Transgenerational Reproductive and Developmental Toxicity Induced by N-Nitrosodimethylamine and Its Metabolite Formaldehyde in Drosophila melanogaster.

Abstract

N-Nitrosodimethylamine (NDMA) is a known water disinfection byproduct (DBP) characterized as a potent hepatotoxin, promutagen, and probable human carcinogen; this is because of the metabolites associated with its biotransformation. The metabolism of NDMA produces formaldehyde, another alkylating agent and DBP. Both compounds are generated from natural and anthropogenic sources, but the safety restrictions applied to NDMA do not extend to the uses of formaldehyde. Hence, potential health and ecological risks are of concern. Due to limited information on the long-term effects of exposure to these compounds at environmentally relevant concentrations, this work aimed to compare the transgenerational reproductive and developmental toxicity of separate exposures to NDMA or its metabolite formaldehyde in Drosophila melanogaster over four generations. The parental flies were fed NDMA or formaldehyde (1.19E-06 to 5 mM) for 48 h during the third larval instar. Subsequent offspring (F1-F3) were grown under compound-free conditions. In the parental generation, both exposures modified the time to emergence and reduced the number of progenies. NDMA, but not formaldehyde, was lethal, affected fertility, and weakly induced malformations. In the next generations, both exposures induced malformed flies and modified the number of offspring. Reproductive toxicity and malformations were maintained for at least three generations, suggesting that detrimental effects could extend to unexposed offspring. This is the first study reporting the associated individual transgenerational effects on reproduction and development between NDMA and its metabolite formaldehyde in D. melanogaster, highlighting the relevance of evaluating multiple generations to accurately determine the health and environmental risks of pollutants.