Environmental Health

Exposure to select PFAS and PFAS mixtures alters response to platinum-based chemotherapy in endometrial cancer cell lines

Abstract Background Exposure to per- and poly-fluoroalkyl substances (PFAS) has been associated with significant alterations in female reproductive health. These include changes in menstrual cyclicity, timing of menarche and menopause, and fertility outcomes, as well as increased risk of endometriosis, all of which may contribute to an increased risk of endometrial cancer. The effect of PFAS on endometrial cancer cells, specifically altered treatment response and biology, however, remains poorly studied. Like other gynecologic malignancies, a key contributor to lethality in endometrial cancer is resistance to chemotherapeutics, specifically to platinum-based agents that are used as the standard of care for patients with advanced-stage and/or recurrent disease. Objectives To explore the effect of environmental exposures, specifically PFAS, on platinum-based chemotherapy response and mitochondrial function in endometrial cancer. Methods HEC-1 and Ishikawa endometrial cancer cells were exposed to sub-cytotoxic nanomolar and micromolar concentrations of PFAS/PFAS mixtures and were treated with platinum-based chemotherapy. Survival fraction was measured 48-h post-chemotherapy treatment. Mitochondrial membrane potential was evaluated in both cell lines following exposure to PFAS ± chemotherapy treatment. Results HEC-1 and Ishikawa cells displayed differing outcomes after PFAS exposure and chemotherapy treatment. Cells exposed to PFAS appeared to be less sensitive to carboplatin, with instances of increased survival fraction, indicative of platinum resistance, observed in HEC-1 cells. In Ishikawa cells treated with cisplatin, PFAS mixture exposure significantly decreased survival fraction. In both cell lines, increases in mitochondrial membrane potential were observed post-PFAS exposure ± chemotherapy treatment. Discussion Exposure of endometrial cancer cell lines to PFAS/PFAS mixtures had varying effects on response to platinum-based chemotherapies. Increased survival fraction post-PFAS + carboplatin treatment suggests platinum resistance, while decreased survival fraction post-PFAS mixture + cisplatin exposure suggests enhanced therapeutic efficacy. Regardless of chemotherapy sensitivity status, mitochondrial membrane potential findings suggest that PFAS exposure may affect endometrial cancer cell mitochondrial functioning and should be explored further.

Occupational exposure to pesticides and endometrial cancer in the Screenwide case-control study

Abstract Background Endometrial cancer is the most common gynaecological tumour in developed countries and disease burden is expected to increase over the years. Identifying modifiable risk factors may help developing strategies to reduce the expected increasing incidence of these neoplasms. Objective This study evaluates the association between occupational exposure to pesticides and endometrial cancer using data from a recent case-control study in Spain. Methods The analyses included data from 174 consecutive incident endometrial cancer cases and 216 hospital controls frequency-matched by age. Data were collected through structured epidemiological questionnaires and exposure to pesticides was assessed using a Spanish job-exposure matrix (MatEmESp). Results Overall, 12% of controls and 18% of cases were occupationally exposed to pesticides. We observed a positive association between occupational exposure to pesticides and endometrial cancer (OR = 2.08; 95% CI = 1.13–3.88 compared to non-exposed). In general, exposures that occurred farther in the past were significantly associated with endometrial cancer. Exposure to insecticides, fungicides and herbicides were positively associated with endometrial cancer (OR = 2.08; 95% CI = 1.13–3.88, OR = 4.40; 95% CI = 1.65–13.33, and OR = 5.25; 95% CI = 1.84–17.67, respectively). The agricultural, poultry and livestock activities scenario was associated with endometrial cancer (OR = 4.16; 95% CI = 1.59–12.32), while the cleaning exposure scenario was not (OR = 1.22; 95% CI = 0.55–2.67). Conclusions Assessment of occupational exposure to pesticides assessed using a Spanish job-exposure matrix revealed a positive association with endometrial cancer. The elucidation of the role of pesticide compounds on endometrial cancer should shed a light on the aetiology of this tumour.

Higher plasma AFB1 concentration is associated with increased risk of HPV 16 and HPV 18 detection and persistence among Ugandan women

Abstract Introduction Aflatoxins are environmental hazards; potent carcinogenic and immunosuppressive agents that contaminates corn and other crops. A high proportion of hepatocellular carcinoma cases are caused by exposure to dietary aflatoxins. Cervical cancer is common among Ugandan women; this malignancy is caused by persistent infection with oncogenic HPV types. An analysis was performed to examine associations between plasma aflatoxin B1 (AFB1) detection and oncogenic HPV detection (HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68) and persistence among Ugandan women. Methods Ugandan women were enrolled in a prospective cohort study. Annual cervical swabs (Enrollment, Month 12 and Month 24) were tested for oncogenic HPV. Plasma AFB1 concentration was measured (as AFB1-lysine conjugate, or AFB1-lys) at Enrollment and Month 12. Multivariable regression models were fitted to examine associations of plasma AFB1-lys concentrations and oncogenic HPV controlling for demographic and behavioral characteristics. Results The analytical sample consisted of 114 women with a mean age of 33.2 years; 60 women were living with HIV; 59 were receiving antiretroviral therapy (ART) at enrollment. AFB1-lysine adducts (AFB1-lys) was detected in plasma from all 114 women. Multivariable regression models showed that plasma AFB1-lys concentration was associated with a higher risk of detection of HPV 16 (OR = 2.64, 95% CI = 1.42–4.90, p = 0.002) and HPV 18 (OR = 2.24, 95% CI = 1.27–3.96, p = 0.005), and persistence of HPV 16 (OR = 3.16, 95% CI = 1.59–6.26, p = 0.001) and HPV 18 (OR = 2.06, 95% CI = 1.09–3.90, p = 0.025), controlling for age, marital status, years of education, home ownership, distance to health care, number of lifetime sex partners, age of first sex, and HIV status. Conclusions AFB1 is an environmental hazard that is prevalent among Ugandan women. Higher plasma AFB1-lys concentration was associated with detection and persistence of HPV 16 and HPV 18; this association was independent of HIV status. As a result, these women may be at increased risk of cervical cancer. Further studies are needed to determine the mechanisms involved.