Project description:Perfluoroalkyl substances (PFAS) are a class of synthetic chemicals that are persistent in the environment. Due to concerns linked with longer chain PFAS, shorter chain chemicals were used as replacements, but developmental toxicity assessments of the shorter chain chemicals are limited. The aim of this study was to compare the developmental toxicity of three perfluoroalkyl acids (PFAAs): perfluorooctanoic acid (PFOA), composed of 8 carbon (C8), perfluorohexanoic acid (PFHxA, C6), and perfluorobutanoic acid (PFBA, C4) using the zebrafish (Danio rerio). LC50s at 120 hour post fertilization (hpf) were determined to assess the potency of each PFAA by exposing developing zebrafish (1-120 hpf) to a range of concentrations. In sublethal assessments, zebrafish were exposed to 0, 4, 40, or 400 parts per billion (ppb; µg/L) of the PFAAs throughout embryonic development (1-72 hpf). Effects of the embryonic exposure on locomotor activities was completed with the visual motor response test at 120 hpf. At 72 hpf, morphological changes including total body length, head length, and head width were assessed. Additionally, transcriptomic profiles of PFOA, PFHxA, and PFBA were determined at 72 hpf to compare altered molecular and disease pathways. The LC50 ranking was PFOA > PFHxA > PFBA, which followed trend as expected based on chain length. PFOA caused hyperactivity and PFBA hypoactivity, while PFHxA did not change behavior. PFOA, PFHxA, and PFBA caused morphological and transcriptomic alterations that were unique for each chemical and were concentration dependent. Cancer was a top enriched disease for PFOA, while FXR/RXR activation was a top canonical pathway in all PFBA exposures. Overall, an embryonic exposure to PFOA, PFHxA, or PFBA resulted in morphological alterations in zebrafish eleuthero-embryos; however, only PFOA and PFBA induced neurobehavioral alterations. The transcriptomic profile of each chemical was unique indicating different toxicity mechanisms and were aligned with human adverse health outcomes supporting predictive value.

Project description:A systems toxicology investigation comparing and integrating transcriptomic and proteomic results was conducted to pursue a holistic understanding of the effects of the explosives degradation product 2-amino-4,6-dinitrotoluene (2A-DNT) dosing on the health of the wildlife bird model, Northern bobwhite (Colinus virginianus). A subchronic 60d toxicology bioassay was leveraged where both sexes were dosed via daily gavage with 0, 3, 14, or 30 mg/kg-d 2-ADNT. Effects on global transcript expression were investigated in liver and kidney tissue using custom microarrays for C. virginianus in both sexes at all doses, while effects on the proteome expression were investigated in liver for both sexes and kidney in males, all at the 30 mg/kg-d dose. As expected, transcript expression was not directly indicative of protein expression in response to 2A-DNT. However, a high degree of correspondence was observed among platforms when investigating higher-order functional responses including statistically enriched gene networks and canonical pathways, especially when connected to toxicological outcomes of 2A-DNT exposure. Specifically, comparison of gene networks statistically enriched from differentially expressed transcripts and for proteins showed common responses including inhibition of programmed cell death and arrest of cell cycle in liver tissues at 2A-DNT doses that caused liver necrosis and death in females. Additionally, both transcript and protein expression in liver tissue was indicative of induced phase I and II xenobiotic metabolism potentially as a mechanism to detoxify and excrete 2A-DNT. Nuclear signaling, transcript expression and protein expression assays each implicated PPAR nuclear signaling as a primary molecular target in the 2A-DNT exposure with significant downstream enrichment of PPAR-regulated pathways including various lipid metabolic pathways and gluconeogenesis suggesting impaired bioenergetic potential. Although the relative expression of transcripts and proteins within enriched pathways was at times divergent, transcript expression assays identified many critical metabolic pathways involved in 2A-DNT toxicity as well as impaired PPAR signaling, a key molecular initiating event known to be affected in di- and tri-nitrotoluene exposures. The animal exposure design is presented in a study by Quinn et al (2010). Five treatment groups consisting of 12 male and 12 female bobwhites each were administered 2A-DNT at 0, 0.5, 3, 14, or 30 mg/kg/day via oral gavage for 60 days. Controls received a volume of corn oil equivalent to the mean volume given to birds in the highest dose group without compound. Microarray hybridizations were conducted using completely randomized design experiments including a 2 x 4 factorial treatment arrangement to investigate the conditions: sex (male and female) and 2A-DNT dose (control, 3, 14, and 30 mg/kg-d) for both liver and kidney tissues. All conditions included 4 biological replicates. REFERENCE: Quinn Jr. MJ, McFarland CA, LaFiandra EM, Bazar MA, Johnson MS (2010) Acute, subacute, and subchronic exposure to 2A-DNT (2-amino-4,6-dinitrotoluene) in the northern bobwhite (Colinus virginianus) Ecotoxicology 19:945-952.

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Effects of Gestational and Lactational Exposure to Perfluorohexanoic Acid on the cerebellar transcriptome

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