title: A novel mode-of-action mediated by the fetal muscle nicotinic acetylcholine receptor resulting in developmental toxicity in rats.
abstract: Sulfoxaflor (X11422208), a novel agricultural molecule, induced fetal effects (forelimb flexure, hindlimb rotation, and bent clavicle) and neonatal death in rats at high doses (≥ 400 ppm in diet); however, no such effects occurred in rabbit dietary studies despite achieving similar maternal and fetal plasma exposure levels. Mode-of-action (MoA) studies were conducted to test the hypothesis that the effects in rats had a single MoA induced by sulfoxaflor agonism on the fetal rat muscle nicotinic acetylcholine receptor (nAChR). The studies included cross-fostering and critical windows of exposure studies in rats, fetal ((α1)(2)β1γδ) and adult ((α1)(2)β1δε) rat and human muscle nAChR in vitro agonism experiments, and neonatal rat phrenic nerve-hemidiaphragm contracture studies. The weight of evidence from these studies supported a novel MoA where sulfoxaflor is an agonist to the fetal, but not adult, rat muscle nAChR and that prolonged agonism on this receptor in fetal/neonatal rats causes sustained striated muscle contracture resulting in concomitant reduction in muscle responsiveness to physiological nerve stimulation. Fetal effects were inducible with as little as 1 day of exposure at the end of gestation, but were rapidly reversible after birth, consistent with a pharmacological MoA. With respect to human relevance, sulfoxaflor was shown to have no agonism on human fetal or adult muscle nAChRs. Taken together, the data support the hypothesis that the developmental effects of sulfoxaflor in rats are mediated via sustained agonism on the fetal muscle nAChR during late fetal development and are considered not relevant to humans.
authors.affiliation: Toxicology & Environmental Research and Consulting, The Dow Chemical Company, Midland, MI 48674, USA. rrasoulpour@dow.com
authors.forename: Reza J
authors.initials: RJ
authors.lastname: Rasoulpour
authors.forename: Robert G
authors.initials: RG
authors.lastname: Ellis-Hutchings
authors.forename: Claire
authors.initials: C
authors.lastname: Terry
authors.forename: Neil S
authors.initials: NS
authors.lastname: Millar
authors.forename: Carol L
authors.initials: CL
authors.lastname: Zablotny
authors.forename: Alasdair
authors.initials: A
authors.lastname: Gibb
authors.forename: Valerie
authors.initials: V
authors.lastname: Marshall
authors.forename: Toby
authors.initials: T
authors.lastname: Collins
authors.forename: Edward W
authors.initials: EW
authors.lastname: Carney
authors.forename: Richard
authors.initials: R
authors.lastname: Billington
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D004305:Dose-Response Relationship, Drug; D005260:Female; D005333:Fetus / Q000187:drug effects / Q000378:metabolism; D005865:Gestational Age; D006801:Humans; D007306:Insecticides / Q000633:toxicity*; D008297:Male; D018811:Maternal Exposure; D009119:Muscle Contraction / Q000187:drug effects*; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000196:embryology / Q000378:metabolism; D018722:Nicotinic Agonists / Q000633:toxicity*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D011725:Pyridines / Q000633:toxicity*; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000187:drug effects / Q000378:metabolism; D012098:Reproduction / Q000187:drug effects; D018570:Risk Assessment; D013457:Sulfur Compounds / Q000633:toxicity*; D014982:Xenopus laevis
chemical_list: D007306:Insecticides; D018722:Nicotinic Agonists; D011725:Pyridines; D011978:Receptors, Nicotinic; D011994:Recombinant Proteins; D013457:Sulfur Compounds; C560328:sulfoxaflor