title: Embryo toxicity and teratogenicity of formaldehyde.
abstract: C-14 formaldehyde crosses the placenta and enters fetal tissues. The incorporated radioactivity is higher in fetal organs (i.e., brain and liver) than in maternal tissues. The incorporation mechanism has not been studied fully, but formaldehyde enters the single-carbon cycle and is incorporated as a methyl group into nucleic acids and proteins. Also, formaldehyde reacts chemically with organic compounds (e.g., deoxyribonucleic acid, nucleosides, nucleotides, proteins, amino acids) by addition and condensation reactions, thus forming adducts and deoxyribonucleic acid-protein crosslinks. The following questions must be addressed: What adducts (e.g., N-methyl amino acids) are formed in the blood following formaldehyde inhalation? What role do N-methyl-amino adducts play in alkylation of nuclear and mitochondrial deoxyribonucleic acid, as well as mitochondrial peroxidation? The fact that the free formaldehyde pool in blood is not affected following exposure to the chemical does not mean that formaldehyde is not involved in altering cell and deoxyribonucleic acid characteristics beyond the nasal cavity. The teratogenic effect of formaldehyde in the English literature has been sought, beginning on the 6th day of pregnancy (i.e., rodents) (Saillenfait AM, et al. Food Chem Toxicol 1989, pp 545-48; Martin WJ. Reprod Toxicol 1990, pp 237-39; Ulsamer AG, et al. Hazard Assessment of Chemicals; Academic Press, 1984, pp 337-400; and U.S. Department of Health and Human Services. Toxicological Profile of Formaldehyde; ATSDR, 1999 [references 1-4, respectively, herein]). The exposure regimen is critical and may account for the differences in outcomes. Pregnant rats were exposed (a) prior to mating, (b) during mating, (c) or during the entire gestation period. These regimens (a) increased embryo mortality; (b) increased fetal anomalies (i.e., cryptochordism and aberrant ossification centers); (c) decreased concentrations of ascorbic acid; and (d) caused abnormalities in enzymes of mitochondria, lysosomes, and the endoplasmic reticulum. The alterations in enzymatic activity persisted 4 mo following birth. In addition, formaldehyde caused metabolic acidosis, which was augmented by iron deficiency. Furthermore, newborns exposed to formaldehyde in utero had abnormal performances in open-field tests. Disparities in teratogenic effects of toxic chemicals are not unusual. For example, chlorpyrifos has not produced teratogenic effects in rats when mothers are exposed on days 6-15 (Katakura Y, et al. Br J Ind Med 1993, pp 176-82 [reference 5 herein]) of gestation (Breslin WJ, et al. Fund Appl Toxicol 1996, pp 119-30; and Hanley TR, et al. Toxicol Sci 2000, pp 100-08 [references 6 and 7, respectively, herein]). However, either changing the endpoints for measurement or exposing neonates during periods of neurogenesis (days 1-14 following birth) and during subsequent developmental periods produced adverse effects. These effects included neuroapoptosis, decreased deoxyribonucleic acid and ribonucleic acid synthesis, abnormalities in adenylyl cyclase cascade, and neurobehavioral effects (Johnson DE, et al. Brain Res Bull 1998, pp 143-47; Lassiter TL, et al. Toxicol Sci 1999, pp 92-100; Chakraborti TK, et al. Pharmacol Biochem Behav 1993, pp 219-24; Whitney KD, et al. Toxicol Appl Pharm 1995, pp 53-62; Chanda SM, et al. Pharmacol Biochem Behav 1996, pp 771-76; Dam K, et al. Devel Brain Res 1998, pp 39-45; Campbell CG, et al. Brain Res Bull 1997, pp 179-89; and Xong X, et al. Toxicol Appl Pharm 1997, pp 158-74 [references 8-15, respectively, herein]). Furthermore, the terata caused by thalidomide is a graphic human example in which the animal model and timing of exposure were key factors (Parman T, et al. Natl Med 1999, pp 582-85; and Brenner CA, et al. Mol Human Repro 1998, pp 887-92 [references 16 and 17, respectively, herein]). Thus, it appears that more sensitive endpoints (e.g., enzyme activity, generation of reactive oxygen species, timing of exposure) for the measurement of toxic effects of environmental agents on embryos, fetuses, and neonates are more coherent than are gross terata observations. The perinatal period from the end of organogenesis to the end of the neonatal period in humans approximates the 28th day of gestation to 4 wk postpartum. Therefore, researchers must investigate similar stages of development (e.g., neurogenesis occurs in the 3rd trimester in humans and neonatal days occur during days 1-14 in rats and mice, whereas guinea pigs behave more like humans). Finally, screening for teratogenic events should also include exposure of females before mating or shortly following mating. Such a regimen is fruitful inasmuch as environmental agents cause adverse effec
authors.affiliation: Sam-1 Trust, Alto, New Mexico, USA.
authors.forename: J D
authors.initials: JD
authors.lastname: Thrasher
authors.forename: K H
authors.initials: KH
authors.lastname: Kilburn
mesh_terms: D000818:Animals; D002872:Chromosome Deletion; D004195:Disease Models, Animal; D004622:Embryo, Mammalian / Q000187:drug effects*; D004781:Environmental Exposure / Q000009:adverse effects* / Q000032:analysis; D004784:Environmental Monitoring / Q000379:methods; D005260:Female; D005557:Formaldehyde / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D005865:Gestational Age; D006801:Humans; D008431:Maternal-Fetal Exchange; D008452:Maximum Allowable Concentration; D051379:Mice; D009154:Mutation / Q000187:drug effects / Q000235:genetics; D011247:Pregnancy; D011261:Pregnancy Trimester, First; D051381:Rats; D013723:Teratogens / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*
chemical_list: D013723:Teratogens; D005557:Formaldehyde