Novel Disinfection Byproducts Formed from the Pharmaceutical Gemfibrozil Are Bioaccumulative and Elicit Increased Toxicity Relative to the Parent Compound in Marine Polychaetes (Neanthes arenaceodentata)

Abstract

Formation of halogenated disinfection byproducts (DBPs) from pharmaceutically active compounds has been observed in water supply systems following wastewater chlorination. Although research has been limited thus far, several studies have shown that halogenated DBPs may elicit increased toxicity compared to their parent compounds. For example, the lipid regulator gemfibrozil has been shown to form chlorogemfibrozil (Cl-gemfibrozil) and bromogemfibrozil (Br-gemfibrozil) following chlorination, which are more potent antiandrogens in male Japanese medaka (Oryzias latipes) compared to their parent compounds. In the present study, we aimed to characterize the bioaccumulative ability of halogenated gemfibrozil DBPs in marine polychaetes via chronic sediment exposures and, consequently, to assess the chronic and acute toxicity of halogenated gemfibrozil DBPs through sediment (in vivo) and aqueous (in vivo and in silico) toxicity evaluations. Following 28 day sediment exposures, Cl-gemfibrozil and Br-gemfibrozil bioaccumulated within Neanthes arenaceodentata, with both compounds reducing survival and growth. The biota−sediment accumulation factors determined for Clgemfibrozil and Br-gemfibrozil were 2.59 and 6.86, respectively. Furthermore, aqueous 96 h toxicity tests with N. arenaceodentata indicated that gemfibrozil DBPs elicited increased toxicity compared to the parent compound. While gemfibrozil had an acute LC50 value of 469.85 ± 0.096 mg/L, Cl-gemfibrozil and Br-gemfibrozil had LC50 values of 12.34 ± 0.085 and 9.54 ± 0.086 mg/L, respectively. Although acute toxicity is relatively low, our results indicate that halogenated gemfibrozil DBPs are bioaccumulative and may elicit effects in apex food web organisms prone to accumulation following lifelong exposures.

Methylation and Demethylation of Emerging Contaminants Changed Bioaccumulation and Acute Toxicity in Daphnia magna

“…For aquatic organisms, increased bioaccumulation of contaminants is often attributed to a compound’s hydrophobicity, as bioaccumulation is driven by lipids in an organism and is positively related to hydrophobicity or log K ow for neutral compounds. ,,,, Increased bioaccumulation after methylation was previously observed for diclofenac in aquatic invertebrates. Bioaccumulation of methylated diclofenac was found to be 25–110-fold that of diclofenac in H.…”

“…The consensus QSAR method in the U.S. EPA’s Toxicity Estimation Software Tool (T.E.S.T., version 5.1.2) was used to predict the acute toxicity of the target compounds in D. magna . The BCF and the biotransformation half-life values of test compounds were obtained by using the BCFBAF model in the U.S. EPA’s EPI Suite software (version 4.11).…”

Enhanced Disrupting Effect of Benzophenone-1 Chlorination Byproducts to the Androgen Receptor: Cell-Based Assays and Gaussian Accelerated Molecular Dynamics Simulations

“…The generation of more hydrophobic transformation products was also shown to enhance the disruption of key receptors in relation to their parent compounds, such as triclosan and bisphenol S. 50 As the AR antagonists currently in use are halogenated, 24,51 the enhanced AR-disrupting effect of chlorinated BP-1 products may be directly related to the chlorine moiety. Similarly, gemfibrozil was transformed into Cl-gemfibrozil and Brgemfibrozil following disinfection, 15,52 resulting in higher antiandrogenic activity in male Japanese medakas as well as increased bioaccumulation and acute toxicity in Neanthes arenaceodentata. Because antagonism to AR during the critical stage of mammary gland development was associated with an irreversible demasculinizing consequence and aberrant development of the male reproductive tract, 53,54 the enhanced antiandrogenic activity of BP-1 introduced by chlorination may trigger a risk for deteriorated health.…”

“…The chlorination of chemicals has frequently been observed during the disinfection process. , Previous studies have shown that free chlorine at dosages up to 200 μM can transform benzophenones into various chlorinated products, , which was associated with increased acute toxicity to luminescent bacteria, − and higher genotoxicity. − The recommended residual chlorine level for swimming pools is 0.2–1.0 mg/L for safe use; however, whether this low level of residual chlorine could trigger the natural occurrence of BP-1 chlorination remains unknown. Additionally, little is known concerning the joint toxicity of a potentially large number of chlorinated byproducts with varying toxicities .…”

Late-stage modification of bioactive compounds: Improving druggability through efficient molecular editing

“…Next year, they reported DMSO-catalyzed chlorination of bioactive molecules using NCS, demonstrating the compatibility of this mild reaction condition with numerous natural products and drugs ( Scheme 8 c) 136 . Notably, the chlorination of gemfibrozil, a lipid-lowering drug, was shown to decrease its solubility in water 137 , and potentially enhance its antiandrogen activity 138 . In 2021, they also developed alternative system in which DMSO was replaced by nitroxides appeared and expanded the substrate scope of the past work 139 .…”