu, African-relevant PDVs associated with altered protein structure at Ca2+ binding sites, early-onset PCa associated with PDVs and germline structural variants in Africans (Linear regression models, -6.42 years, 95% CI = -10.68 to -2.16, P-value = 0.003) and ANO7 as an inter-chromosomal PCa-related gene fusion partner in African derived tumours. CONCLUSIONS: Here we provide not only validation for ANO7 as an African-relevant protein-altering PCa-risk locus, but additional evidence for a role of inherited and acquired ANO7 variance in the observed phenotypic heterogeneity and African-ancestral health disparity.

Alterations in the Epigenetic Machinery Associated with Prostate Cancer Health Disparities.

Prostate cancer is driven by acquired genetic alterations, including those impacting the epigenetic machinery. With African ancestry as a significant risk factor for aggressive disease, we hypothesize that dysregulation among the roughly 656 epigenetic genes may contribute to prostate cancer health disparities. Investigating prostate tumor genomic data from 109 men of southern African and 56 men of European Australian ancestry, we found that African-derived tumors present with a longer tail of epigenetic driver gene candidates (72 versus 10). Biased towards African-specific drivers (63 versus 9 shared), many are novel to prostate cancer (18/63), including several putative therapeutic targets (CHD7, DPF3, POLR1B, SETD1B, UBTF, and VPS72). Through clustering of all variant types and copy number alterations, we describe two epigenetic PCa taxonomies capable of differentiating patients by ancestry and predicted clinical outcomes. We identified the top genes in African- and European-derived tumors representing a multifunctional "generic machinery", the alteration of which may be instrumental in epigenetic dysregulation and prostate tumorigenesis. In conclusion, numerous somatic alterations in the epigenetic machinery drive prostate carcinogenesis, but African-derived tumors appear to achieve this state with greater diversity among such alterations. The greater novelty observed in African-derived tumors illustrates the significant clinical benefit to be derived from a much needed African-tailored approach to prostate cancer healthcare aimed at reducing prostate cancer health disparities.

Prostate cancer genetic risk and associated aggressive disease in men of African ancestry.

African ancestry is a significant risk factor for prostate cancer and advanced disease. Yet, genetic studies have largely been conducted outside the context of Sub-Saharan Africa, identifying 278 common risk variants contributing to a multiethnic polygenic risk score, with rare variants focused on a panel of roughly 20 pathogenic genes. Based on this knowledge, we are unable to determine polygenic risk or differentiate prostate cancer status interrogating whole genome data for 113 Black South African men. To further assess for potentially functional common and rare variant associations, here we interrogate 247,780 exomic variants for 798 Black South African men using a case versus control or aggressive versus non-aggressive study design. Notable genes of interest include HCP5, RFX6 and H3C1 for risk, and MKI67 and KLF5 for aggressive disease. Our study highlights the need for further inclusion across the African diaspora to establish African-relevant risk models aimed at reducing prostate cancer health disparities.

Linking African ancestral substructure to prostate cancer health disparities.

Prostate cancer (PCa) is a significant health burden in Sub-Saharan Africa, with mortality rates loosely linked to African ancestry. Yet studies aimed at identifying contributing risk factors are lacking within the continent and as such exclude for significant ancestral diversity. Here, we investigate a series of epidemiological demographic and lifestyle risk factors for 1387 men recruited as part of the multi-ethnic Southern African Prostate Cancer Study (SAPCS). We found poverty to be a decisive factor for disease grade and age at diagnosis, with other notably significant PCa associated risk factors including sexually transmitted diseases, erectile dysfunction, gynaecomastia, and vertex or complete pattern balding. Aligned with African American data, Black ethnicity showed significant risk for PCa diagnosis (OR = 1.44, 95% CI 1.05-2.00), and aggressive disease presentation (ISUP ≥ 4: OR = 2.25, 95% CI 1.49-3.40). New to this study, we demonstrate African ancestral population substructure associated PCa disparity, observing increased risk for advanced disease for the southern African Tsonga people (ISUP ≥ 4: OR = 3.43, 95% CI 1.62-7.27). Conversely, South African Coloured were less likely to be diagnosed with aggressive disease overall (ISUP ≥ 3: OR = 0.38, 95% 0.17-0.85). Understanding the basis for PCa health disparities calls for African inclusion, however, lack of available data has limited the power to begin discussions. Here, focusing on arguably the largest study of its kind for the African continent, we draw attention to the contribution of within African ancestral diversity as a contributing factor to PCa health disparities within the genetically diverse region of southern Africa.

Environmental pollutants and diseases of sexual development in humans and wildlife in South Africa: harbingers of impact on overall health?

This study deals with disorders of sexual development in humans, wildlife and animals in an urban nature reserve (RNR) and a currently DDT-sprayed malarial area. High levels of oestrogenic chemical residues in water, sediment and tissue; skewed sex ratios; reduced biodiversity; gonadal malformations in sharptooth catfish and freshwater snails; intersex in catfish; and impaired spermatogenesis in catfish and striped mouse are of serious concern in the RNR. Persistent eggshell thinning in African darter eggs, intersex in male Mozambican tilapia, follicular atresia in females and impaired spermatogenesis in males following laboratory exposure of parent fish to environmentally relevant DDT and DDE concentrations, and abnormalities in freshwater snails were found in the DDT-sprayed area. Human studies related to DDT exposure indicated impaired semen quality, a weak association with sperm chromatin defects and higher risks for external urogenital birth defects in those who were born to mothers whose houses were sprayed and those who were homemakers (stay at home mother) instead of being employed. These findings indicate that diseases of sexual development occurred in both human and wildlife populations exposed to environmental endocrine disruptor chemicals in South Africa. The chemical mixtures, possibly related to disorders of sexual differentiation (DSD), were very different between the two. However, DSD occurred concurrently in the malarial area, possibly indicating that humans and wildlife shared exposures. Moreover, it emphasizes the importance of suspecting disease in the other when disease is found in either human or wildlife populations.

EDCs and male urogenital cancers.

Male sex determination and sexual differentiation occur between 6-12 weeks of gestation. During the "male programming window" the fetal testes start to produce testosterone that initiates the development of the male reproductive tract. Exposure to endocrine disrupting chemicals (EDCs) able to mimic or disrupt steroid hormone actions may disrupt testicular development and adversely impact reproductive health at birth, during puberty and adulthood. The testicular dysgenesis syndrome (TDS) occurs as a result inhibition of androgen action on fetal development preceding Sertoli and Leydig cell dysfunction and may result from direct or epigenetic effects. Hypospadias, cryptorchidism and poor semen quality are elements of TDS, which may be considered a risk factor for testicular germ cell cancer (TGCC). Exposure to estrogen or estrogenic EDCs results in developmental estrogenization/estrogen imprinting in the rodent for prostate cancer (PCa). This can disrupt prostate histology by disorganization of the epithelium, prostatic intraepithelial neoplasia (PIN) lesions, in particular high-grade PIN (HGPIN) lesions which are precursors of prostatic adenocarcinoma. These defects persist throughout the lifespan of the animal and later in life estrogen exposure predispose development of cancer. Exposure of pregnant dams to vinclozolin, a competitive anti-androgen, and results in prominent, focal regions of inflammation in all exposed animals. The inflammation closely resembles human nonbacterial prostatitis that occurs in young men and evidence indicates that inflammation plays a central role in the development of PCa. In conclusion, in utero exposure to endocrine disrupters may predispose to the development of TDS, testicular cancer (TCa) and PCa and are illustrations of Developmental Origins of Health and Disease (DOHaD).

DNA methylation profiles unique to Kalahari KhoeSan individuals.

Genomes of KhoeSan individuals of the Kalahari Desert provide the greatest understanding of single nucleotide diversity in the human genome. Compared with individuals in industrialized environments, the KhoeSan have a unique foraging and hunting lifestyle. Given these dramatic environmental differences, and the responsiveness of the methylome to environmental exposures of many types, we hypothesized that DNA methylation patterns would differ between KhoeSan and neighbouring agropastoral and/or industrial Bantu. We analysed Illumina HumanMethylation 450 k array data generated from blood samples from 38 KhoeSan and 42 Bantu, and 6 Europeans. After removing CpG positions associated with annotated and novel polymorphisms and controlling for white blood cell composition, sex, age and technical variation we identified 816 differentially methylated CpG loci, out of which 133 had an absolute beta-value difference of at least 0.05. Notably SLC39A4/ZIP4, which plays a role in zinc transport, was one of the most differentially methylated loci. Although the chronological ages of the KhoeSan are not formally recorded, we compared historically estimated ages to methylation-based calculations. This study demonstrates that the epigenetic profile of KhoeSan individuals reveals differences from other populations, and along with extensive genetic diversity, this community brings increased accessibility and understanding to the diversity of the human genome.

Testicular microlithiasis and neoplastic lesions in wild eland (Tragelaphus oryx): possible effects of exposure to environmental pollutants?

The purpose of the study was to compare wildlife in the proximity and away from the sources of known industrial pollution. Macroscopic, focal, gritty areas that appeared white were observed in the testes of all 24 South African eland (Tragelaphus oryx) culled in the Rietvlei Nature Reserve (RNR; n=17) between 2001 and 2003 and Suikerbosrand Nature Reserve (SNR; n=7) in 2004. Histopathological evaluation of testes showed multiple intratubular dystrophic calcifications, focal areas of sperm stasis and interstitial chronic cell infiltrates with fibrosis. Spermatogenesis was generally impaired; a few atypical germ cells were also encountered. Sertoli cell vacuolization and sloughing of the seminiferous epithelium were evident. Adenomatous changes of the rete testis, reflective of possible chronic estrogenic exposure, were found. In testes collected from three reference eland in 2007 from the Molopo Nature Reserve (MNR) in the Kalahari/Kgalagadi Desert, except for one focal area of sperm stasis and another with microcalcification, the seminiferous epithelium as well as collecting/rete tubules were normal. Analyses of fat tissue for environmental pollutants showed that 11 out of 17 RNR eland contained a detectable estrogenic chemical p-nonylphenol (mean+/-SD: 184.8+/-24.6 microg/kg fat); no organochlorine chemicals or polychlorinated biphenyls were detected. Of the 7 SNR eland, 5 had detectable octylphenol residues (50.2+/-30.9 microg/kg fat), 3 had detectable p-nonylphenol (137.8+/-77.9 microg/kg fat), 3 had o-p'-DDT (114.9+/-31.1 microg/kg fat), 3 had p-p'-DDT (127.3+/-49.9 microg/kg(79.5+/-30.4 microg/kg fat) and 5 contained o-p'-DDE (27.7+/-9.9 microg/kg fat). One eland from the MNR contained one 70.6 microg o-p'-DDT/kg fat and another p-p'-DDE 61.3 microg/kg fat. Therefore, in eland with testicular abnormalities, significant amounts of various estrogenic chemicals were bioaccumulated in fat samples. It therefore seems likely that the lesions found in RNR and SNR were associated with the relatively high body-burden of environmental pollutants (phenols), although the possibility of systemic infections cannot be ruled out. No testicular abnormalities were found in reference eland. These findings are the first indication of mammalian wildlife being affected by environmental pollution of endocrine disrupting chemicals in South Africa.

Intersex in feral indigenous freshwater Oreochromis mossambicus, from various parts in the Luvuvhu River, Limpopo Province, South Africa.

This study reports on intersex in Oreochromis mossambicus, an indigenous fish species inhabiting most aquatic systems throughout South Africa (SA). Male fish were collected from three sites in the Luvuvhu River, Limpopo Province, SA: Albasini Dam (AD), Nandoni Dam (ND), and Xikundu Weir (XW). The latter two sites are situated in a currently dichloro-diphenyl-trichloroethane (DDT) sprayed area. A laboratory-bred reference group (Aq R) were included for a histological comparison. 48% of the fish at AD were intersex individuals compared with 63% at ND, and 58% at XW. The Aq R fish had no cases of intersex. o,p'- and p,p'-DDT and metabolites dichlorodiphenyldichloroethane (DDD) and -dichlorodiphenyldichloroethylene (DDE) were detected in fat samples, indicative of contamination of the aquatic environment and subsequent exposure of fish to these chemicals. Although some of the fat samples contained levels of DDTs no association could be established between intersex and chemical contaminants in fish.

Sperm chromatin integrity in DDT-exposed young men living in a malaria area in the Limpopo Province, South Africa.

BACKGROUND: There is mounting evidence that deteriorated semen quality may be associated with increased serum concentration of 1,1,1-trichloro-2,2-bis(chlorodiphenyl)ethane (DDT) and its metabolites. The problem is exacerbated in situations where DDT is the only resource available to control malaria mosquitoes and DDT metabolite plasma concentration can reach 1000-fold the level found in other populations. There are limited and contradictory epidemiological data on whether DDT/dichlorodiphenyl-dichloroethylene (DDE) can also damage sperm DNA. Therefore, there is a need to investigate the possible adverse effects on human sperm genetic integrity in a sufficiently large study population with adequate exposure contrasts, especially in the high exposure range. METHODS: We conducted a cross-sectional study, recruiting 209 young males from three communities in an endemic malaria area where DDT is sprayed annually. Blood plasma p,p'-DDT and its metabolite p,p'-DDE levels were measured and expressed as lipid adjusted p,p'-DDT and p,p'-DDE values. The sperm chromatin structure assay and Aniline Blue test were used to assess sperm DNA/chromatin integrity. RESULTS: The lipid adjusted p,p'-DDT mean (+/-SD) and median concentrations were 109.2 (+/-106.6) and 83.9 microg/g, respectively; and the lipid adjusted p,p'-DDE mean (+/-SD) and median concentrations were 246.2 (+/-218.5) and 177.8 microg/g, respectively. The results point to a weak association between DDT/DDE plasma concentration and the incidence of sperm with chromatin defects. CONCLUSIONS: The results suggest that non-occupational environmental DDT exposure may have a negative impact on sperm chromatin integrity in young South African males.