PFAS and PBDEs in traditional subsistence foods from Sivuqaq, Alaska.

The Arctic is a hemispheric sink for both legacy and current use persistent organic pollutants (POPs). Once in the Arctic, POPs biomagnify in food webs, potentially reaching concentrations in high trophic level animals that pose a health concern for people who subsist on those animals. Indigenous Peoples of the Arctic may be highly exposed to POPs through their traditional diets. The objective of this study was to assess concentrations of polybrominated diphenyl ethers (PBDEs) and per- and polyfluoroalkyl substances (PFAS) in tissues of traditionally harvested foods from Sivuqaq (St. Lawrence Island), Alaska. Community health researchers identified volunteer households and local hunters to donate tissues from traditionally harvested animals. Target species included bowhead whale (Balaena mysticetus), Pacific walrus (Odobenus rosmarus), ringed seal (Pusa hispida), bearded seal (Erignathus barbatus), ribbon seal (Histriophoca fasciata), spotted seal (Phoca largha), and reindeer (Rangifer tarandus). PBDEs were frequently detected in all species and tissues. PBDE concentrations tended to be highest in lipid-rich tissues of seals. PFAS were infrequently detected and did not show obvious patterns among species or tissues. This and other studies demonstrate that POPs such as PBDEs are present in tissues of traditional food animals from Sivuqaq, as they are throughout the Arctic, and consumption of these animals likely contributes to exposure among Arctic Indigenous Peoples.

Health Impacts of Perchlorate and Pesticide Exposure: Protocol for Community-Engaged Research to Evaluate Environmental Toxicants in a US Border Community.

BACKGROUND: The Northern Arizona University (NAU) Center for Health Equity Research (CHER) is conducting community-engaged health research involving "environmental scans" in Yuma County in collaboration with community health stakeholders, including the Yuma Regional Medical Center (YRMC), Regional Center for Border Health, Inc. (RCBH), Campesinos Sin Fronteras (CSF), Yuma County Public Health District, and government agencies and nongovernmental organizations (NGOs) working on border health issues. The purpose of these efforts is to address community-generated environmental health hazards identified through ongoing coalitions among NAU, and local health care and research institutions. OBJECTIVE: We are undertaking joint community/university efforts to examine human exposures to perchlorate and agricultural pesticides. This project also includes the parallel development of a new animal model for investigating the mechanisms of toxicity following a "one health" approach. The ultimate goal of this community-engaged effort is to develop interventions to reduce exposures and health impacts of contaminants in Yuma populations. METHODS: All participants completed the informed consent process, which included information on the purpose of the study, a request for access to health histories and medical records, and interviews. The interview included questions related to (1) demographics, (2) social determinants of health, (3) health screening, (4) occupational and environmental exposures to perchlorate and pesticides, and (5) access to health services. Each participant provided a hair sample for quantifying the metals used in pesticides, urine sample for perchlorate quantification, and blood sample for endocrine assays. Modeling will examine the relationships between the concentrations of contaminants and hormones, demographics and social determinants of health, and health status of the study population, including health markers known to be impacted by perchlorate and pesticides. RESULTS: We recruited 323 adults residing in Yuma County during a 1-year pilot/feasibility study. Among these, 147 residents were patients from either YRMC or RCBH with a primary diagnosis of thyroid disease, including hyperthyroidism, hypothyroidism, thyroid cancer, or goiter. The remaining 176 participants were from the general population but with no history of thyroid disorder. The pilot study confirmed the feasibility of using the identified community-engaged protocol to recruit, consent, and collect data from a difficult-to-access, vulnerable population. The demographics of the pilot study population and positive feedback on the success of the community-engaged approach indicate that the project can be scaled up to a broader study with replicable population health findings. CONCLUSIONS: Using a community-engaged approach, the research protocol provided substantial evidence regarding the effectiveness of designing and implementing culturally relevant recruitment and dissemination processes that combine laboratory findings and public health information. Future findings will elucidate the mechanisms of toxicity and the population health effects of the contaminants of concern, as well as provide a new animal model to develop precision medicine capabilities for the population. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/15864.

A fish with no sex: gonadal and adrenal functions partition between zebrafish NR5A1 co-orthologs.

People with NR5A1 mutations experience testicular dysgenesis, ovotestes, or adrenal insufficiency, but we do not completely understand the origin of this phenotypic diversity. NR5A1 is expressed in gonadal soma precursor cells before expression of the sex-determining gene SRY. Many fish have two co-orthologs of NR5A1 that likely partitioned ancestral gene subfunctions between them. To explore ancestral roles of NR5A1, we knocked out nr5a1a and nr5a1b in zebrafish. Single-cell RNA-seq identified nr5a1a-expressing cells that co-expressed genes for steroid biosynthesis and the chemokine receptor Cxcl12a in 1-day postfertilization (dpf) embryos, as does the mammalian adrenal-gonadal (interrenal-gonadal) primordium. In 2dpf embryos, nr5a1a was expressed stronger in the interrenal-gonadal primordium than in the early hypothalamus but nr5a1b showed the reverse. Adult Leydig cells expressed both ohnologs and granulosa cells expressed nr5a1a stronger than nr5a1b. Mutants for nr5a1a lacked the interrenal, formed incompletely differentiated testes, had no Leydig cells, and grew far larger than normal fish. Mutants for nr5a1b formed a disorganized interrenal and their gonads completely disappeared. All homozygous mutant genotypes lacked secondary sex characteristics, including male breeding tubercles and female sex papillae, and had exceedingly low levels of estradiol, 11-ketotestosterone, and cortisol. RNA-seq showed that at 21dpf, some animals were developing as females and others were not, independent of nr5a1 genotype. By 35dpf, all mutant genotypes greatly under-expressed ovary-biased genes. Because adult nr5a1a mutants form gonads but lack an interrenal and conversely, adult nr5a1b mutants lack a gonad but have an interrenal, the adrenal, and gonadal functions of the ancestral nr5a1 gene partitioned between ohnologs after the teleost genome duplication, likely owing to reciprocal loss of ancestral tissue-specific regulatory elements. Identifying such elements could provide hints to otherwise unexplained cases of Differences in Sex Development.

Gonadal soma controls ovarian follicle proliferation through Gsdf in zebrafish.

BACKGROUND: Aberrant signaling between germ cells and somatic cells can lead to reproductive disease and depends on diffusible signals, including transforming growth factor-beta (TGFB) -family proteins. The TGFB-family protein Gsdf (gonadal soma derived factor) controls sex determination in some fish and is a candidate for mediating germ cell/soma signaling. RESULTS: Zebrafish expressed gsdf in somatic cells of bipotential gonads and expression continued in ovarian granulosa cells and testicular Sertoli cells. Homozygous gsdf knockout mutants delayed leaving the bipotential gonad state, but then became a male or a female. Mutant females ovulated a few oocytes, then became sterile, accumulating immature follicles. Female mutants stored excess lipid and down-regulated aromatase, gata4, insulin receptor, estrogen receptor, and genes for lipid metabolism, vitellogenin, and steroid biosynthesis. Mutant females contained less estrogen and more androgen than wild-types. Mutant males were fertile. Genomic analysis suggests that Gsdf, Bmp15, and Gdf9, originated as paralogs in vertebrate genome duplication events. CONCLUSIONS: In zebrafish, gsdf regulates ovarian follicle maturation and expression of genes for steroid biosynthesis, obesity, diabetes, and female fertility, leading to ovarian and extra-ovarian phenotypes that mimic human polycystic ovarian syndrome (PCOS), suggesting a role for a related TGFB signaling molecule in the etiology of PCOS. Developmental Dynamics 246:925-945, 2017. © 2017 Wiley Periodicals, Inc.