HPTE-Induced Embryonic Thymocyte Death and Alteration of Differentiation Is Not Rescued by ERα or GPER Inhibition but Is Exacerbated by Concurrent TCR Signaling.

Organochlorine pesticides, such as DDT, methoxychlor, and their metabolites, have been characterized as endocrine disrupting chemicals (EDCs); suggesting that their modes of action involve interaction with or abrogation of endogenous endocrine function. This study examined whether embryonic thymocyte death and alteration of differentiation induced by the primary metabolite of methoxychlor, HPTE, rely upon estrogen receptor binding and concurrent T cell receptor signaling. Estrogen receptor inhibition of ERα or GPER did not rescue embryonic thymocyte death induced by HPTE or the model estrogen diethylstilbestrol (DES). Moreover, adverse effects induced by HPTE or DES were worsened by concurrent TCR and CD2 differentiation signaling, compared with EDC exposure post-signaling. Together, these data suggest that HPTE- and DES-induced adverse effects on embryonic thymocytes do not rely solely on ER alpha or GPER but may require both. These results also provide evidence of a potential collaborative signaling mechanism between TCR and estrogen receptors to mediate adverse effects on embryonic thymocytes, as well as highlight a window of sensitivity that modulates EDC exposure severity.

Loperamide cases reported to United States poison centers, 2010-2022.

BACKGROUND: Intentional use of high doses of loperamide has been linked to serious cardiac toxicity. The objective of this study is to investigate the characteristics and trends of loperamide cases reported to United States (US) poison centers and to evaluate the changes in reported loperamide cases following US Food and Drug Administration (FDA) warnings, labeling requirements, and packaging restrictions for loperamide starting in 2016, with an emphasis on intentional exposures. METHODS: Data from the National Poison Data System were analyzed. RESULTS: There were 12,987 cases reported to US poison centers from 2010 to 2022, for which, loperamide was the most likely substance responsible for observed clinical effects. Although 46.1% of these cases were associated with minor or no effect, 13.4% resulted in a serious medical outcome, including 59 deaths (0.5%). Eight percent (8.1%) of cases were admitted to a critical care unit and 5.0% were admitted to a non-critical care unit. Among cases with a serious medical outcome, most were associated with loperamide abuse (38.0%), intentional-misuse (15.7%), or suspected suicide (27.5%). The majority (60.0%; n = 33) of fatalities were related to abuse, followed by suspected suicide (20.0%; n = 11) and intentional-misuse (5.5%, n = 3). The rate of loperamide cases per 100,000 US population reported to US PCs decreased from 0.44 in 2010 to 0.36 in 2015 (p = 0.0290), followed by an increase to 0.46 in 2017 (p = 0.0013), and then a trend reversal with a decrease to 0.28 in 2022 (p < 0.0001). The rate of serious medical outcomes related to loperamide increased from 0.03 in 2010 to 0.05 in 2015 (p = 0.0109), which subsequently increased rapidly to 0.11 in 2017 (p < 0.0001), and then demonstrated a trend reversal and decreased to 0.04 in 2022 (p < 0.0001). CONCLUSIONS: FDA warnings, labeling requirements, and packaging restrictions may have contributed to the observed trend reversal and decrease in reports to US poison centers of loperamide cases related to intentional misuse, abuse, and suspected suicide. This demonstrates the potential positive effect that regulatory actions may have on public health. These findings contribute to the evidence supporting the application of similar prevention efforts to reduce poisoning from other medications associated with intentional misuse, abuse, and suicide.