Theses and Dissertations

Date of Award

8-1-2026

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Human Genetics

First Advisor

John VandeBerg

Second Advisor

Satish Kumar

Third Advisor

John Blangero

Abstract

Benzo[a]pyrene (B[a]P) is a widespread combustion-derived environmental contaminant with established mutagenic and developmental toxicity, yet mechanistic studies of mammalian organ development are constrained by the inaccessibility of prenatal stages. The gray short-tailed opossum, Monodelphis domestica, is born after approximately 14 days of gestation and completes substantial organ maturation postnatally, providing direct experimental access to developmental processes that occur in utero in placental mammals. This dissertation evaluated M. domestica as an extrauterine model for determining how postnatal B[a]P exposure is associated with the development of the brain, eyes, and liver. Litters were assigned to untreated, olive-oil vehicle control, or to groups receiving 2, 8, or 32 mg/kg B[a]P. Pups received daily subcutaneous injections from postnatal days 15 through 21 and were evaluated at 29 or 36 days. Gross anatomy, body-weight adjusted organ mass, mass spectrometry based proteomics and phosphoproteomics, differential abundance testing, gene set enrichment, and protein-interaction analyses were integrated to define organ-, dose-, and age-associated responses.

In the brain, treatment was associated with adjusted brain weight at both ages; the clearest pairwise difference was an approximately 12.5% decrease in adjusted brain weight in 36-day males exposed to 32 mg/kg B[a]P relative to male controls. Molecular responses were broader than the gross phenotype and involved mitochondrial translation and energy metabolism, oxidative stress pathways, vesicular transport, neuronal signaling, and phosphorylation-related regulation. In the eyes, developmental age was the dominant source of molecular variation. The 29-day to 36-day interval was characterized by increased metabolic and neural specialization programs and decreased proliferative programs, while matched comparisons of the 32 mg/kg and control groups showed limited whole-eye proteomic differences. In the liver, the 32 mg/kg group had the highest body-weight-adjusted liver weight at 29 days, and representative sections showed prominent lipid-associated vacuolation. Livers exhibited distinct, nonmonotonic molecular responses involving fatty-acid and cholesterol metabolism, interferon-associated pathways, cell-cycle programs, mitochondrial organization, ribosome biogenesis, and phosphorylation-related regulation.

Because substantial organ development in M. domestica occurs after birth during stages that occur prenatally in humans, this species provides direct experimental access to immature mammalian tissues without requiring the exposure to pass first through maternal metabolism and placental transport. These findings support M. domestica as a comparative platform for testing how environmental exposures, developmental stage, and genetic background interact to alter conserved human processes, while recognizing that direct pup dosing does not reproduce the maternal-placental toxicokinetics of human pregnancy.

The results indicate that molecular remodeling and B[a]P-associated responses depend on organ, dose, and developmental stage rather than following a single linear dose-response pattern. Because treatment was assigned by litter and the omics analyses were exploratory, the results identify candidate pathways rather than a definitive toxicity hierarchy. Overall, this work is a proof of concept that M. domestica can serve as a unique extrauterine mammalian model for mechanistic, functional, and longitudinal studies of developmental perturbations in response to exposure to environmental toxicants.

Comments

Copyright 2026 Ricardo Pedro Perez. All Rights Reserved. https://proquest.com/docview/3409129316

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