PhD Student University of Nebraska Medical Center Omaha, Nebraska, United States
Abstract Authors: Rasha Ghorab1 , Jitu W. George2 , Kendra L. Clark1,3,4 1Department of Obstetrics and Gynecology, Olson Center for Women’s Health, University of Nebraska Medical Center, Omaha, NE 2University of Minnesota Genomics Center, University of Minnesota, Minneapolis, MN 3Department of Environmental, Agricultural, and Occupational Health, University of Nebraska Medical Center, Omaha, NE 4Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE
Abstract Text: Per- and polyfluoroalkyl substances (PFAS) are a class of man-made chemicals known for their resistance to biodegradation and environmental persistence. These compounds are commonly found in consumer products such as non-stick cookware, food packaging, upholstery, and personal care items. As a result, PFAS contribute significantly to water and soil contamination. Exposure to PFAS has been linked to delayed menarche, irregular menstrual cycles, early menopause due to primary ovarian insufficiency, and disruptions in steroid hormone levels in both human and animal models. Despite the phase-out of many PFAS nearly a decade ago, they are still detectable in humans and animals. While most PFAS exist in the environment as mixtures, research has primarily focused on individual, long-chain “legacy” PFAS, such as perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS), and their effects on ovarian function. However, studies examining the impact of short-chain “alternative” PFAS, including undecafluoro2-methyl-3-oxahexanoic acid (GenX/HFPO-DA) and perfluorobutanesulfonic acid (PFBS), or PFAS mixtures on the mammalian ovary remain limited. We have previously established that adolescent exposure to a PFAS mixture impacts ovarian function in adulthood by depleting the ovarian reserve, endocrine disruption, and increased ovarian fibrosis, though the timeline for the induction of these changes was still unclear. Thus, we hypothesized that exposure to a PFAS mixture initiates changes in ovarian function during exposure rather than manifesting solely in adulthood. Postnatal day (PND) 30 female CD-1 mice were orally exposed (pipette administration in the cheek pouch) to vehicle control (distilled water with 1% DMSO; n = 10) or PFAS mixture (0.1 mg/kg of PFOA/PFOS/GenX/PFBS each; n = 10) for 15 days (PND45). Dosage was selected based on previously reported lowest observed adverse effect level (LOAEL) on developmental endpoints in neonatal and juvenile mice. Body weight was recorded weekly and vaginal cytology was monitored 10 days prior to euthanasia at PND45. Analyses of reproductive hormones were measured via ELISA. Exposure of adolescent mice to a PFAS mixture did not impact body weight or reproductive organ weights, although liver weight was increased (P < 0.05). Mice treated with the PFAS mixture displayed a disturbance in the estrous cycle, spending more time (P < 0.05) in estrus and less time (P < 0.05) in metestrus/diestrus than control treated mice. Additionally, PFAS treated mice cycled more frequently (P < 0.05) than the control treated mice. Hormone analysis revealed no changes in serum progesterone, estradiol, testosterone, or luteinizing hormone. The impact of environmental toxicant exposure on female reproductive function is largely influenced by the developmental stage at which exposure occurs, along with its intensity and duration. Understanding the timeline of PFAS-induced reproductive toxicity is critical for assessing longterm fertility risks. The observed estrous cycle disruptions and increased cycling frequency indicate early reproductive alterations, highlighting the need for further investigation into the mechanisms driving these changes.
